**boehringer ingelheim pharmaceuticals, inc.**

**Tipranavir**

**Anti-viral Drugs advisory committee (AVDAC)**

**Briefing document**

**NDA 21-814**

**April 19, 2005**

***available for public disclosure without redaction***

TABLE OF CONTENTS

**List of abbreviations [6](#__RefHeading___Toc101398901)**

SUMMARY [8](#__RefHeading___Toc101398902)

1\. INTRODUCTION [13](#__RefHeading___Toc101398903)

2\. NONCLINICAL PHARMACOLOGY AND TOXICOLOGY
[15](#__RefHeading___Toc101398904)

3\. MICROBIOLOGY [21](#__RefHeading___Toc101398905)

3.1 Mechanism Of Action [21](#__RefHeading___Toc101398906)

3.2 Antiviral Activity *In Vitro* [21](#__RefHeading___Toc101398907)

4\. OVERVIEW OF CLINICAL DEVELOPMENT PROGRAM
[23](#__RefHeading___Toc101398908)

4.1 EARLY DEVELOPMENT [23](#__RefHeading___Toc101398909)

4.2 DOSE-FINDING TRIAL [23](#__RefHeading___Toc101398910)

4.3 PHASE III PIVOTAL TRIAL PROGRAM [25](#__RefHeading___Toc101398911)

4.3.1 Trial design [25](#__RefHeading___Toc101398912)

4.3.2 Trial design issues [28](#__RefHeading___Toc101398913)

4.3.2.1 Choice of comparator PI [28](#__RefHeading___Toc101398914)

4.3.2.2 Open-label study design [29](#__RefHeading___Toc101398915)

4.3.2.3 Resistance status of study cohort
[30](#__RefHeading___Toc101398916)

4.3.2.4 RESIST study amendments and relevant protocol deviations
[31](#__RefHeading___Toc101398917)

4.3.2.5 Non-inferiority testing [32](#__RefHeading___Toc101398918)

4.4 ADDITIONAL CLINICAL DATA [33](#__RefHeading___Toc101398919)

5\. CLINICAL PHARMACOLOGY [35](#__RefHeading___Toc101398920)

5.1 Clinical Pharmacokinetics [35](#__RefHeading___Toc101398921)

5.1.1 Demographic subpopulations [37](#__RefHeading___Toc101398922)

5.1.2 Absorption, distribution, metabolism, elimination (ADME)
[38](#__RefHeading___Toc101398923)

5.1.2.1 Absorption [38](#__RefHeading___Toc101398924)

5.1.2.2 Distribution [40](#__RefHeading___Toc101398925)

5.1.2.3 Metabolism [40](#__RefHeading___Toc101398926)

5.1.2.4 Excretion [41](#__RefHeading___Toc101398927)

5.1.3 Drug interactions [42](#__RefHeading___Toc101398928)

5.1.3.1 Effect on tipranavir [42](#__RefHeading___Toc101398929)

5.1.3.2 Interactions with reverse transcriptase inhibitors
[43](#__RefHeading___Toc101398930)

5.1.3.3 Interactions with protease inhibitors
[45](#__RefHeading___Toc101398931)

5.1.3.4 Interactions with non-ARV medications
[46](#__RefHeading___Toc101398932)

5.1.3.5 Potential drug interactions [48](#__RefHeading___Toc101398933)

5.1.4 Hepatic or renal impairment [53](#__RefHeading___Toc101398934)

5.2 Pharmacokinetic Conclusions [54](#__RefHeading___Toc101398935)

6\. EFFICACY [55](#__RefHeading___Toc101398936)

6.1 Early Clinical Data [55](#__RefHeading___Toc101398937)

6.2 Dose Selection (BI 1182.52) [56](#__RefHeading___Toc101398938)

6.3 Efficacy results of pivotal, active-controlled trials (RESIST
Trials) [59](#__RefHeading___Toc101398939)

6.3.1 Study population [59](#__RefHeading___Toc101398940)

6.3.1.1 Baseline genotypic resistance 62

6.3.1.2 Baseline phenotypic resistance 63

6.3.2 Pre-selection of comparator PI and enfuvirtide
[64](#__RefHeading___Toc101398941)

6.3.2.1 Stratification by pre-selected PI and enfuvirtide use
[64](#__RefHeading___Toc101398942)

6.3.2.2 Use of new vs. ongoing or susceptible vs. resistant\
comparator PIs 67

6.3.3 Differences between RESIST studies
[67](#__RefHeading___Toc101398943)

6.3.4 Patient disposition [68](#__RefHeading___Toc101398944)

6.3.5 Analysis of treatment response: primary and secondary endpoints
[69](#__RefHeading___Toc101398945)

6.3.5.1 Treatment response [69](#__RefHeading___Toc101398946)

6.3.5.2 Response by pre-selected PI strata
[72](#__RefHeading___Toc101398947)

6.3.5.3 Viral load change from baseline at 24 weeks (FAS population)
[74](#__RefHeading___Toc101398948)

6.3.5.4 Virologic response (\< 400 and \< 50 copies/mL) and immunologic
response at 24 weeks (FAS population) [76](#__RefHeading___Toc101398949)

6.3.5.5 New onset of AIDS events [78](#__RefHeading___Toc101398950)

6.3.6 Impact of active background antiretroviral drugs
[78](#__RefHeading___Toc101398951)

6.3.7 Impact of baseline viral load and CD4+ count
[82](#__RefHeading___Toc101398952)

6.3.8 Sensitivity analyses [83](#__RefHeading___Toc101398953)

6.4 Efficacy RESULTS IN SPECIAL POPULATIONS
[84](#__RefHeading___Toc101398954)

6.5 EFFICACY CONCLUSIONS [87](#__RefHeading___Toc101398955)

7\. RESISTANCE [88](#__RefHeading___Toc101398956)

7.1 Development Of Tipranavir Resistance *In Vitro*
[88](#__RefHeading___Toc101398957)

7.2 Clinical Resistance (*In Vivo)* [88](#__RefHeading___Toc101398958)

7.3 GENOTYPIC SCORES [89](#__RefHeading___Toc101398959)

7.3.1 Key protease mutations (HIV protease codons 33, 82, 84 and 90)
[90](#__RefHeading___Toc101398960)

7.3.2 Tipranavir score [91](#__RefHeading___Toc101398961)

7.3.3 FDA protease gene mutations [92](#__RefHeading___Toc101398962)

7.4 Relationship of Genotype to Phenotype
[92](#__RefHeading___Toc101398963)

7.5 Impact of Genotype on Virologic Response
[94](#__RefHeading___Toc101398964)

7.6 Impact of Phenotype on Virologic Response
[97](#__RefHeading___Toc101398965)

7.7 Predictors OF VIRAL Load RESPONSE at 24 Weeks
[99](#__RefHeading___Toc101398966)

7.8 RESISTANCE Conclusions [100](#__RefHeading___Toc101398967)

8\. SAFETY [101](#__RefHeading___Toc101398968)

8.1 EXPOSURE [101](#__RefHeading___Toc101398969)

8.2 SAFETY DATA FROM EARLY CLINICAL TRIALS
[101](#__RefHeading___Toc101398970)

8.3 CLINICAL SAFETY DATA OF PIVOTAL, ACTIVE-CONTROLLED TRIALS (RESIST-1
AND RESIST-2) [103](#__RefHeading___Toc101398971)

8.3.1 Exposure and disposition [105](#__RefHeading___Toc101398972)

8.3.2 Adverse Events in RESIST trials
[106](#__RefHeading___Toc101398973)

8.3.3 Serious adverse events [108](#__RefHeading___Toc101398974)

8.3.4 Adverse events leading to discontinuation of treatment
[110](#__RefHeading___Toc101398975)

8.3.5 Exploratory analyses of medically selected terms
[111](#__RefHeading___Toc101398976)

8.4 LABORATORY EVALUATIONS OF PIVOTAL, ACTIVE-CONTROLLED TRIALS
(RESIST-1 AND RESIST-2) [114](#__RefHeading___Toc101398977)

8.4.1 Overview of DAIDS Grade 3 and 4 Laboratory Adnormalities in the
Safety Update 114

8.4.2 Hepatic Transaminase Elevations in the Safety Update 115

8.4.2.1 Evaluation of ALT and/or AST Abnormalities 115

8.4.2.2 Multivariable Analysis for Risk of LFT Elevations 117

8.4.2.3 Actions Taken with LFT Abnormalities 118

8.4.2.4 Clinical Hepatic Adverse Events 120

8.4.2.5 Summary of Hepatic Findings 121

8.4.3 Fasting Lipid Elevations 122

8.4.3.1 Triglyceride Elevations 122

8.4.3.2 Cholesterol Elevations 124

8.5 mortality and aids progression 125

8.5.1 Deaths in all TPV Trials 125

8.5.2 AIDS Progression Events in RESIST Trials 126

8.5.3 Deaths in RESIST trials 127

8.5.4 Adjustment for Exposure in RESIST Trials 127

8.5.5 Analysis of Patients who Rolled over to Trial BI 1182.17 from the
CPI/r arm of RESIST Trials and Died 129

8.5.6 Contrast of Deaths in the rollover study: Patients from RESIST
Clinical Program compared to Patients from other TPV Trials 130

8.5.7 Review of hepatic deaths 131

8.5.8 Summary of Deaths 134

8.6 Safety results in special populations 135

8.6.1 Long-term safety from rollover Trial BI 1182.17 135

8.6.2 Pediatric Trial BI 1182.14 137

8.6.3 Emergency Use and Expanded Access Programs 138

8.6.4 Safety in Women and Minorities 140

8.7 safety conclusions 141

9\. OVERALL Conclusions [142](#__RefHeading___Toc101398980)

10\. PLANS FOR COMPLETING REQUIREMENTS FOR TRADITIONAL APPROVAL
[148](#__RefHeading___Toc101398981)

APPENDIX 1 NONCLINICAL PHARMACOLOGY AND TOXICOLOGY
[149](#__RefHeading___Toc101398982)

Appendix 1.1 Overview [149](#__RefHeading___Toc101398983)

Appendix 1.2 General and Safety Pharmacology
[150](#__RefHeading___Toc101398984)

Appendix 1.3 Absorption, Distribution, Metabolism, and Excretion
[151](#__RefHeading___Toc101398985)

Appendix 1.4 Toxicology [152](#__RefHeading___Toc101398986)

Appendix 1.4.1 Single dose toxicity studies (acute toxicity)
[152](#__RefHeading___Toc101398987)

Appendix 1.4.2 Chronic studies [153](#__RefHeading___Toc101398988)

Appendix 1.4.3 TPV-ritonavir co-administration studies
[154](#__RefHeading___Toc101398989)

Appendix 1.4.4 Genotoxicity studies [157](#__RefHeading___Toc101398990)

Appendix 1.4.5 Reproduction toxicology
[157](#__RefHeading___Toc101398991)

Appendix 1.4.6 Other toxicity [158](#__RefHeading___Toc101398992)

APPENDIX 2 TPV Clinical Trial Program
[161](#__RefHeading___Toc101398993)

Appendix 2.1 Biopharmaceutic Studies [161](#__RefHeading___Toc101398994)

Appendix 2.2 Human Pharmacokinetic Studies
[164](#__RefHeading___Toc101398995)

Appendix 2.3 Human Pharmacodynamic Studies
[172](#__RefHeading___Toc101398996)

Appendix 2.4 Clinical Efficacy and Safety Studies
[174](#__RefHeading___Toc101398997)

Appendix 3 DRUG INTERACTIONS [182](#__RefHeading___Toc101398998)

Appendix 4 FATAL EVENTS IN RESIST TRIALS
[185](#__RefHeading___Toc101398999)

[]{#__RefHeading___Toc101398901 .anchor}**List of abbreviations**

AE Adverse event

ALT Alanine aminotransferase

APV Amprenavir

ARV Antiretroviral (agent)

BI Boehringer Ingelheim

BID Twice a day

BLQ Below limit of quantitation

CD4+ Cluster of differentiation 4 (antigen marker on T-lymphocytes)

CI Confidence interval

CPI/r Comparator protease inhibitor with ritonavir

C~12h~ Plasma concentration of drug at 12 hours

EFV Efavirenz

ENF Enfuvirtide, also referred to as T-20

EAP Expanded Access Program

EUP Emergency Use Program (BI Trial 1182.58)

FAS Full analysis set

FC Fold-change

GSS Genotypic sensitivity score

HAART Highly active antiretroviral therapy

HFC Hard filled capsule

HIV Human immunodeficiency virus

IC~50~ Concentration of drug required to produce 50% inhibition

IDV Indinavir

ITT Intent-to-treat (population)

IQR Interquartile range; 25^th^ percentile and 75^th^ percentile around
median

KM Kaplan Meier probability

LOCF Last observation carried forward

LPV Lopinavir

mg Milligram

mL Milliliter

mm^3^ Cubic millimeter

N Number of patients

NCC Non-completer considered censored

NCF Non-completer considered failure

NRTI Nucleoside reverse transcriptase inhibitor

NNRTI Non-nucleoside reverse transcriptase inhibitor

OBR Optimized background regimen

OLSS Open-Label Safety Study

OR Odds ratio

OT On treatment

p Probability

PBMC Peripheral blood mononuclear cells

PCR Polymerase chain reaction

PEY Person exposure years

PI Protease inhibitor

PK Pharmacokinetics

PPS Per protocol set

P&U Pharmacia and Upjohn

RESIST-1 Randomized Evaluation of Strategic Intervention in multi-drug
resistant patients with Tipranavir \[BI Trial 1182.12\]

RESIST-2 Randomized Evaluation of Strategic Intervention in multi-drug
resistant patients with Tipranavir \[BI Trial 1182.48\]

RNA Ribonucleic acid

RR Relative risk

RTV Ritonavir

SAE Serious adverse event

SCS Summary of Clinical Safety

SEC Soft elastic capsule

SEDDS Self-emulsifying drug delivery system

SQV Saquinavir

SQV/r Saquinavir with ritonavir

SOC System organ class

TPV Tipranavir

TPV/r Tipranavir co-administered with ritonavir

TR Treatment response

μM Micromole

VL Viral load

WT Wild type

[]{#__RefHeading___Toc101398902 .anchor}SUMMARY

Highly Active Antiretroviral Therapy (HAART) has had a marked impact on
the course of the HIV epidemic in the developed world. These potent
antiretroviral combination therapies are able to effectively suppress
viral replication and are associated with reconstitution of the immune
system. However, non-adherence to HAART regimens and increased
transmission of drug-resistant HIV-1 are common problems in the clinic,
and this has led to the development of a large patient population with
multi-drug resistant HIV-1 infection. Each of the major classes of
antiretroviral agents (ARVs) is affected by resistance, including
protease inhibitors (PI). As a result, novel therapeutic agents are
needed to construct active regimens for PI-experienced patients to
reduce viral replication and decrease HIV-related morbidity and
mortality. Tipranavir (TPV) is a non-peptidic protease inhibitor active
against the majority of protease inhibitor resistant HIV-1 seen in
clinical practice. Both a soft gelatin capsule and a liquid formulation
have been developed to meet the clinical needs of HIV-positive patients.
The subject of this document is the capsule formulation only (NDA
21-814). Tipranavir helps to address a continued unmet clinical need for
new drugs to treat patients with multidrug resistant HIV-1.

Patients in the tipranavir clinical development program demonstrated
multi-drug resistance with varying degrees of cross-resistance to the
currently available PIs. In this briefing document, we present 2- and
24-week data demonstrating the antiviral activity of tipranavir,
co-administered with low-dose ritonavir (TPV/r), in PI-experienced
patients with established PI-resistant viruses.

As of 30 September 2004, the cut-off date for the Safety Update, a total
of 3,367 HIV-positive patients have been treated with TPV/r. In the
clinical trial database, 1,870 of these patients have been treated with
TPV/r representing 1,760 patient-years of exposure. Nearly half of the
patients (47%) have been treated for ≥48 weeks with a maximum exposure
of 5 years. 1,411 patients have been treated with the TPV/r 500/200 mg
dose with 1,206 having received this to-be-marketed dose for at least 24
weeks.

The ongoing RESIST[^1] trial program, which compares TPV/r to a
ritonavir-boosted comparator PI (CPI/r) on an optimized background
regimen (OBR), is one of the largest programs undertaken in a
PI-experienced population. Comparator PIs in the RESIST trials include
ritonavir-boosted lopinavir, indinavir, saquinavir, and amprenavir. The
intrinsic activity of TPV/r is demonstrated by the ≥ 1 log~10~ reduction
observed at 2 weeks after the initiation of TPV/r therapy. After 24
weeks of treatment (interim analysis), TPV/r had superior antiviral
activity compared to CPI/r as shown below:

Overview of Week 24 efficacy endpoints - combined RESIST trials

+------------------------------------+---------+-----------+-----------+
|                                    | TPV/r + | CPI/r +   | p-value   |
|                                    | OBR     | OBR       |           |
|                                    |         |           |           |
|                                    | N=582   | N=577     |           |
+------------------------------------+---------+-----------+-----------+
| Median baseline viral load         | 4.83    | 4.82      |           |
+------------------------------------+---------+-----------+-----------+
| Median baseline CD4+ count         | 155     | 158       |           |
+------------------------------------+---------+-----------+-----------+
|                                    |         |           |           |
+------------------------------------+---------+-----------+-----------+
| Treatment Response (confirmed      | 41%     | 19%       | \<0.0001  |
| [\>]{.underline} 1 log~10~ VL      |         |           |           |
| decrease)                          |         |           |           |
+------------------------------------+---------+-----------+-----------+
| Median HIV VL change from baseline | -0.80   | -0.25     | \<0.0001  |
| (log~10~ copies/mL)                |         |           |           |
+------------------------------------+---------+-----------+-----------+
| HIV VL \< 400 copies/mL            | 34%     | 15%       | \<0.0001  |
+------------------------------------+---------+-----------+-----------+
| HIV VL \< 50 copies/mL             | 24%     | 9%        | \<0.0001  |
+------------------------------------+---------+-----------+-----------+
| Median increase in CD4+ cell count | 34      | 4         | \<0.0001  |
| (cells/mm^3^)                      |         |           |           |
+------------------------------------+---------+-----------+-----------+

At 24 weeks, TPV/r had superior virological and immunological responses
which were associated with a non-significant decrease in AIDS
progression events in patients with PI‑resistant HIV-1. The 24‑week
responses were of greater magnitude when TPV/r is combined with other
active antiretroviral agents, for example enfuvirtide.

It has been shown that TPV must be co-administered with low-dose
ritonavir to achieve adequate drug levels. Patients taking TPV/r
generally achieve plasma concentrations that are many-fold above the
protein-adjusted IC~90~ for the majority of PI-resistant HIV-1 strains
in the clinic. Despite being an inducer of the cytochrome P450 isoenzyme
3A (CYP3A) when given alone, TPV when combined with 200 mg of ritonavir
produces a net inhibition of CYP3A. The pharmacokinetic drug
interactions for most non-antiretroviral concomitant medications are
similar to other ritonavir-boosted PIs.

Drug levels for ritonavir-boosted lopinavir, saquinavir, and amprenavir
were significantly reduced when combined with TPV/r, therefore these
combinations are not recommended. Protease inhibitor levels for novel
dual PI regimens containing TPV/r cannot be predicted without formal
drug interaction studies possibly due to the mixed patterns of
inhibition and induction of CYP pathways seen with these drug
combinations.

While reductions in plasma concentrations of abacavir and zidovudine
have been observed when they are combined with TPV/r, the clinical
relevance of these changes has not been established and no dose
adjustment can be recommended at this time.

We have undertaken an extensive evaluation of the resistance profile of
TPV/r and have defined the genotypic and phenotypic correlates
associated with treatment response. The best correlations of the
antiviral activity of TPV/r with a genotypic score were obtained
with (1) the key mutations in the HIV-1 protease at positions 33, 82,
84, and 90, and (2) a tipranavir score derived from correlation of
mutations in HIV-1 protease to viral phenotype and viral load responses
seen in the Phase II and III programs. Based on these analyses, it takes
3 key mutations and \> 4 TPV-score mutations to produce decreased TPV
susceptibility ([\>]{.underline} 3-fold wild-type) *in vitro* or
decreased antiviral responses in the clinic. High level resistance
([\>]{.underline} 10-fold wild type) usually requires all 4 key
mutations or \> 7 TPV-score mutations which are uncommon in clinical
HIV-1 isolates from treatment-experienced patients. These *in vitro* and
clinical data confirm that there is a high genetic barrier to resistance
with TPV.

Many of the mutations which are associated with decreased susceptibility
to TPV have not been associated with drug resistance to currently
available PIs. While one or more mutations at protease codons 33, 82,
84, 90 can produce high level resistance to currently available PIs, it
takes at least three of these mutations produce reduced susceptibility
to TPV/r. The predominant emerging mutations with virologic failure in
PI-experienced patients receiving TPV/r are 33F/I/V, 82T/L, and 84V; the
drug resistance pattern which will result from treatment of drug naïve
patients is not yet established.

The types and rates of adverse events (AEs) and serious AEs reported for
TPV/r in the RESIST trials are similar to CPI/r and are consistent with
AEs associated with the use of other ritonavir-boosted PIs except for
increased rates of Grade 3/4 elevations in ALT/AST, cholesterol and
triglycerides which were more common with TPV/r than with CPI/r. The
hepatic events were generally asymptomatic and most patients were
successfully continued on treatment. These laboratory abnormalities can
be managed with routine monitoring except in patients with chronic
Hepatitis B or C co‑infection or elevated baseline LFTs where increased
monitoring of LFTs is recommended.

There was a nonsignificant difference in fatalities between the TPV/r
and CPI/r arms of the RESIST trials at 24 weeks (p=0.64). The types and
rate of fatalities in the TPV/r development program are consistent with
what has been described for patients with advanced HIV disease. There
have been a limited number of cases of clinical hepatitis or death due
to hepatic failure in the TPV development program, primarily in patients
with advanced HIV disease taking multiple concomitant medications. A
causal relationship to TPV/r could not be established.

In summary, tipranavir, co-administered with low-dose ritonavir, is a
novel HIV protease inhibitor which retains significant antiviral
activity in the face of multiple PI mutations. Regimens containing TPV/r
in the RESIST population of patients with highly PI-resistant viruses
had superior virologic and immunologic activity at 24 weeks compared
with the CPI/r‑based regimens. Genotypic resistance testing can assist
in the selection of drugs to combine with TPV/r and in determination of
which patients are most likely to benefit from a TPV/r-based regimen.
Similar to other ritonavir-boosted PIs, pharmacokinetic interactions
between TPV/r and other drugs metabolized by CYP3A should be expected.
The net effect of TPV/r is CYP3A inhibition. Finally, the safety profile
of TPV/r is similar to other ritonavir-boosted PIs in a PI-experienced
population, except for increased rates of ALT/AST, cholesterol and
triglyceride elevations which were seen for the TPV/r arms in the RESIST
trials.

The use of TPV/r-based regimens in treatment-experienced patients with
PI-resistant HIV-1 helps to meet a large unmet clinical need. The
balance of the benefits and risks of drug regimens containing tipranavir
co-administered with low-dose ritonavir supports the indication for use
in PI treatment-experienced patients with HIV-1 infection.

[]{#__RefHeading___Toc101398903 .anchor}1. INTRODUCTION

With the introduction of the new class of HIV protease inhibitors (PI)
in the mid-1990s, the Highly Active Antiretroviral Therapy (HAART) era
began. This was associated with dramatic decreases in HIV-related
morbidity and mortality and subsequent prolongation of the course of HIV
infection.[^2] However, the first PIs were associated with poor
bioavailability, complex dosing demands, and/or significant GI
intolerability. These factors led to development of PI resistance,
treatment failure, and an understanding of the importance of treatment
adherence.

The second wave of protease inhibitor development focused on making
agents that were easier to tolerate, had an improved and more forgiving
pharmacokinetic profile, and could overcome established PI drug
resistance. These newer agents to varying degrees have fulfilled this
need. However, concurrent resistance to reverse transcriptase inhibitors
developed during this period to the point where many
antiretroviral-experienced patients have evolved significant three-class
HIV drug resistance. This population of patients harbouring multi-drug
resistant HIV represents a growing difficult to treat group.[^3]

Tipranavir is a novel non-peptidic HIV protease inhibitor that was
developed with the specific goal of being able to overcome broad PI
cross-resistance. It belongs to the class of
4‑hydroxy‑5,6‑dihydro‑2‑pyrone sulfonamides. The chemical name of
tipranavir is 2-Pyridinesulfonamide,
N-\[3-\[(1R)-1-\[(6R)-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl\]propyl\]phenyl\]-5-(trifluoromethyl).
Its molecular formula is C~31~H~33~F~3~N~2~O~5~S with a corresponding
molecular weight of 602.7 (Figure 1: 1).

![](media/image1.wmf){width="3.0881944444444445in"
height="1.7291666666666667in"}

Figure 1: 1 Structural formula of tipranavir

Early *in vitro* studies showed that viral isolates cross-resistant to
most of the commercially available PIs retained susceptibility to
tipranavir.[^4] The IC90 for multi-drug resistant clinical HIV isolates
ranged from 0.31-0.86 µM, and most clinical HIV isolates had a
serum-adjusted IC90 of ≤ 2 µM. This is in contrast to an IC90 of 0.18 µM
for WT HIV-1 in PBMC.

Although the number of new AIDS diagnoses and deaths has fallen since
the introduction of highly active antiretroviral therapy (HAART) in the
mid-1990's, many HIV-positive patients have not had adequate responses
to the regimens, cannot tolerate the toxic effects, or have difficulty
complying with treatment regimens that involve large numbers of pills.
Up to 50% of patients fail their initial regimens, and there is an
increasing population of patients infected with drug-resistant HIV-1
strains who need new agents with improved resistance profiles compared
to those of existing ARVs.[^5] Thus, the initial tipranavir clinical
development program focused on the study of PI-experienced patients in
need of new therapy.

Phase II and III clinical trials in patients with a PI-resistant HIV-1
have confirmed that tipranavir has potent antiviral activity. Thus,
tipranavir represents a significant advance in the treatment
armamentarium for clinicians treating drug-resistant HIV-1 infection.

[]{#__RefHeading___Toc101398904 .anchor}2. NONCLINICAL PHARMACOLOGY AND
TOXICOLOGY

General/Safety pharmacology studies were performed with TPV to assess
effects on the cardiovascular, central nervous, pulmonary, renal, and
gastrointestinal (GI) systems. These studies indicated that the drug was
well-tolerated, with some effects noted in the renal and GI systems.
Studies to investigate effects on the cardiovascular system showed an
inhibitory effect *in vitro* on the HERG-associated potassium channel
(IC50 = 2.9 µM; U02-1175), but no changes were noted in the guinea pig
papillary muscle assay at similar concentrations, nor were any effects
noted on QTc prolongation in the ECGs of conscious dogs following single
administration of up to 160 mg/kg. Overall, these results suggest that
TPV has little potential to prolong the QTc interval. No evidence of
cardiovascular effects was noted in toxicity studies of up to 26 weeks
in dogs with TPV/r or up to 39 weeks in dogs with TPV, and no
prolongation of the QTc interval has been observed in multiple clinical
studies.

Pharmacokinetic studies in humans have demonstrated the requirement for
RTV co‑administration with TPV treatment in order to achieve and
maintain required plasma levels of TPV for anti-viral activity. In
humans, TPV is primarily metabolized by CYP3A and is a substrate for
Pgp. The boosting effect of RTV on TPV plasma levels noted in humans is
also observed in animals. However, the boosting effect seen in
nonclinical species does not fully reflect that observed in humans, as
there can be distinct species differences in CYP450 and Pgp
selectivities. RTV co-administration resulted in an increase in TPV
systemic exposure in all nonclinical species: mice (12- to 22-fold),
rats (6‑to 7-fold), dogs (3‑to 13‑fold), and monkeys (2-fold). In rats
and dogs, co‑administration of RTV resulted in a 4- to 5-fold decrease
in clearance of TPV, consistent with inhibition of drug-metabolizing
enzymes by RTV. In toxicity studies in animals at higher dose levels the
boosting effect of RTV is lower in magnitude, perhaps due to a
saturation of the boosting mechanism. In humans, in contrast, the
boosting effect is more pronounced with co-administration of RTV
(200 mg) with TPV (500 mg) at the proposed human dose level resulting in
a 45-fold increase in Cmin, a 4-fold increase in Cmax, and an 11-fold
increase in overall systemic exposure (![](media/image2.wmf)). RTV is
clearly increasing plasma concentrations of TPV by inhibiting
metabolism, as the levels of metabolites in rats and humans are
negligible following RTV co‑administration.

It has been noted in toxicity studies that TPV exposure in animals, even
at the highest dose levels tested, is approximately equivalent to or
only slightly above that achieved at the human dose level of 500 mg/200
mg TPV/r BID. Toxicity testing on TPV commenced with TPV administered as
a singular entity. Once it was recognized that TPV was to be
co‑administered with RTV in humans to achieve therapeutic plasma levels,
co‑administration studies in animals were initiated to investigate the
toxicity of the two compounds given concurrently and to increase plasma
levels of TPV in animals. Co-administration of TPV with RTV does
increase plasma levels of TPV in animals, notably at lower dose levels.
However, this effect diminishes at higher dose levels, and does not
reach the magnitude of the boosting effect that is achieved in humans.
Rats in a 26-week TPV study administered 400 mg/kg/day TPV were exposed
to maximum plasma concentrations of 90/209 µM in males/females and
plasma exposure levels of 910/2320 µM·h (M/F). No total exposure was
calculated in the 26-week TPV/r study, but plasma levels measured 8
hours after TPV administration ranged from 180 to 334 µM at the highest
dose level tested of 1200/320 mg/kg/day TPV/r. Highest exposure in dogs
was achieved in a 39‑week study at a dose level of 320 mg/kg/day TPV
where Cmax and AUC values of 114 µM and 1155 µM·h (sexes combined),
respectively, were achieved. These are in contrast to plasma levels
reached at the human therapeutic dose level of 500/200 mg BID TPV/r,
where a Cmax of 103 µM and an AUC0-24 of 1542 µM·h were achieved.

Toxicities seen in repeat-dose studies in rats and dogs are not
considered to preclude chronic administration of TPV to the intended
patient population, even in view of their observance at plasma levels
equivalent to or below human exposure. The reasons for this are
primarily their reversibility, manageability, species specificity, and
correlation with species-specific hepatic enzyme-inducing effects of TPV
in the rodent. Primary target organs identified in rats and dogs
included the liver and GI tract. Co-administration of TPV and RTV in
rats and dogs revealed only signs of toxicity or target organ effects
evident when each compound was administered alone. More importantly,
co‑administration did not exacerbate the toxicity of either drug.

Changes in the GI tract in nonclinical studies have included emesis,
soft stools, diarrhea, and/or excessive salivation post-dosing.
Excessive salivation after TPV administration was attributed to the
bitter taste of TPV, which animals were exposed to during gavage
administration.

In rats and dogs, TPV plasma levels declined with repeated dosing
relative to Day 1, indicative of enzyme induction. This was supported by
increases in CYP450 isoforms CYP3A and CYP2B in both species, increases
in smooth endoplasmic reticulum, increased liver weights, and
hepatocellular hypertrophy. These increases in enzyme levels in animals
are considered an adaptive response to exposure to a xenobiotic and not
evidence of toxicity. Hepatic effects of TPV were dose-related, and
reversible with discontinuation of treatment, or transient and of no
clinical relevance.

Hepatic microsomal enzyme induction has resulted in secondary changes
during toxicity studies in rodents. These include increased clearance of
thyroid hormones with resultant increased thyroid weight and thyroid
follicular hypertrophy/hyperplasia, slight increases in plasma proteins,
and increases in coagulation parameters. All of these effects were found
to be reversible with termination of treatment. Increases in plasma
proteins are considered to reflect their increased synthesis in the
liver due to enzyme induction. Thyroid effects in rats due to hepatic
microsomal enzyme induction are not considered relevant to humans.
Reversible increases in coagulation indices (PT and APTT), observed only
in rodents administered TPV or TPV/r, were judged secondary to hepatic
enzyme induction rather than a direct effect of the drug. Some increases
in PT and fibrinogen were observed in mice, but not consistently, and no
increases in coagulation parameters have been observed in beagle dogs.
In response to these findings in rodents, monitoring of PT was performed
in early clinical trials, but no increases in PT have been observed in
humans.

Other hepatic changes in rodents included degeneration, vacuolation,
necrosis, mineral deposition, and karyomegaly. Karyomegaly was noted at
a low incidence in rats treated with TPV/r over 26-weeks. In these
animals, the incidence of karyomegaly was not related to TPV dose. A
much higher incidence was noted in RTV‑treated animals, and has been
previously observed in rat studies on RTV performed by Abbott
Laboratories. This finding is therefore an effect of RTV administration
and not considered to be of concern for humans administered TPV/r, as in
the combination therapy, RTV plasma levels are low. The other hepatic
findings, along with elevations of ALT and AST, appeared predominantly
in the mouse and were possibly related to tissue anoxia from circulatory
derangements caused by hepatocellular hypertrophy. These changes were
not observed in rats and dogs and may reflect a species-specific effect.
Based on the disparity between species, the implications for humans are
not clear. As liver function may be readily monitored, the appearance of
increased ALT and AST in one species should not preclude the use of TPV
in humans.

In beagle dogs, mild elevations in alkaline phosphatase in TPV or TPV/r
treated groups may be related to enzyme induction, but may also be
caused by an effect on the biliary system. The alkaline phosphatase
increases in dogs were shown in the 26-week SEDDS safety study to be due
to the hepatic isoform. Based on a lack of other findings indicating
cholestasis, this change raises no concern for humans.

Testicular degeneration and/or atrophy were observed in long-term
studies in rats and dogs at high dose levels. Re-evaluation of these
data by an expert panel indicated that the findings in the beagle dog
were within normal limits of variation. The testicular changes in rats,
seen in only three animals at a high dose level, were morphologically
and pathogenically unrelated and therefore not related to drug
treatment. Consequently, testes are not considered to be a target organ
of toxicity.

Genotoxicity studies with TPV have shown no potential for mutagenicity
or clastogenicity in standard assays both *in vitro* and *in vivo*.
Carcinogenicity studies are ongoing; therefore no definitive statements
may be made regarding the potential for TPV to induce tumors. A lack of
genotoxicity suggests that TPV would not induce tumors by a mutagenic or
clastogenic mechanism. The potential effects of TPV on hepatic enzyme
induction with consequent hepatic and/or thyroid tumors in rodent
carcinogenicity has already been discussed and at this time are not
considered to be a risk to humans taking TPV chronically.

Reproductive toxicity of TPV was assessed in standard studies in rats
and rabbits. At a maximum plasma concentration in rats of 258 µM (2-fold
human Cmax), no effects on spermatogenesis, estrous cycles, copulation,
fertility, implantation, or early embryonic development were observed.
In studies investigating exposure at the time of organogenesis, the no
observed adverse effect levels (NOAEL) in rats and rabbits corresponding
to exposures (AUC0-24) of 340 µM·h and 66 µM·h were determined. Maternal
toxicity, embryotoxicity, and/or developmental toxicity were observed at
greater exposure levels. Human exposure levels, at the recommended dose
level, are above these NOAEL exposure levels in animals. Consequently,
TPV should be given during pregnancy only if the benefit to the mother
and the fetus outweighs the risk to the fetus. The definitive study in
rabbits resulted in gross malformations at a maternally toxic dose
level. These findings were judged to be due to a litter effect and not a
drug effect, as marked maternal toxicity was observed at this dose
level, and in a previous study at the same and higher dose levels there
were no similar findings. Consequently, TPV was judged not to be a
selective developmental toxicant and consequently is not teratogenic.
TPV retarded pup growth in rats when administered during gestation and
into the postpartum period. Distribution studies in rats administered
14C-TPV have demonstrated that radioactivity is excreted into the milk
of rats. Consequently, women should be cautioned to avoid breastfeeding
while taking TPV.

The immunotoxic potential of TPV was assessed in a standard assay
testing the functioning of the humoral component of the immune system,
the T-dependent antigen response to sheep red blood cells (sRBC).
Treatment with TPV co-administered with RTV or TPV alone did not
adversely affect the functional ability of the humoral component of the
immune system in female CD-1 mice, as evaluated in the IgM
antibody-forming cell response to the T‑dependent antigen, sRBC.

Toxicity of impurities in TPV drug substance and degradation products of
TPV in drug product have been evaluated in general toxicity and
genotoxicity studies, as recommended by ICH guidances Q3A(R) and Q3B(R).
Impurities in TPV drug substance and drug product have been qualified at
levels equal to or greater than the proposed acceptance criteria.

TPV is administered in self-emulsifying drug delivery system (SEDDS)
formulations, with both the bulk fill solution and the oral solution
each containing a special mixture of excipients. A 26-week safety study
was designed in dogs to evaluate the toxicity of the bulk fill solution,
with special attention given to the dose levels of one excipient,
Cremophor EL (CrEL). CrEL is also present in the co‑administered RTV
capsule formulation, as it is an excipient included in Norvir® capsules
at 60 mg/mL (communication from Abbott Laboratories). Assessment of the
bulk fill solution formulation in rats and dogs in toxicity studies of
13 and 26 weeks, respectively, confirm its safety at the human dose
level of 500/200 mg BID TPV/r.

Literature assessment of components of the TPV oral solution indicate no
toxicity concerns when used as instructed. Levels of propylene glycol
(PG) in the TPV oral solution co‑administered with RTV oral solution are
considered safe when administered to adults and children greater than 2
years of age. Due to the low levels of the PG-metabolizing enzyme
alcohol dehydrogenase expressed by young livers, caution must be
exercised when administering this combination to infants or children
less than 2 years of age when administering TPV oral and RTV oral
solutions along with other prescription and/or non‑prescription
medications containing propylene glycol and/or ethanol. Due to the
presence of Vitamin E TPGS in the TPV oral solution, Vitamin E
supplementation should not be taken along with the oral solution since
the Vitamin E content of this product exceeds the Recommended Daily
Intake. Due to anticoagulant effects of high dose levels of Vitamin E,
the possibility exists that this excipient could exacerbate coagulation
defects in individuals who are deficient in Vitamin K or are receiving
anticoagulant therapy and suggests that caution is warranted.

The nonclinical evaluation of TPV/r has confirmed the safety, efficacy,
and bioavailability of TPV for its use in man for the treatment of HIV.

[]{#__RefHeading___Toc101398905 .anchor}3. MICROBIOLOGY

In the course of the development of tipranavir, numerous *in vitro* and
*in vivo* studies have been conducted to examine its antiviral activity.
Particular focus has been on viral isolates containing mutations (and
the patients who harbor these) that confer protease inhibitor
resistance. These studies have shown that susceptibility to tipranavir
is often maintained despite the development of broad cross-resistance to
currently available PIs. In addition, *in vitro* passage experiments
have shown that selection of mutations that confer resistance is slow;
ongoing studies in antiretroviral naïve patients should help define
whether or not there is a signature mutation that confers resistance to
tipranavir.

[]{#__RefHeading___Toc101398906 .anchor}3.1 Mechanism Of Action

Tipranavir is a non-peptidic protease inhibitor (NPPI) of HIV belonging
to the class of 4‑hydroxy‑5,6‑dihydro‑2‑pyrone sulfonamides. In
enzymatic assays, TPV demonstrates potent inhibition of the cleavage of
a peptidic substrate by the HIV-1 protease with an inhibition constant
(Ki) of 8.9 ± 6.8 pM. Using the same assay, TPV also inhibits the
activities of HIV-2 protease (Ki \< 1 µM) and of mutant HIV-1 proteases
carrying the mutations V82A (Ki = 3 nM) or V82F/I84V (Ki = 0.25 µM).
Selectivity for the HIV protease was demonstrated by high Ki values
against the human aspartyl proteases pepsin (Ki = 2 µM), cathepsin D (Ki
= 15 µM), and cathepsin E (Ki = 9 µM). Therefore, TPV is both a potent
and a selective inhibitor of the HIV protease.

[]{#__RefHeading___Toc101398907 .anchor}3.2 Antiviral Activity *In
Vitro*

Tipranavir inhibits the replication of laboratory strains and clinical
isolates in acute models of T-cell infection, with 50% effective
concentrations (EC~50~) ranging from 0.03 to 0.07 µM (18-42 ng/mL).
Tipranavir is also effective at inhibiting the replication of M-tropic
strains of HIV (EC~90\ ADA~ = 0.75 uM, 452 ng/mL and EC~90\ DGV~ = 0.3
µM, 180 ng/mL) and at inhibiting the extracellular accumulation of the
p24 capsid protein from H-9 cells chronically infected with HIV-1 IIIB
(EC~50~ of 0.39 µM, 235 ng/mL). Protein binding studies have shown that
the antiviral activity of tipranavir decreases on average 3.75-fold in
conditions where human serum is present. When used in combination with
other antiretrovirals, tipranavir shows synergy to additivity with the
NRTI zidovudine, the NNRTI delavirdine and the PI ritonavir. Activities
ranging from synergy to slight antagonism were reported when tipranavir
was used in combination with other currently available ARV drugs. No
evidence of strong antagonism was seen in any of the drugs combined with
TPV, and these data have been recently confirmed by additional analyses
of mixed drug cell cultures for all currently available PIs.

A large subset of isolates from PI-experienced patients entering the
pivotal Phase III RESIST trials were evaluated for the presence of
phenotypic susceptibility to commercially available PIs and TPV.
Analyses using these samples are presented in Section 7 on TPV
resistance.

[]{#__RefHeading___Toc101398908 .anchor}4. OVERVIEW OF CLINICAL
DEVELOPMENT PROGRAM

[]{#__RefHeading___Toc101398909 .anchor}4.1 EARLY DEVELOPMENT

Tipranavir was discovered by Pharmacia and Upjohn (P&U) and licensed for
development by Boehringer Ingelheim (BI) in 2000. The initial
development of tipranavir conducted by P&U involved optimizing the soft
gelatin capsule SEDDS formulation and characterizing the
ritonavir-boosting effect, so as to address issues of bioavailability
and plasma exposure typical for PIs.

At BI, the TPV clinical development program was initially focused on
PI-experienced patients, as this group has the greatest unmet medical
needs. To provide additional data on the possible use of TPV/r in other
populations, studies in pediatric and treatment naïve adult patients are
ongoing.

Overall, through 30 September 2004[^6], 3,367 HIV-positive patients and
769 HIV-negative volunteer subjects have been exposed to TPV/r.

Early open-label, dose ranging studies (BI 1182.3, 1182.2 and 1182.4)
demonstrated that tipranavir reduces viral load in HIV-positive patients
with variable levels of treatment experience (naïve, single- and
multiple-PI-experienced). However, these trials failed to determine the
optimal TPV/r dose, thus a Phase II dose-defining study was designed
(BI 1182.52).

[]{#__RefHeading___Toc101398910 .anchor}4.2 DOSE-FINDING TRIAL

BI 1182.52 was the definitive dose-finding study that evaluated three
TPV/r doses (TPV/r 500/100, 500/200, and 750/200 given twice daily). The
doses chosen for testing in this study were based on data from the Phase
I and II trial program and were considered the three best doses for
possible further study in the Phase III program.

The study was conducted in patients very similar to those studied in the
Phase III RESIST trials. All patients were triple ARV class, two
PI-based regimen-experienced and had baseline viral isolates with at
least one primary protease mutation (30N, 46I/L, 48V, 50V, 82A/L/F/T,
84V and 90M), with not more than 2 mutations among 82L/T, 84V or 90M.
The presence of a primary protease mutation was required to support
adherence to the previous treatment regimen. The specific primary
protease mutations selected were drawn from a mutation list that had
been used in a number of prior clinical trials including the Genotypic
Antiretroviral Resistance Testing (GART) and Multiple Drug Resistance
(MDR-HIV) studies.[^7] The requirement to have no more than 2 mutations
among 82L/T, 84V and 90M was based on *in vitro* TPV resistance
selection studies, HIV-1 isolates from early Phase II TPV/r trials and a
large panel of highly PI-resistant clinical isolates.[^8]

BI 1182.52 was a double-blind study with three TPV/r doses: TPV/r
500/100 mg, TPV/r 500/200 mg and TPV/r 750/200 mg, all given twice daily
with a genotypically optimized background regimen (OBR) that was
individually chosen by investigators. The first 2 weeks of the study
were the functional monotherapy phase, in which patients changed the PI
they were taking at entry to one of the three TPV/r doses, but
maintained the same OBR. The antiviral effect observed in the first
2 weeks was likely due to TPV/r, thereby allowing critical analyses of
the activity of the three doses. The study also tested the PK and safety
of the three doses.

Based on a composite of optimal safety, PK and antiviral activity
against PI-resistant viruses, the TPV/r 500/200 mg dose group was
selected for study in Phase III trials. In addition, BI 1182.52
confirmed that patients with virus containing three or more mutations at
HIV protease positions 33, 82, 84 or 90 were unlikely to obtain a
durable response to TPV/r or the alternative boosted PIs available.
These data were discussed with the FDA at an End-of-Phase II meeting
prior to the initiation of the Phase III trial program.

[]{#__RefHeading___Toc101398911 .anchor}4.3 PHASE III PIVOTAL TRIAL
PROGRAM

[]{#__RefHeading___Toc101398912 .anchor}4.3.1 Trial design

The Phase III Trials (BI 1182.12 \[RESIST-1\] and BI 1182.48
\[RESIST-2\]) are ongoing, large, randomized, open-label, multicenter
trials designed to evaluate the efficacy and safety of TPV/r in
comparison to ritonavir-boosted comparator PIs (CPI/r). Similar to the
Phase IIB dose-finding study, patients in the RESIST trials were triple
ARV class, two PI-based regimen experienced with HIV RNA 1,000 copies/mL
at baseline. The study was originally designed for 48 weeks, but has now
been extended for up to five years of follow up.

Genotyping was conducted at screening for the study and patients had to
demonstrate at least one primary protease mutation (30N, 46I/L, 48V,
50V, 82A/L/F/T, 84V or 90M), with not more than 2 mutations at codons
33, 82, 84 or 90. Patients screening for the RESIST studies with 3 or
more of these key mutations were eligible for the companion dual-booted
PI study, BI 1182.51.

Both the general design of the tipranavir development program and the
protocols in the Phase III program (BI 1182.12, 1182.48, and 1182.51)
were reviewed with the FDA and important design elements were agreed
upon. The RESIST studies also received a Special Protocol Assessment
prior to initiation.

Figure 4.3.1: 1 General design of the tipranavir Phase II---III
development program

The genotypic inclusion requirement in both BI 1182.52 and in the RESIST
trials was based on the need to test a documented PI-experienced patient
population for proof of the efficacy of TPV/r in these
treatment-experienced patients. Patients were required to have at least
one primary mutation to demonstrate that they had taken and failed a
PI-containing regimen with sufficient adherence to select for a
mutation. Importantly, any one of the mutations on the list would have
been insufficient to develop resistance to all of the 4 comparator PIs
used in RESIST.

In earlier *in vitro* and clinical data (BI 1182.52), the presence of
multiple mutations at protease codons 33[^9], 82, 84, or 90 had been
associated with reduced VL responses to TPV/r and shown to produce high
level resistance to currently available PIs (specifically LPV, IDV, SQV,
and APV). By allowing a maximum of two mutations at positions 33, 82,
84, or 90, patients who had clear evidence of PI resistance but still
had a sufficient chance to respond to either study arm were selected for
the RESIST trials.

Since it was anticipated that patients with three or more mutations at
codons 33, 82, 84, or 90 would be unlikely to achieve a durable 1
log~10~ response with either TPV/r or any of the CPI/r treatments, a
dual boosted PI companion study (BI 1182.51) was designed. The objective
of this study was to evaluate the PK, safety and preliminary efficacy of
a dual-boosted PI regimen containing TPV in patients with 3 or 4
mutations at codons 33, 82, 84, or 90.

To ensure that both arms of the RESIST trials had a balanced number of
patients with similar characteristics, the OBR had to be pre-selected
prior to randomization. Specifically, using baseline genotyping results
and patient treatment history, investigators had to pre-select the PI
their patients would receive if they were randomized to the CPI/r arm.
In addition, investigators had to pre-select the OBR and decide whether
they would choose enfuvirtide as part of the OBR.

Following the selection of the preferred PI and the OBR, patients in the
RESIST trials were then randomized 1:1 to either TPV/r or to the
comparator arm (CPI/r) Patients in the CPI/r would receive the PI that
had been pre-selected (lopinavir \[LPV\], indinavir \[IDV\], saquinavir
\[SQV\] or amprenavir \[APV\]). Importantly, the randomizations were
stratified according to both the pre-selected PI and on whether or not
they intended to use enfuvirtide.

It was intended that all patients receive the best possible treatment
available. If the patient\'s treatment history and genotype indicated
that the PI that was part of the screening regimen was the best option
for the patient (an 'ongoing PI'), this could be the pre-selected PI
chosen by the investigator for the RESIST trial.

In general, the designs of the two RESIST trials are similar except for
the timing of the interim trial endpoints, the statistical hypotheses,
and the resistance testing methods used. The primary endpoint for both
trials is treatment response after 48 weeks. As defined in the protocol,
the analysis for accelerated approval submission was to be performed at
Week 24.

In the two RESIST studies, the key efficacy endpoint for the 24-week
analysis was 'treatment response,' a composite endpoint of the
proportion of patients with two consecutive viral load measurements 1
log10 below baseline without evidence of: confirmed virological failure
to \< 1 log10 reduction, introduction of a new ARV (for reasons other
than toxicity or intolerance to a background drug), permanent
discontinuation of study drug, loss to follow-up, or death.

It is the 24-week interim analyses of the RESIST studies that form the
foundation of the data provided in the TPV NDA package submitted for
accelerated approval.

[]{#__RefHeading___Toc101398913 .anchor}4.3.2 Trial design issues

[]{#__RefHeading___Toc101398914 .anchor}4.3.2.1 Choice of comparator PI

The comparator arm treatments in the RESIST studies were selected as an
"optimized standard of care." Following the 1:1 randomization, patients
could be treated with any of four RTV-boosted comparator PIs along with
an OBR. The choice of both the comparator PI and the OBR was made prior
to randomization by each investigator and was based on individual
treatment history and the screening genotype data provided. As noted
above, the objective of the pre‑randomization selection of all
medications was to ensure balance between the two treatment arms, to
provide the optimal treatment response for patients who were randomized
to the comparator arm, and to eliminate a potential source of bias.

If needed, investigators were offered the use of an external panel of
resistance experts to assist with drug selection (as needed) and to
optimize the PI treatments chosen for use in the CPI/r arm. The use of
enfuvirtide was allowed if it was pre‑declared prior to randomization
and could be made available from the start of treatment. The
randomization was stratified on both the choice of comparator PI and the
use of enfuvirtide.

The use of a single RTV-boosted PI in the comparator arm (e.g., LPV/r)
would have simplified the study analyses and allowed for blinding, and
BI carefully considered this approach. BI concluded that the limitations
of this approach outweighed the benefits. First, the trial would have
been very slow to enroll; if there had been just one PI option in the
CPI/r arm, patients and investigators might have considered the trial
less attractive since that CPI/r option may not have been optimal for
their treatment. Second, use of a single RTV-boosted PI in the CPI/r arm
would have limited the amount of comparative data in this
treatment-experienced population. Third, patients in the comparator arm
would not necessarily be taking an "optimized standard of care" regimen,
and a large number of comparator arm drop-outs might have resulted that
could have invalidated the study efficacy endpoints. Finally, providing
the best possible individualized option for each patient who randomized
to the comparator arm appeared to be the most ethical approach for such
patients since this optimized the opportunity for a treatment response
in the CPI/r arm.

[]{#__RefHeading___Toc101398915 .anchor}4.3.2.2 Open-label study design

BI recognizes the advantages of conducting pivotal registrational trials
in a randomized, double-blind study design. However, the open-label
design of the two RESIST trials allowed the use of the best possible
RTV-boosted PI for patients randomized to the CPI/r arm. Using blinded
drug supplies in the study would have required patients to take more
capsules and this might have reduced patient adherence in both treatment
arms; this would have also required a complex, time-consuming set of
blinded drug supply agreements between five different pharmaceutical
companies. The open-label nature of the RESIST studies was discussed
with the FDA and concurrence was achieved on these important design
elements.

To help overcome potential biases in this open‑label study design, BI
took multiple precautions. First, an objectively defined composite
primary endpoint---one log viral load reduction from baseline---was
chosen which would be unlikely to be subject to bias. Second, the
conservative intent-to-treat, non-completer considered failure approach
has been used for the primary analysis, and multiple sensitivity
analyses have been performed[^10]. Third, investigators were required to
pre-select both the CPI/r and OBR to be used. Finally, BI statistical,
data management, and clinical teams were internally blinded to
individual patient treatment assignment during the conduct of the study
until after database lock. In spite of these precautions, BI was aware
that the open-label study design might have a higher rate of
discontinuations in the comparator arm since patients were knowingly not
receiving TPV/r, a potentially preferred treatment option.

It is important to note that patients in the comparator arm could leave
the study after Week 8 if they had confirmed virologic failure in order
to receive TPV treatment outside of the RESIST program (in the BI
1182.17 long-term safety follow-up study). To reduce the number of
patients who might not strictly adhere to the comparator arm treatments,
all RESIST investigators were required to carefully document virologic
failure and to provide confirmed comparator PI plasma concentrations
prior to patients being able to receive TPV in BI 1182.17. Due to the
subjective nature of adverse event reporting, patients leaving the
comparator arm of RESIST for safety reasons were not considered for
participation in BI 1182.17.

[]{#__RefHeading___Toc101398916 .anchor}4.3.2.3 Resistance status of
study cohort

The RESIST study population was chosen as a representative sample of
patients with PI treatment-experience who demonstrated PI resistance.

**Prior to patient randomization** in the two RESIST studies, the study
protocol was amended (Amendment 2) to allow investigators to pre-select
a comparator PI that was interpreted as "resistant" on the baseline
genotype report.

This important protocol amendment was necessary because initial genotype
reports indicated that 57.4-73.8% of patients had resistance to the
selected PI, making it impossible to enroll eligible patients and
complete the trial within a reasonable time period. Patients with
pan-resistance to available PIs and very limited treatment options would
at least have a 50% chance of receiving TPV/r. Additional considerations
included the knowledge that the genotype report gives an interpretation
of resistance primarily based on unboosted PIs, while RTV-boosted PIs
were exclusively used in the comparator PI arm. BI encouraged
investigators to review the actual mutations listed on the resistance
report (in addition to the interpretation) and to make use of the expert
resistance consultant panel[^11]. Finally, BI recognized the importance
of providing TPV/r to patients in the RESIST studies if they had
virologic failure on the CPI/r arm, and this was made available through
BI 1182.17, the long term rollover trial.

[]{#__RefHeading___Toc101398917 .anchor}4.3.2.4 RESIST study amendments
and relevant protocol deviations

There were six RESIST protocol amendments by the time of the 24-week
interim analysis. These amendments did not fundamentally change the
study objectives, nor did their implementation have a clinically
relevant impact on patients participating in the study (with the
exception of Amendment 2). The primary goals of each amendment are
described in the following paragraph.

*Amendment 1* was implemented prior to the start of patient treatment to
allow the use of tenofovir in Canada, where the drug previously had not
been commercially available. As noted above, *Amendment 2* (as discussed
above) was implemented prior to the start of patient treatment to allow
the entry of patients who had a baseline genotypic interpretation
indicating 'resistance' to all of the available PIs[^12],[^13].
*Amendment 3* was implemented in the first several weeks of the study to
provide protocol clarifications where the language might have been
subject to misinterpretation, and to provide guidelines for the
management of vomiting. *Amendment 4* was implemented in the first three
months of the study to create a separate pharmacokinetic sub-study of
women. *Amendment 5* was implemented in the eighth month of the study to
extend the study to 96 weeks from the originally planned 48 weeks.
*Amendment 6* was implemented after the data cut-off for the 24‑week
analysis to correct a DAIDS adverse event severity grading scale that
had been erroneously included in the protocol.

The relevant protocol deviations were broadly characterized in the trial
protocols and specified in more detail in the trial statistical analysis
plans. Final decisions about relevant protocol violations were made
independently by the trial teams in the blinded report planning meetings
held for each study, and these take place prior to internal unblinding
of the data base. It is important to point out that each trial team was
permitted to make their own decisions about relevant protocol deviations
and reconciliations between the two RESIST study teams was not required.
During the review process by the international TPV project team,
relevant protocol deviations were re-assessed using the same fundamental
criteria as used by each individual trial. As a result, a modified
per-protocol set was derived that is slightly smaller than the
per-protocol set report analyzed at 24 weeks in the individual RESIST
clinical trial reports. This modified per-protocol set reduces the TPV/r
group by six patients and the CPI/r group by 14 patients, leaving no
substantive impact on the conclusion of superiority for the TPV/r arm.

[]{#__RefHeading___Toc101398918 .anchor}4.3.2.5 Non-inferiority testing

For the pre-planned analyses at 24 weeks, both RESIST clinical trial
protocols had planned to use a test of non-inferiority of TPV/r to
CPI/r, followed by a test of superiority of TPV/r to CPI/r if
non-inferiority was confirmed. Both tests were to be performed by the
calculation of the same 95% confidence interval for the differences in
response rates, taking into account the stratified randomization in the
two arms of the trials.

The test of non-inferiority was originally included in the protocol
statistical analysis plans because the control group was expected to
show a response rate comparable to that of the TPV/r arm, at least in a
large sub-group of the participating patients who would have viruses
sensitive to both TPV and their chosen CPI. However, after Amendment #2
was implemented and it was recognized from the analysis of the
composition of the trial population and the response rate of the CPI/r
group, it became obvious that the response rate in the CPI/r group was
incompatible with a response of a fully active control arm. As a result,
BI concluded that a demonstration of non-inferiority was insufficient to
demonstrate the antiviral efficacy of TPV/r and that a demonstration of
superiority was required.

[]{#__RefHeading___Toc101398919 .anchor}4.4 ADDITIONAL CLINICAL DATA

In support of the RESIST pivotal program, further extensive clinical
data have been generated. These include an initial study of the impact
of TPV in very highly treatment experienced patients, too resistant for
participation in the RESIST trials (BI 1182.51).

In addition, a large amount of data on the resistance profile of TPV,
evaluating the clinical impact of TPV resistance on treatment response
and identifying predictors of TPV treatment response, has been
generated, providing a resistance profile database superior to that of
any currently available ARV.

In parallel, an extensive and highly detailed analysis and
characterization of the pharmacokinetic and drug interaction profile of
TPV/r has been performed.

At the time of NDA submission, data on 37 pediatric patients with up to
four weeks of TPV/r exposure was available. This 48-week, 100-patient
pediatric study in HIV-infected children and adolescents between 2 and
18 years of age now has been fully accrued and will be the subject of a
future efficacy supplement.

Finally, a Phase III study of TPV/r versus LPV/r in antiretroviral naïve
patients has recently completed enrolment.

All studies in the TPV development program have used standard research
approaches to design, conduct, and analysis that are consistent with
other ARV drug development programs. A listing of all 39 clinical trials
conducted in support of TPV may be found in Appendix 2.

[]{#__RefHeading___Toc101398920 .anchor}5. CLINICAL PHARMACOLOGY

[]{#__RefHeading___Toc101398921 .anchor}5.1 Clinical Pharmacokinetics

To achieve effective tipranavir plasma concentrations using a
twice-daily (BID) dosing regimen, co-administration of tipranavir with
low-dose ritonavir twice-daily is essential. Ritonavir acts by
inhibiting hepatic cytochrome P450 3A (CYP 3A), the intestinal
P‑glycoprotein (Pgp) efflux pump, and possibly intestinal cytochrome
P450 3A as well. As demonstrated in a dose‑ranging evaluation in 113
HIV-negative healthy male and female volunteers (BI 1182.5), ritonavir
increases tipranavir AUC0-12h, Cmax and Cmin by decreasing its
clearance.

Tipranavir 500 mg, co-administered with low-dose ritonavir 200 mg (TPV/r
500/200 mg), BID for 21 days was associated with a 48-fold increase in
the geometric mean morning steady-state trough plasma concentrations of
tipranavir as compared with tipranavir 500 mg given BID without
ritonavir for 11 days (Figure 5.1: 1).

![](media/image3.wmf){width="4.839583333333334in"
height="4.079861111111111in"}

Figure 5.1: 1 Steady state plasma tipranavir concentrations on the
11^th^-day of 500 mg BID administration without ritonavir (open circles)
and following the addition of 200 mg ritonavir BID for 14 days (closed
circles)

Given alone, TPV induces hepatic CYP 3A and RTV inhibits CYP 3A. To
understand the net effect of coadministration of tipranavir and
ritonavir on hepatic CYP 3A, a single 200 mg dose of ritonavir
co-administered with 500 mg tipranavir was studied using an erythromycin
breath test (ERMBT).

Tipranavir rapidly induced CYP 3A when given alone. When ritonavir was
added the expected inhibitory effect on CYP 3A was predominant. This net
inhibition of CYP 3A for the TPV/r combination was nearly complete on
Study Day 1. Following withdrawal of drug administration, CYP 3A
activity returned to baseline levels by Study Day 3, likely due to
hepatic enzyme turnover.

These data confirm that tipranavir and ritonavir must be taken together
and doses should not be missed. Patients should be cautioned to take
their tipranavir and ritonavir together as prescribed and to not run out
of the booster drug, ritonavir. Full hepatic enzyme inhibition is
necessary to deliver adequate exposure to tipranavir.

The recommended dose of tipranavir is 500 mg (two 250 mg capsules or
5 mL of oral solution), co-administered with 200 mg ritonavir (low-dose
ritonavir), twice daily. Steady state is attained in patients after 7
days of dosing. TPV/r exhibits linear pharmacokinetics at steady state
and the half-life is 6.0 hours in HIV‑positive patients. Trough
concentrations 60‑fold above the protein-adjusted IC~50~ for protease
inhibitor-resistant HIV-1 clinical isolates (i.e., IQ  60) are achieved
at doses of TPV/r 500/200 mg, and have been associated with a 1 log~10~
viral load reduction in clinical studies of treatment-experienced
patients.

[]{#__RefHeading___Toc101398922 .anchor}5.1.1 Demographic subpopulations

Demographic subpopulations were also analyzed. For example, evaluation
of steady-state plasma trough tipranavir concentrations at 10-14 h after
dosing from the RESIST studies demonstrated that there was no change in
median trough tipranavir concentrations as age increased for either
gender through 65 years of age. The trend of consistent trough
tipranavir concentrations with increasing age through 80 years for men
was supported.

In addition, females generally had higher tipranavir concentrations than
males. After 4 weeks of TPV/r 500 mg/200 mg BID, the median plasma
trough concentration of tipranavir was 43.9 M for females and 31.1 M for
males.

Finally, white males generally had more variability in tipranavir
concentrations than black males, but the median concentration and the
range making up the majority of the data are comparable between the
races. Table 5.1.1: 1 summarizes pharmacokinetic parameters by gender
and HIV status.

Table 5.1.1: 1 Population pharmacokinetic assessment by gender and HIV
status

+-----------------------------+--------+----------+--------+--------+
| Pharmacokinetic parameter   | HIV+   |          | HIV-   |        |
|                             | pa     |          | su     |        |
|                             | tients |          | bjects |        |
+-----------------------------+--------+----------+--------+--------+
|                             | F      | Males    | F      | Males  |
|                             | emales |          | emales |        |
|                             |        | (N =     |        | (N =   |
|                             | (N =   | 106)     | (N =   | 42)    |
|                             | 14)    |          | 25)    |        |
+-----------------------------+--------+----------+--------+--------+
| Cp~0h,12h~ (M)              | 30.94  | 31.63    | 43.26  | 32.97  |
+-----------------------------+--------+----------+--------+--------+
| Cmax (M)                    | 92.33  | 75.87    | 114.71 | 90.08  |
+-----------------------------+--------+----------+--------+--------+
| Tmax (h)                    | 2.9    | 2.9      | 3.0    | 2.9    |
+-----------------------------+--------+----------+--------+--------+
| AUC~0-12h~ (h•M)            | 792.8  | 681.0    | 1005.3 | 781.8  |
+-----------------------------+--------+----------+--------+--------+
|                             |        |          |        |        |
+-----------------------------+--------+----------+--------+--------+
| CL (L/h)                    | 1.05   | 1.22     | 0.83   | 1.06   |
+-----------------------------+--------+----------+--------+--------+
| V (L)                       | 7.7    | 10.2     | 5.3    | 7.0    |
+-----------------------------+--------+----------+--------+--------+
|                             |        |          |        |        |
+-----------------------------+--------+----------+--------+--------+
| t~1/2~ (h)                  | 6.0    |          | 4.8    |        |
+-----------------------------+--------+----------+--------+--------+
|                             | 5.5    | 6.0      | 4.7    | 4.8    |
+-----------------------------+--------+----------+--------+--------+
|                             |        |          |        |        |
+-----------------------------+--------+----------+--------+--------+
| Ka (h^-1^)                  | 0.5142 | 0.5291   | 0.4406 | 0.4780 |
+-----------------------------+--------+----------+--------+--------+
| Ke (h^-1^)                  | 0.1354 | 0.1200   | 0.1560 | 0.1510 |
+-----------------------------+--------+----------+--------+--------+
| free fraction protein       | 0.015% |          | 0.019% |        |
| binding                     | 0.006% |          | 0.076% |        |
+-----------------------------+--------+----------+--------+--------+

[]{#__RefHeading___Toc101398923 .anchor}5.1.2 Absorption, distribution,
metabolism, elimination (ADME)

[]{#__RefHeading___Toc101398924 .anchor}5.1.2.1 Absorption

Because tipranavir is a Biopharmaceutics Classification Scheme (BCS)
Class II compound, with low solubility and high permeability, absorption
of tipranavir in humans is limited, though no quantification of absolute
absorption is available.

A self-emulsifying drug delivery system (SEDDS) to create a
microemulsion environment in the gastrointestinal tract upon agitation
with water is required to get maximum dispersion of tipranavir in the
gastrointestinal tract as a solution.

*Food\
*Tipranavir capsules, administered under high fat meal conditions or
with a light snack of toast and skim milk, were tested in a multiple
dose study. Food enhanced the extent of bioavailability (AUC point
estimate 1.31, confidence interval 1.23‑1.39), but had minimal effect on
peak tipranavir concentrations (Cmax point estimate 1.16, confidence
interval 1.09‑1.24). Based on these data, tipranavir may be safely taken
with standard or high-fat meals and food appears to improve GI
tolerability and aid in the emulsification of the drug.

*Antacid\
*When TRV/r was co-administered with 20 mL of aluminium and
magnesium-based liquid antacid, tipranavir AUC012h, Cmax and C12h were
reduced by 25-29%. Consideration should be given to separating TPV/r
dosing from antacid administration to prevent reduced absorption of
tipranavir.

The effect of a proton pump inhibitor on tipranavir absorption has not
been studied in a formal drug interaction trial. However, for the 80
patients on proton pump inhibitors in the RESIST studies, the median
trough tipranavir concentration was 41 µM compared to a median 34 µM
concentration observed in the group of 570 patients not on proton pump
inhibitors.

*Formulation Excipients\
*Despite the significant amounts of the emulsifier Cremophor EL®
ingested each day with tipranavir and ritonavir capsules, systemic
ricinoleic acid concentrations have not been detected after 6 months of
chronic therapy demonstrating that the large molecular weight excipient
is not absorbed.

*Loperamide\
*Loperamide is often co-administered with TPV/r to control diarrhea. A
pharmacodynamic interaction study in healthy volunteers demonstrated
that administration of loperamide 16mg and TPV/r 750 mg/200 mg does not
cause any clinically relevant change in the respiratory response to
carbon dioxide, a surrogate marker for CNS entry of loperamide and its
metabolite.

The pharmacokinetic analysis showed that the AUC and Cmax of loperamide
and its metabolite were reduced by greater than 50%, whereas the AUC and
C~max~ for tipranavir remained unchanged and the Cmin decreased by 26%.
Since the primary pharmacologic activity of loperamide is local, lower
systemic loperamide concentrations are not of clinical concern. This
data does suggest that TPV/r has an inductive effect on efflux
transporters *in vivo*.

[]{#__RefHeading___Toc101398925 .anchor}5.1.2.2 Distribution

Tipranavir is extensively bound to plasma proteins (\>99.9%). From
clinical samples of healthy volunteers and HIV-1 positive subjects who
received tipranavir the mean fraction of tipranavir unbound in plasma
was similar in both populations (healthy volunteers 0.015% 0.006%;
HIV-positive subjects 0.019% 0.076%). Total plasma tipranavir
concentrations for these samples ranged from 9 to 82 M. The unbound
fraction of tipranavir appeared to be independent of total drug
concentration over this concentration range.

Since tipranavir is highly protein bound, dialysis is unlikely to be
beneficial in significant removal of this medicine in an overdose
situation.

[]{#__RefHeading___Toc101398926 .anchor}5.1.2.3 Metabolism

*In vitro\
*In an *in vitro* drug interaction assessment using tipranavir alone the
I/K~i~ ratios, based on in vivo maximum plasma tipranavir concentrations
(bound and free) following ritonavir-boosted tipranavir administration,
were greater than 1 (interaction likely) for the inhibition of CYP1A2,
CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Follow-up *in vivo* evaluations
using probe substrate drugs for these isoforms have not yet been
conducted to rule out these potential interactions. During the conduct
of the RESIST trials, patients were on co-medications that were
substrates for these major human isoforms. A review of the case reports
for patients co-prescribed a CYP2C19 substrate carisoprodol (n=5), a
CYP1A2 substrate olanzapine (n=6), and a CYP2C9 substrate phenytoin
(n=9) failed to show a need for dose adjustment of the substrate drug.
For the CYP1A2, CYP2C19, CYP2C9, CYP3A4 substrate warfarin (n=3),
frequent INR monitoring due to the ritonavir component of tipranavir
therapy is warranted.

*In vitro* metabolism studies with human liver microsomes indicated that
CYP3A is the predominant CYP isoform involved in tipranavir metabolism.

*In vivo\
*Tipranavir is a substrate of intestinal and hepatic CYP3A activity and
Pgp, and appears to be both an inhibitor and an inducer of these
metabolic and transport systems, but the clinical significance of these
findings is not yet established. Steady state is attained after 7 days
of dosing. TPV/r exhibits linear pharmacokinetics at steady state.

As noted above, the ERMBT data confirmed *in vitro* analyses indicating
that tipranavir induces the cytochrome P450 CYP3A enzyme system after
multiple doses. Hepatic CYP3A activity, as measured by the ERMBT,
increased from basal levels following oral administration of 500 mg
tipranavir alone for 11 days, thus indicating hepatic CYP3A enzyme
auto-induction. With the addition of 200 mg of ritonavir, the percent of
erythromycin metabolised per hour dropped to negligible values. This
indicates that the net systemic effect of TPV/r is inhibition of the
hepatic CYP3A enzyme system.

The oral clearance of tipranavir decreased after the addition of
ritonavir which may represent diminished first-pass clearance of the
drug at the gastrointestinal tract and the liver. With repeated dosing,
tipranavir plasma concentrations are lower than predicted from single
dose data, presumably due to efflux transporter induction as the
metabolism of tipranavir in the presence of low-dose ritonavir is
minimal.

In a ^14^C-tipranavir human study (BI 1182.24) radio-labelled tipranavir
(^14^C‑tipranavir) given with unlabelled RTV 200 mg, unchanged
tipranavir was the predominant form detected, accounting for 98.4% or
greater of the total plasma radioactivity circulating at 3, 8, or 12
hours after dosing. Only a few TPV metabolites were found in plasma, and
all were at trace levels (0.2% or less of the plasma radioactivity).

[]{#__RefHeading___Toc101398927 .anchor}5.1.2.4 Excretion

Administration of ^14^C-tipranavir to subjects (n = 8) who received
TPV/r 500/200 mg BID dosed to steady-state demonstrated that the
majority of radioactivity (median 82.3%) was excreted in feces. Only a
median of 4.4% of the radioactive dose administered was recovered in
urine.

In addition, 56% was excreted between 24 and 96 hours after dosing. A
minor fraction of the dose, attributed to colonic bacteria, was detected
as metabolites in the feces; the overwhelming majority of the dose was
excreted unchanged.

The effective mean elimination half-life of tipranavir/ritonavir in
healthy volunteers (n = 67) and HIV-infected adult patients (n = 120)
was 4.8 and 6.0 hours, respectively, at steady state following a dose of
TPV/r 500/200 mg BID with a light meal.

[]{#__RefHeading___Toc101398928 .anchor}5.1.3 Drug interactions

[]{#__RefHeading___Toc101398929 .anchor}5.1.3.1 Effect on tipranavir

Since tipranavir and ritonavir are both metabolized by CYP3A, studies
evaluating the TPV/r co-administration with agents that induce CYP3A
(e.g., efavirenz) or inhibit CYP3A (e.g., fluconazole) were performed.

The analyses in Table 5.1.3.1: 1 demonstrate that if ritonavir 200 mg is
chronically co-administered with tipranavir, then the CYP3A enzyme
induction effect of efavirenz will not decrease the systemic tipranavir
or ritonavir exposure. However, both fluconazole and clarithromycin
increased the tipranavir concentration even in the presence of 200 mg
ritonavir. When only ritonavir 100 mg is co-administered with tipranavir
enzyme induction by efavirenz produces significant decreases in
tipranavir exposure.

Table 5.1.3.1: 1 Mean Pharmacokinetic Ratios\* of Tipranavir in the
Presence of Co-administered Drug Based on Historical Tipranavir Data for
Normal (HIV-) Volunteers. (No Effect = 1.00)

  -------------------------- ------------- --------------- ---------------
  Regimen                    Cmax\         AUC\            Cmin\
                             (µM)          (µM•h)          (µM)

  TPV/r 500/200 mg BID &\    1.40\         1.66\           2.00\
  Clarithromycin 500 mg BID\ (1.24 --      (1.43 -- 1.73)  (1.58 -- 2.47)
  (n=24)                     1.47)                         

  TPV/r 500/200 mg BID &\    1.32\         1.50\           1.69\
  Fluconazole 100 mg QD\     (1.18 --      (1.29 -- 1.73)  (1.33 -- 2.09)
  (n=20)                     1.47)                         

  TPV/r 500/100 mg BID &\    0.79\         0.69\           0.58\
  Efavirenz 600 mg QD\       (0.69 --      (0.57 -- 0.83)  (0.36 -- 0.86)
  (n=24)                     0.89)                         

  TPV/r 750/200 mg BID &\    0.97\         1.01\           0.97\
  Efavirenz 600 mg QD\       (0.85 --      (0.85 -- 1.18)  (0.69 -- 1.28)
  (n=21)                     1.09)                         
  -------------------------- ------------- --------------- ---------------

> ^\*^ Mean pharmacokinetic ratios with 90% confidence intervals (5 and
> 95 percentiles) following 2000 bootstrap samples. Design did not
> permit a true cross-over comparison.

[]{#__RefHeading___Toc101398930 .anchor}5.1.3.2 Interactions with
reverse transcriptase inhibitors

When administered alone, tipranavir is an inducer of hepatic CYP3A.
TPV/r at the recommended dosage, is a net inhibitor of the hepatic
CYP3A. TPV/r may therefore increase plasma concentrations of agents that
are primarily metabolised by CYP3A similar to other ritonavir-boosted
PIs. These increases in plasma concentrations of co-administered agents
could increase or prolong their therapeutic effect and adverse effects.

The systemic exposures of stavudine, lamivudine, tenofovir, efavirenz,
and nevirapine are not affected by TPV/r (Table 5.1.3.2: 1).

Zidovudine systemic exposure decreases by \>40%, with no impact on
glucuronidated-ZDV levels. Similarly, TPV/r decreases the extent of
abacavir systemic exposure by approximately 40% and co-administration
with enteric-coated didanosine is associated with a 10-20% reduction in
didanosine levels. Based on the metabolic pathways for NRTIs, an
interaction with TPV/r of this magnitude was unexpected and the
mechanism(s) is unknown.

It should be noted that the prescribing information for zidovudine
states that routine dose adjustment is not warranted for decreases of
25-47% in zidovudine exposure. It is possible that the drug interaction
between didanosine and TPV/r was due to food and may be minimized by
separating the didanosine administration by at least 2 hours from the
dose of TPV/r taken with food. The clinical relevance of the decreases
in exposure to ZDV, abacavir, and ddI are not known. No recommendation
for dose adjustment of ZDV, abacavir or ddI can be made at this time. No
dosage adjustments are necessary when the NNRTIs nevirapine or efavirenz
are co-administered with TPV/r at the 500/200 mg dose.

Most NRTIs, without significant changes in plasma concentrations, may be
safely co-administered with TPV/r. For ZDV and ABC, the clinical
relevance of the reductions in plasma concentrations is not established
and further studies are needed. As these drug-drug interaction studies
between TPV/r and NRTIs measured only plasma concentrations of the
NRTIs, studies to measure intracellular triphosphorylated drug levels of
ZDV and abacavir are currently being planned.

Table 5.1.3.2: 1 Comparison of NRTI and NNRTI levels when combined with
TPV/r, ritonavir alone, or ritonavir-boosted lopinavir.

  ----------------- ------------------- ----------------- -----------------
  Substrate Drug    Ritonavir-boosted   Ritonavir alone\  Ritonavir boosted
                    tipranavir result   result            lopinavir result

  Abacavir          40% AUC\            NR                NR
                    45% Cmax                              

  Zidovudine        43% AUC\            25% AUC\          NR
                    56% Cmax            27% Cmax          

  Didanosine        10% AUC\            13% AUC\          NR
                    20% Cmax            16% Cmax          

  Stavudine         0-20%               NR                NR

  Lamivudine        5-15%               NR                NR

  Tenofovir         no change in AUC,\  NR                NR
                    except 38% Cmax                       

  Efavirenz         0-12%               NR                10-15%

  Nevirapine        3-14%               NR                5-15%
  ----------------- ------------------- ----------------- -----------------

NR = not reported in prescribing information for Norvir® or Kaletra®

[]{#__RefHeading___Toc101398931 .anchor}5.1.3.3 Interactions with
protease inhibitors

Protease inhibitor (PI) levels for dual-boosted protease inhibitor
regimens containing TPV/r cannot be predicted without a formal drug
interaction study due to the mixed patterns of inhibition and induction
of CYP pathways seen with these boosted-drug combinations.

In a clinical study (BI 1182.51) of dual-boosted PI combination therapy
in multiple-treatment experienced HIV-positive adults, TPV/r, was
combined with ritonavir-boosted lopinavir, saquinavir, or amprenavir.
When tipranavir, lopinavir, and ritonavir were co-administered, there
was a 55% reduction in lopinavir systemic exposure and a 70% reduction
in the C~min~ of lopinavir. When tipranavir, saquinavir, and ritonavir
were co-administered, there was a 76% reduction in saquinavir exposure
and \>80% reduction in the C~min~ of saquinavir. When tiparanavir,
amprenavir, and ritonavir were co-administered, there was a 45%
reduction in amprenavir systemic exposure and a 55% reduction in the
C~min~ of amprenavir[^14].

In the absence of having established appropriate doses for the
combination of TPV/r and LPV, SQV, or APV, these combinations are not
recommended.

[]{#__RefHeading___Toc101398932 .anchor}5.1.3.4 Interactions with
non-ARV medications

Interactions between TPV/r and medications commonly used by patients
with HIV were also performed.

*Fluconazole\
*TPV/r does not substantially affect ([\<]{.underline} 10% decrease) the
steady-state pharmacokinetics of fluconazole (Table 5.1.3.4: 1). As
previously noted, fluconazole increases the AUC and Cmin of tipranavir
by over 50% when compared to historical data. Fluconazole doses
200 mg/day are not recommended as an initial dose to be combined with
TPV/r[^15].

*Atorvastatin\
*TPV/r increases the plasma concentrations of atorvastatin (Table
5.1.3.4: 1) by approximately 8-10 fold and reduces the extents of
exposures of the hydroxyl-metabolites by \>85%. This observed
interaction is comparable to the interactions observed with other
ritonavir-boosted protease inhibitors. Atorvastatin does not
significantly change the AUC, Cmax or Cmin of tipranavir. It is
recommended to initiate atorvastatin treatment with the lowest possible
dose with careful monitoring or, alternatively, to consider the use of
other HMG-CoA reductase inhibitors such as pravastatin, fluvastatin or
rosuvastatin[^16].

*Rifabutin\
*TPV/r increases plasma concentrations of rifabutin (Table 5.1.2.4: 1)
by up to 3 fold, and the 25-O-desacetyl-rifabutin active metabolite by
up to 20 fold. Rifabutin increases the Cmin of tipranavir by 16%. Dosage
reductions of rifabutin by at least 75% of the usual 300 mg/day are
recommended (i.e., 150 mg three times per week). Further dosage
reduction may be necessary for some individuals.

*Clarithromycin\
*TPV/r increases the AUC and Cmin of clarithromycin by 19% and 68%,
respectively, and decreases the extent of exposure of the 18‑hydroxy
active metabolite by over 95%. These changes are not considered
clinically relevant unless treating *Haemophilus influenzae*. As
described earlier, clarithromycin 500 mg doubles the Cmin of tipranavir.
This large increase in Cmin may be clinically relevant. Patients should
therefore use the 500 mg BID dose of clarithromycin and should be
carefully monitored if higher doses are required. Because the metabolic
pathway for clarithromycin elimination has been altered, the renal
pathway is expected to predominate. For patients with renal impairment
the following dosage adjustments should be considered: For patients with
CL~CR~ 30 to 60 ml/min the dose of clarithromycin should be reduced by
50%. For patients with CL~CR~ 30 ml/min the dose of clarithromycin
should be decreased by 75%. No dosage adjustments for patients with
normal renal function are necessary.

*Ethinyl Estradiol\
*TPV/r decreases the AUC and Cmax of ethinyl estradiol by 50% (Table
5.1.3.4:1), but does not significantly alter the pharmacokinetic
behavior of norethindrone. As a result of the reduction in estrogen
levels, alternative or additional contraceptive measures should be used
when estrogenic-based oral contraceptives are co-administered with
TPV/r. Women using ethinyl estradiol co-administered with TPV/r may have
an increased rate of nonserious rash.

Table 5.1.3.4: 1 Comparison of non-ARV levels when combined with TPV/r,
ritonavir alone, or ritonavir-boosted lopinavir.

+-----------------+-----------------+-----------------+-----------------+
| Substrate Drug  | TPV/r           | RTV alone       | LPV/r           |
+-----------------+-----------------+-----------------+-----------------+
| Clarithromycin  | AUC 19%,        | AUC 77%,        | NR              |
|                 |                 |                 |                 |
|                 | Cmin 68%,\      | Cmax 31%,\      |                 |
|                 | metabolite      | metabolite      |                 |
|                 | \>97%           | \>99%           |                 |
+-----------------+-----------------+-----------------+-----------------+
| Fluconazole     | 6-10%           | NR              | NR              |
+-----------------+-----------------+-----------------+-----------------+
| Rifabutin       | 3 x,\           | 4 x,\           | 3 x,\           |
|                 | metabolite 21 x | metabolite 35 x | metabolite 48 x |
+-----------------+-----------------+-----------------+-----------------+
| Atorvastatin    | 9.4 x\          | NR              | 5.9 x\          |
|                 | metabolite      |                 | metabolite NR   |
|                 | \>85%           |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Ethinyl         | 45-50%          | 40%             | 42%             |
| Estradiol       |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

NR = not reported in prescribing information for Norvir® or Kaletra®

[]{#__RefHeading___Toc101398933 .anchor}5.1.3.5 Potential drug
interactions

*Theoretical\
*Based on the drug interaction studies conducted to date and the
similarity of the results between ritonavir-boosted tipranavir,
ritonavir alone, and other ritonavir-boosted protease inhibitors, the
following drugs are contraindicated or not recommended for
co-administration with tipranavir (Table 5.1.3.5: 1). These
recommendations are based on predicted interactions due to the expected
magnitude of interaction and potential for serious events or loss of
efficacy and specific studies with TPV/r have not been performed.

Table 5.1.3.5: 1 Drugs that should not be co-administered with TPV/r.

+--------------------------+-------------------------------------------+
| **Drug Class/Drug Name** | **Clinical Comment**                      |
+--------------------------+-------------------------------------------+
| **Antiarrhythmics:**     | **CONTRAINDICATED** due to potential for  |
|                          | serious and/or life-threatening reactions |
| Amiodarone, bepridil,    | such as cardiac arrhythmias secondary to  |
| flecainide, propafenone, | increases in plasma concentrations of     |
| quinidine                | antiarrhythmics.                          |
+--------------------------+-------------------------------------------+
| **Antihistamines:**      | **CONTRAINDICATED** due to potential for  |
|                          | serious and/or life-threatening reactions |
| Astemizole, terfenadine  | such as cardiac arrhythmias.              |
+--------------------------+-------------------------------------------+
| **Antimycobacterials:**  | May lead to loss of virologic response    |
|                          | and possible resistance to tipranavir or  |
| rifampin                 | to the class of protease inhibitors.      |
+--------------------------+-------------------------------------------+
| **Ergot derivatives:**   | **CONTRAINDICATED** due to potential for  |
|                          | serious and/or life-threatening reactions |
| Dihydroergotamine,       | such as acute ergot toxicity              |
| ergonovine, ergotamine,  | characterized by peripheral vasospasm and |
| methylergonovine         | ischemia of the extremities and other     |
|                          | tissues.                                  |
+--------------------------+-------------------------------------------+
| **GI motility agents:**  | **CONTRAINDICATED** due to potential for  |
|                          | serious and/or life-threatening reactions |
| Cisapride                | such as cardiac arrhythmias.              |
+--------------------------+-------------------------------------------+
| **Herbal products:**     | May lead to loss of virologic response    |
|                          | and possible resistance to tipranavir or  |
| St. John\'s wort         | to the class of protease inhibitors.      |
+--------------------------+-------------------------------------------+
| **HMG CoA reductase      | Potential for serious reactions such as   |
| inhibitors:**            | risk of myopathy including                |
|                          | rhabdomyolysis.                           |
| Lovastatin, simvastatin  |                                           |
+--------------------------+-------------------------------------------+
| **Neuroleptics:**        | **CONTRAINDICATED** due to potential for  |
|                          | serious and/or life-threatening reactions |
| Pimozide                 | such as cardiac arrhythmias.              |
+--------------------------+-------------------------------------------+
| **Sedatives/hypnotics:** | **CONTRAINDICATED** due to potential for  |
|                          | serious and/or life threatening reactions |
| Midazolam, triazolam     | such as prolonged or increased sedation   |
|                          | or respiratory depression.                |
+--------------------------+-------------------------------------------+

*Empirical\
*Based on the drug interaction studies conducted to date and the
similarity of the results between ritonavir-boosted tipranavir,
ritonavir alone, and other ritonavir-boosted protease inhibitors, the
following interactions, which may require dose adjustments or clinical
monitoring when TPV/r is co-administered, are summarized in the Table
5.1.3.5: 2. Many of these studies have been performed, but those not
performed are indicated in the table.

Table 5.1.3.5: 2 Established and Other Potentially Significant Drug
Interactions: Alterations in Dose or Regimen May be Recommended Based on
Drug Interaction Studies or Predicted Interactions

+----------------------+----------------------+-----------------------+
| **Concomitant Drug   | **Effect on          | **Clinical Comment**  |
| Class:**             | Concentration of     |                       |
|                      | Tipranavir or        |                       |
| **Drug name**        | Concomitant Drug**   |                       |
+======================+======================+=======================+
| HIV-Antiviral Agents |                      |                       |
+----------------------+----------------------+-----------------------+
| **Nucleoside reverse | Abacavir             | Clinical relevance of |
| transcriptase        | concentrations by    | reduction in abacavir |
| inhibitors:**        | approx. 40%          | levels not            |
|                      |                      | established. No dose  |
| Abacavir             | Didanosine by 10-20% | adjustment            |
|                      |                      | recommended.          |
| Didanosine (EC)      | Zidovudine           |                       |
|                      | concentrations by    | Clinical relevance of |
| Zidovudine           | approx. 50%. ZDV     | reduction in          |
|                      | glucuronide          | didanosine levels not |
|                      | concentrations were  | established. For      |
|                      | unaltered.           | optimal absorption,   |
|                      |                      | didanosine should be  |
|                      |                      | separated from TPV/r  |
|                      |                      | dosing by at least 2  |
|                      |                      | hours. No dose        |
|                      |                      | adjustment            |
|                      |                      | recommended.          |
|                      |                      |                       |
|                      |                      | Clinical relevance of |
|                      |                      | reduction in          |
|                      |                      | zidovudine levels not |
|                      |                      | established. No dose  |
|                      |                      | adjustment            |
|                      |                      | recommended.          |
+----------------------+----------------------+-----------------------+
| **Protease           | Amprenavir Cmin by   | In the absence of     |
| inhibitors           | 55%,                 | having established    |
| (co-administered     |                      | appropriate doses for |
| with low-dose        | Lopinavir Cmin by    | the combination of    |
| ritonavir):**        | 70%,                 | tipranavir/ritonavir  |
|                      |                      | and ritonavir-boosted |
| Amprenavir           | Saquinavir Cmin by   | amprenavir,           |
|                      | \>80%,               | saquinavir, or        |
| Lopinavir            |                      | lopinavir, these      |
|                      |                      | combinations cannot   |
| Saquinavir           |                      | be recommended.       |
+----------------------+----------------------+-----------------------+
| Other Agents for     |                      |                       |
| Opportunistic        |                      |                       |
| Infections           |                      |                       |
+----------------------+----------------------+-----------------------+
| **Antifungals:**     | Tipranavir \>50%,    | Fluconazole increases |
|                      |                      | TPV concentrations,   |
| Fluconazole          | ↔ Fluconazole        | but dose adjustments  |
|                      |                      | are not needed.       |
| Itraconazole         | Itraconazole (not    | Fluconazole doses 200 |
|                      | studied),            | mg/day are not        |
| Ketoconazole         |  Ketoconazole (not   | recommended.          |
|                      | studied),\           |                       |
| Voriconazole         | Voriconazole (not    | Based on theoretical  |
|                      | studied)             | considerations        |
|                      |                      | itraconazole and      |
|                      |                      | ketoconazole should   |
|                      |                      | be used with caution. |
|                      |                      | High doses (200       |
|                      |                      | mg/day) are not       |
|                      |                      | recommended.          |
+----------------------+----------------------+-----------------------+
| **A                  | Tipranavir (not      | Concomitant use of    |
| ntimycobacterials:** | studied)             | tipranavir and        |
|                      |                      | rifampin is           |
| Rifampin             | Tipranavir not       | contraindicated.      |
|                      | changed,             | Alternate             |
| Rifabutin            |                      | antimycobacterial     |
|                      | Rifabutin 3-fold     | agents such as        |
| Clarithromycin       |                      | rifabutin should be   |
|                      | Desacetyl-rifabutin  | considered.           |
|                      | 21-fold              |                       |
|                      |                      | Dosage reductions of  |
|                      | Tipranavir 2-fold,   | rifabutin by 75% are  |
|                      |                      | recommended (e.g.,    |
|                      | Clarithromycin       | 150 mg three times a  |
|                      | 20-68%,              | week). Increased      |
|                      |                      | monitoring for        |
|                      | 18-hydroxy           | adverse events in     |
|                      | metabolite \>97%     | patients receiving    |
|                      |                      | the combination is    |
|                      |                      | warranted. Further    |
|                      |                      | dosage reduction may  |
|                      |                      | be necessary.         |
|                      |                      |                       |
|                      |                      | No dose adjustment of |
|                      |                      | tipranavir or         |
|                      |                      | clarithromycin for    |
|                      |                      | patients with normal  |
|                      |                      | renal function is     |
|                      |                      | necessary.            |
|                      |                      |                       |
|                      |                      | For patients with     |
|                      |                      | renal impairment the  |
|                      |                      | following dosage      |
|                      |                      | adjustments should be |
|                      |                      | considered:           |
|                      |                      |                       |
|                      |                      | -   For patients with |
|                      |                      |     CL~CR~ 30 to 60   |
|                      |                      |     mL/min the dose   |
|                      |                      |     of clarithromycin |
|                      |                      |     should be reduced |
|                      |                      |     by 50%.           |
|                      |                      |                       |
|                      |                      | -   For patients with |
|                      |                      |     CL~CR~ 30 mL/min  |
|                      |                      |     the dose of       |
|                      |                      |     clarithromycin    |
|                      |                      |     should be         |
|                      |                      |     decreased by 75%. |
+----------------------+----------------------+-----------------------+
| Other Agents         |                      |                       |
| Commonly Used        |                      |                       |
+----------------------+----------------------+-----------------------+
| **PDE5 inhibitors:** | Combinations with    | Concomitant use of    |
|                      | TPV/r not studied.   | PDE5 inhibitors with  |
| Sildenafil           |                      | tipranavir and        |
|                      | Sildenafil           | ritonavir should be   |
| Tadalafil            |                      | used with caution and |
|                      | Tadalafil            | in no case should the |
| Vardenafil           |                      | starting dose of:     |
|                      | Vardenafil expected  |                       |
|                      |                      | -   sildenafil exceed |
|                      |                      |     25 mg within 48   |
|                      |                      |     hours             |
|                      |                      |                       |
|                      |                      | -   tadalafil exceed  |
|                      |                      |     10 mg every 72    |
|                      |                      |     hours             |
|                      |                      |                       |
|                      |                      | -   vardenafil exceed |
|                      |                      |     2.5 mg every 72   |
|                      |                      |     hours             |
+----------------------+----------------------+-----------------------+
| **HMG-CoA reductase  | Tipranavir unchanged | Start with the lowest |
| inhibitors:**        |                      | possible dose of      |
|                      | Atorvastatin         | atorvastatin with     |
| Atorvastatin         | 9.4‑fold             | careful monitoring,   |
|                      |                      | or consider other     |
|                      | Hydroxy-metabolites  | HMG-CoA reductase     |
|                      | \>85%                | inhibitors.           |
+----------------------+----------------------+-----------------------+
| **Narcotic           | Methadone by 50%     | Dosage of methadone   |
| analgesics:**        |                      | may need to be        |
|                      | Combinations with    | increased when        |
| Methadone            | TPV/r not studied    | co-administered with  |
|                      |                      | tipranavir and        |
| Meperidine           | Meperidine,          | low-dose ritonavir.   |
|                      | Normeperidine        |                       |
|                      |                      | Dosage increase and   |
|                      |                      | long-term use of      |
|                      |                      | meperidine are not    |
|                      |                      | recommended due to    |
|                      |                      | increased             |
|                      |                      | concentrations of the |
|                      |                      | metabolite            |
|                      |                      | normeperidine which   |
|                      |                      | has both analgesic    |
|                      |                      | activity and CNS      |
|                      |                      | stimulant activity    |
|                      |                      | (e.g. seizures)       |
+----------------------+----------------------+-----------------------+
| **Oral               | Ethinyl-estradiol    | Alternative methods   |
| contra               | concentrations by    | of non-hormonal       |
| ceptives/Estrogens** | 50%                  | contraception should  |
|                      |                      | be used when estrogen |
| Ethinyl-estradiol    |                      | based oral            |
|                      |                      | contraceptives are    |
|                      |                      | co-administered with  |
|                      |                      | tipranavir and        |
|                      |                      | low-dose ritonavir.   |
|                      |                      | Women using estrogens |
|                      |                      | may have an increased |
|                      |                      | risk of non serious   |
|                      |                      | rash.                 |
+----------------------+----------------------+-----------------------+
| **I                  | Combination with     | More frequent         |
| mmunosuppressants:** | TPV/r not studied    | concentration         |
|                      |                      | monitoring of these   |
| Tacrolimus           | Tacrolimus           | medicinal products is |
|                      |                      | recommended until     |
| Sirolimus            | Sirolimus            | blood levels have     |
|                      |                      | been stabilized.      |
| Cyclosporine         | Cyclosporine         |                       |
+----------------------+----------------------+-----------------------+
| Warfarin             | Combination with     | Frequent INR          |
|                      | TPV/r not studied    | (international        |
|                      |                      | normalized ratio)     |
|                      | R- and S warfarin    | monitoring upon       |
|                      | metabolized by       | initiation of         |
|                      | different isozymes   | tipranavir/ritonavir  |
|                      |                      | therapy.              |
+----------------------+----------------------+-----------------------+
| **Hypoglycemics:**   | Combination with     | Because of the        |
|                      | TPV/r not studied    | potential for         |
| Tolbutamide          |                      | ritonavir CYP3A       |
|                      | Tolbutamide          | inhibition or CYP2C9  |
| Glyburide            |                      | induction with        |
|                      | Glyburide            | chronic therapy,      |
| Glipizide            |                      | careful glucose       |
|                      | Glipizide            | monitoring is         |
| Glimepiride          |                      | warranted.            |
|                      | Glimepiride          |                       |
| Repaglinide          |                      |                       |
|                      | Repaglinide          |                       |
| Pioglitazone         |                      |                       |
|                      | Pioglitazone         |                       |
+----------------------+----------------------+-----------------------+
| **SSRIs:**           | Combination with     | Antidepressants have  |
|                      | TPV/r not studied    | a wide therapeutic    |
| fluoxetine           |                      | index, but doses may  |
|                      | fluoxetine           | need to be adjusted   |
| paroxetine           |                      | upon initiation of    |
|                      | paroxetine           | TPV/r therapy.        |
| sertaline            |                      |                       |
|                      | sertaline            |                       |
+----------------------+----------------------+-----------------------+
| **Calcium Channel    | Combination with     | Combinations of TPV/r |
| Blockers:**          | TPV/r not studied    | and calcium channel   |
|                      |                      | blockers should be    |
| verapamil            | verapamil            | avoided because of    |
|                      |                      | the CYP3A activity of |
| nisoldepine          | nisoldepine          | both agents.          |
|                      |                      |                       |
| felodipine           | felodipine           |                       |
+----------------------+----------------------+-----------------------+
| Desipramine          | Combination with     | Dosage reduction and  |
|                      | TPV/r not studied    | concentration         |
|                      |                      | monitoring of         |
|                      | Desipramine          | desipramine is        |
|                      |                      | recommended.          |
+----------------------+----------------------+-----------------------+
| Disu                 | Combination with     | Tipranavir capsules   |
| lfiram/Metronidazole | TPV/r not studied    | contain alcohol they  |
|                      |                      | can produce           |
|                      |                      | disulfiram-like       |
|                      |                      | reactions when        |
|                      |                      | co-administered with  |
|                      |                      | disulfiram or other   |
|                      |                      | drugs which produce   |
|                      |                      | this reaction (e.g.   |
|                      |                      | metronidazole).       |
+----------------------+----------------------+-----------------------+

[]{#__RefHeading___Toc101398934 .anchor}5.1.4 Hepatic or renal
impairment

The pharmacokinetic profiles of single-dose and steady-state TPV/r
500/200 mg in subjects with mild to moderate hepatic insufficiency were
investigated in an open label trial (BI 1182.32). Mildly and moderately
hepatically-impaired patients were paired with control patients
according to age, weight, and other demographics.

Following 7 days of TPV/r 500/200 mg BID dosing in a study comparing 9
patients with mild (Child-Pugh A) hepatic impairment to 9 healthy
volunteer controls, the single and multiple dose pharmacokinetic
dispositions of tipranavir and ritonavir were found to be increased in
patients with hepatic impairment, but still within the range observed in
clinical trials. The geometric mean ratios for the population were
1.30 (AUC~0‑12h~), 1.14 (Cmax) and 1.84 (C~p12h~). No dosing adjustment
is required in patients with mild hepatic impairment.

The influence of moderate hepatic impairment (Child-Pugh B) on the
pharmacokinetics of either tipranavir or ritonavir has not been
evaluated at steady state. Further studies are planned. Because greater
than 80% of the doses of both drug entities are excreted in the feces as
unchanged drug moieties, close clinical and laboratory monitoring of
patients with moderate impaired liver (e.g. Child-Pugh B) function is
important.

The use of TPV/r in Child-Pugh C patients is contraindicated, and
studies in this population are not planned.

Tipranavir pharmacokinetics has not been studied in patients with renal
dysfunction. However, since the renal clearance of tipranavir is
negligible, a decrease in total body clearance is not expected in
patients with renal insufficiency.

[]{#__RefHeading___Toc101398935 .anchor}5.2 Pharmacokinetic Conclusions

-   In treatment-experienced HIV-positive patients, TPV 500 mg must be
    given simultaneously with ritonavir 200 mg to obtain the desired
    drug levels with BID dosing.

-   Despite TPV being an inducer of CYP3A, when combined with 200 mg of
    ritonavir TPV/r produces a net hepatic inhibition of CYP3A. The
    pharmacokinetic drug interactions for most concomitant medications
    are consistent with other ritonavir-boosted PIs.

-   Reductions in zidovudine, abacavir, and didanosine plasma drug
    levels have been observed with TPV/r, but the clinical relevance of
    these reductions has not been established. No dose adjustments can
    be recommended at this time.

-   No dosage adjustments of the NNRTIs nevirapine or efavirenz are
    required when co-administered with TPV/r at the 500/200 mg dose.

-   Drug levels for ritonavir-boosted lopinavir, saquinavir, and
    amprenavir were significantly reduced when combined with TPV/r,
    therefore these combinations are not recommended. PI levels for
    novel dual PI regimens containing TPV/r cannot be predicted without
    formal drug interaction studies possibly due to the mixed patterns
    of inhibition and induction of CYP pathways seen with these drug
    combinations.

```{=html}
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```
-   Based on the interactions observed with TPV/r, the following
    additional drug interaction studies are planned: atazanavir,
    buprenorphine, bupropion, tadalafil, omeprazole,
    Peg-interferon/ribavirin, carbamazepine, methadone, new
    investigational antiretrovirals, and a CYP/Pgp-cocktail study.

[]{#__RefHeading___Toc101398936 .anchor}6. EFFICACY

Since the discovery of tipranavir by Pharmacia and Upjohn (P&U) and its
licensing for development by Boehringer Ingelheim (BI) in 2000, 39
tipranavir clinical trials have been conducted. This summary of efficacy
presents tipranavir efficacy data from nine clinical trials conducted
primarily in treatment-experienced HIV-positive patients.

[]{#__RefHeading___Toc101398937 .anchor}6.1 Early Clinical Data

Early open-label, dose ranging studies (Trials BI 1182.3, 1182.2 and
1182.4, Tables 6.1: 1 and 6.1: 2) showed that TPV reduces viral load in
HIV-positive patients with different levels of treatment experience
(naïve \[BI 1182.3\], single- \[BI 1182.4\] and multiple-PI experienced
\[BI 1182.2\]).

In BI 1182.3, treatment naïve HIV-positive adults were given tipranavir
alone or tipranavir with low dose ritonavir for 14 days. These 14 day
viral activity data (Table 6.1: 1) clearly demonstrate that the addition
of low dose ritonavir is required for an optimal treatment response.

Table 6.1: 1 Median change from baseline in HIV-1 RNA values over 14
days of monotherapy treatment in ARV Treatment Naïve Trial BI 1182.3

  ------------- ------------- -------------------- ----------------------
                TPV 1200 mg   TPV/r 300 mg/200 mg  TPV/r 1200 mg/200 mg

  Baseline VL   4.90          5.20                 4.79

  Day 14 or 15  -0.77 (10)    -1.43 (7)            -1.64 (10)
  ------------- ------------- -------------------- ----------------------

In BI 1182.2, multiple PI regimen-experienced patients (NNRTI-naïve)
were given two doses of TPV/r with efavirenz. The 48 week treatment
response was similar between both dose groups but generally favored the
lower dose used (TPV/r 500/100mg) over the high dose (TPV/r 1000/100mg).
In BI 1182.4, single PI regimen-experienced patients were given two
doses of TPV/r and this was compared against a standard of care regimen
containing SQV/RTV 400/400mg. The 48 week treatment response was similar
for both of the two TPV/r dose groups but appeared to slightly favour
the higher dose (TPV/r 1250/100mg) over the lower dose (TPV/r 500/100mg)
(Table 6.1: 2).

Table 6.1: 2 Virologic efficacy data in Trials BI 1182.2 and 1182.4 -
FAS **(**LOCF or NCF), using combination therapy

+---------------------+--------+--------+----------+--------+--------+
|                     | BI     |        | BI       |        |        |
|                     | 1182.2 |        | 1182.4   |        |        |
+---------------------+--------+--------+----------+--------+--------+
|                     | Mu     |        | Single   |        |        |
|                     | ltiple |        | PI       |        |        |
|                     | PI     |        | Failure  |        |        |
|                     | F      |        |          |        |        |
|                     | ailure |        |          |        |        |
+---------------------+--------+--------+----------+--------+--------+
|                     | TPV/r  | TPV/r  | TPV/r    | TPV/r  | SQV/r  |
|                     | 500    | 1000   | 500      | 1250   | 400    |
|                     | /100mg | /      | /100mg\  | /      | /400mg |
|                     | NRTI   | 100mg\ | 2 NRTIs  | 100mg\ |        |
|                     | and    | NRTI   |          | 2      | 2      |
|                     | NNRTI  | and    |          | NRTIs  | NRTIs  |
|                     |        | NNRTI  |          |        |        |
+---------------------+--------+--------+----------+--------+--------+
| Median Baseline VL  | 4.43   | 4.45   | 4.44     | 4.35   | 4.19   |
| \[log~10~           |        |        |          |        |        |
| copies/mL\]         |        |        |          |        |        |
+---------------------+--------+--------+----------+--------+--------+
| 24-week analysis:   |        |        |          |        |        |
+---------------------+--------+--------+----------+--------+--------+
| > Median VL change  | -2.67  | -2.39  | -1.41    | -1.36  | -1.75  |
| > from baseline     |        |        |          |        |        |
| > \[log~10~         |        |        |          |        |        |
| > copies/mL\]       |        |        |          |        |        |
+---------------------+--------+--------+----------+--------+--------+
| > Patients \< 400   | 79     | 50     | 38       | 29     | 24     |
| > copies/mL \[%\]   |        |        |          |        |        |
+---------------------+--------+--------+----------+--------+--------+
| > Patients \< 50    | 58     | 50     | 17       | 21     | 14     |
| > copies/mL \[%\]   |        |        |          |        |        |
+---------------------+--------+--------+----------+--------+--------+
| 48-week analysis:   |        |        |          |        |        |
+---------------------+--------+--------+----------+--------+--------+
| > Median VL change  | -2.67  | -2.43  | -0.50    | -0.88  | -1.41  |
| > from baseline     |        |        |          |        |        |
| > \[log~10~         |        |        |          |        |        |
| > copies/mL\]       |        |        |          |        |        |
+---------------------+--------+--------+----------+--------+--------+
| > Patients \< 400   | 79     | 50     | 16       | 32     | 17     |
| > copies/mL \[%\]   |        |        |          |        |        |
+---------------------+--------+--------+----------+--------+--------+
| > Patients \< 50    | 68     | 41     | 8        | 27     | 10     |
| > copies/mL \[%\]   |        |        |          |        |        |
+---------------------+--------+--------+----------+--------+--------+

While these trials provided data on the efficacy of TPV/r in patients
with variable treatment experience, no definitive dose was established.
As a result, BI designed and conducted a dose-finding study (BI 1182.52)
using three doses of TPV/r.

[]{#__RefHeading___Toc101398938 .anchor}6.2 Dose Selection (BI 1182.52)

As noted previously, BI designed and conducted a dose-finding study (BI
1182.52) to determine the optimal dose for use in the Phase III trial
program.

Similar to the RESIST study cohort, these patients had two PI-based
regimen experience, and baseline viral isolates with at least one
primary protease mutation (30N, 46I/L, 48V, 50V, 82A/L/F/T, 84V and
90M), and not more than 2 mutations among 82L/T, 84V or 90M. This was a
double-blind study evaluating 3 TPV/r doses: 500/100 mg, 500/200 mg and
750/200 mg, all given BID with a genotypically optimized background
regimen (OBR).

The first 2 weeks of the study were a functional monotherapy phase in
which patients changed the PI they were taking at study entry to one of
three TPV/r doses, but maintained the same OBR. The antiviral effect
from these first 2 weeks was therefore predominantly due to only TPV/r.
During this 2-week functional monotherapy phase, the viral load
reductions from baseline to Week 2 were: TPV/r 500/100 mg, 0.85 log~10~
copies/mL; TPV/ r 500/200 mg, 0.93 log~10~ copies/mL; and TPV/r 750/200
mg, 1.18 log~10~ copies/mL.

For the full study cohort, there was an inverse relationship between the
number of mutations at codons 33, 82, 84, or 90 and viral load reduction
at Week 24. Patients with no mutations at these codons demonstrated a
-1.51 log~10~ copies/mL reduction; one mutation, -0.76 log~10~ copies/mL
reduction; two mutations, -0.62 log~10~ copies/mL reduction; three
mutations, -0.13 log~10~ copies/mL reduction[^17].

For patients with virus containing mutations at three of these key
positions, the antiviral activity for all three doses was reduced.
Across treatment groups, patients with up to two mutations at codons 33,
82, 84, or 90 showed a strong dose-related response at Week 24 in the
LOCF analysis (Table 6.2: 1); there was a statistically significant
difference between the TPV/r 750/200 and 500/100 doses but not between
TPV/r 750/200 and 500/200. This was confirmed when the viral load
responses at 24 weeks were stratified by the number of mutations at
codons 33, 82, 84 or 90. The 500/100 group showed a significant drop in
antiviral activity with 1 mutation while the 500/200 and the 750/200
doses required more mutations before antiviral activity was diminished.
Thus, the 500/100 dose underperformed against the drug resistant viruses
to be evaluated in the TPV pivotal trial program.

Table 6.2: 1 Median log~10~ change from baseline in viral load at 2 and
24 Weeks of TPV/r treatment (FAS-LOCF) by number of baseline mutations
at codons 33, 82, 84, or 90

<table>
<colgroup>
<col style="width: 13%" />
<col style="width: 5%" />
<col style="width: 9%" />
<col style="width: 7%" />
<col style="width: 5%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 5%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 6%" />
<col style="width: 7%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="4"><p>Number of Mutations at codons 33, 82, 84, or 90 at
Baseline/</p>
<p>Weeks of Treatment</p></td>
<td colspan="12">Treatment Group</td>
</tr>
<tr class="even">
<td colspan="3">TPV/r<br />
500/100<br />
(n=73)</td>
<td colspan="3">TPV/r<br />
500/200<br />
(n=72)</td>
<td colspan="3">TPV/r<br />
750/200<br />
(n=71)</td>
<td colspan="3">Total<br />
(n=216)</td>
</tr>
<tr class="odd">
<td colspan="12">Log<sub>10</sub> Change from Baseline in RNA
Copies/mL</td>
</tr>
<tr class="even">
<td>N</td>
<td>Med<sup>a</sup></td>
<td>IQR</td>
<td>N</td>
<td>Med<sup>a</sup></td>
<td>IQR</td>
<td>N</td>
<td>Med<sup>a</sup></td>
<td>IQR</td>
<td>N</td>
<td>Med<sup>a</sup></td>
<td>IQR</td>
</tr>
<tr class="odd">
<td><strong>None</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>2 weeks</td>
<td>5</td>
<td>-1.32</td>
<td>-1.51, -1.04</td>
<td>1</td>
<td>-0.60</td>
<td>-0.60, -0.60</td>
<td>5</td>
<td>-1.35</td>
<td>-1.35, -1.02</td>
<td>11</td>
<td>-1.32</td>
<td>-1.51, -0.82</td>
</tr>
<tr class="odd">
<td>24 weeks</td>
<td>5</td>
<td>-1.92</td>
<td>-2.42, -1.51</td>
<td>1</td>
<td>-1.82</td>
<td>-1.82, -1.82</td>
<td>5</td>
<td>-1.16</td>
<td>-1.20, -0.33</td>
<td>11</td>
<td>-1.51</td>
<td>-2.26, -0.97</td>
</tr>
<tr class="even">
<td><strong>1</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>2 weeks</td>
<td>19</td>
<td>-1.21</td>
<td>-1.48, -0.73</td>
<td>25</td>
<td>-1.15</td>
<td>-1.67, -0.60</td>
<td>31</td>
<td>-1.25</td>
<td>-1.81, -0.58</td>
<td>75</td>
<td>-1.21</td>
<td>-1.61, -0.60</td>
</tr>
<tr class="even">
<td>24 weeks</td>
<td>19</td>
<td>-0.29</td>
<td>-1.72, 0.42</td>
<td>25</td>
<td>-1.05</td>
<td>-2.39, -0.14</td>
<td>31</td>
<td>-1.07</td>
<td>-2.17, -0.18</td>
<td>75</td>
<td>-0.76</td>
<td>-2.28, 0.00</td>
</tr>
<tr class="odd">
<td><strong>2</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>2 weeks</td>
<td>36</td>
<td>-0.68</td>
<td>-1.07, -0.18</td>
<td>25</td>
<td>-1.28</td>
<td>-1.84, -0.78</td>
<td>19</td>
<td>-1.24</td>
<td>-1.62, -0.49</td>
<td>80</td>
<td>-0.93</td>
<td>-1.65, -0.26</td>
</tr>
<tr class="odd">
<td>24 weeks</td>
<td>36</td>
<td>-0.20</td>
<td>-1.68, 0.22</td>
<td>25</td>
<td>-0.59</td>
<td>-2.72, -0.25</td>
<td>19</td>
<td>-1.84</td>
<td>-2.36, -0.42</td>
<td>80</td>
<td>-0.62</td>
<td>-2.28, -0.03</td>
</tr>
<tr class="even">
<td><strong>0, 1, or 2</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>2 weeks</td>
<td>60</td>
<td>-0.91</td>
<td>-1.41, -0.32</td>
<td>51</td>
<td>-1.16</td>
<td>-1.73, -0.60</td>
<td>55</td>
<td>-1.24</td>
<td>-1.68, -0.58</td>
<td>166</td>
<td>-1.13</td>
<td>-1.61, -0.46</td>
</tr>
<tr class="even">
<td>24 weeks</td>
<td>60</td>
<td>-0.44</td>
<td>-1.99, 0.17</td>
<td>51</td>
<td>-1.05</td>
<td>-2.62, -0.24</td>
<td>55</td>
<td>-1.49</td>
<td>-2.26, -0.28</td>
<td>166</td>
<td>-0.87</td>
<td>-2.26, -0.06</td>
</tr>
<tr class="odd">
<td><strong>3</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>2 weeks</td>
<td>13</td>
<td>-0.19</td>
<td>-0.98, 0.20</td>
<td>21</td>
<td>-0.33</td>
<td>-1.10, -0.09</td>
<td>16</td>
<td>-0.54</td>
<td>-1.14, -0.04</td>
<td>50</td>
<td>-0.32</td>
<td>-1.10, 0.12</td>
</tr>
<tr class="odd">
<td>24 weeks</td>
<td>13</td>
<td>0.23</td>
<td>-1.09, 0.29</td>
<td>21</td>
<td>0.05</td>
<td>-0.63, 0.29</td>
<td>16</td>
<td>-0.25</td>
<td>-0.91, -0.13</td>
<td>50</td>
<td>-0.13</td>
<td>-1.09, 0.27</td>
</tr>
</tbody>
</table>

^a^ Median.

Safety analyses of BI 1182.52 demonstrated a dose relationship with
higher frequency of severe adverse events, discontinuations due to
adverse events and DAIDS Grade 3 or 4 ALT elevations observed with
increasing dose. Specifically, 21.2% of patients in the TPV/r 750/200 mg
dose group had Grade 3 or 4 ALT elevations over the course of 24 weeks
of therapy as compared to 5.5% for the TPV/r 500/100 mg dose group and
11.1% for the TPV/r 500/200 mg dose group. Thus, from the standpoint of
optimal safety, PK and efficacy, the TPV/r 500/200 mg dose group was
selected for study in Phase III trials, and these data were reviewed
with the FDA at the End-of-Phase II meeting in December 2002.

[]{#__RefHeading___Toc101398939 .anchor}6.3 Efficacy results of pivotal,
active-controlled trials (RESIST Trials)

[]{#__RefHeading___Toc101398940 .anchor}6.3.1 Study population

Using a treatment population that was very similar to the cohort studied
in BI 1182.52, the RESIST study program studied HIV-positive adults with
triple ARV class experience, including at least two PI-based regimens.
All patients had to be virologically failing on their current PI-based
regimen at the time of study screening in order to get an accurate
analysis of PI resistance; no treatment interruptions prior to study
entry were allowed.

A total of 3309 patients were screened for participation in the two
RESIST studies, and 1816/3309 (54.9%) of these patients failed
screening. Of the 1816 patients who failed screening, the most common
reasons for screening failure were: failure to meet baseline resistance
criteria (66.4%), failure to meet baseline safety lab criteria (26.7%),
unacceptable medical history (15.3%), and failure to have a viral load
of at least 1000 copies/mL (12.9%).

A total of 1483 patients were randomized and treated in the combined
RESIST trials (Table 6.3.1: 1). By 12 March 2004, 1159 patients had
reached the 24-week visit date and data for these patients are included
in full analysis set (FAS) analyses. Within the FAS, a subgroup of
patients (n=731) without any protocol deviations formed the per-protocol
set (PPS) population used in sensitivity analyses.

Table 6.3.1: 1 Summary of population sets for the RESIST trials

+--------------+--------+--------+--------+--------+--------+--------+
|              | RE     |        | RE     |        | Co     |        |
|              | SIST-1 |        | SIST-2 |        | mbined |        |
|              |        |        |        |        | RESIST |        |
|              | BI     |        | BI     |        | Trials |        |
|              | 1      |        | 1      |        |        |        |
|              | 182.12 |        | 182.48 |        |        |        |
+==============+========+========+========+========+========+========+
|              | TPV/r  | CPI/r  | TPV/r  | CPI/r  | TPV/r  | CPI/r  |
+--------------+--------+--------+--------+--------+--------+--------+
|              | N      | N      | N      | N (%)  | N      | N      |
|              |    (%) |    (%) |    (%) |        |    (%) |    (%) |
+--------------+--------+--------+--------+--------+--------+--------+
| > All        | 311    | 309    | 435    | 428    | 746    | 737    |
| > treated    | (      | (      | (      | (      | (      | (      |
| > patients;  | 100.0) | 100.0) | 100.0) | 100.0) | 100.0) | 100.0) |
| > achieve 16 |        |        |        |        |        |        |
| > weeks of   |        |        |        |        |        |        |
| > efficacy   |        |        |        |        |        |        |
| > by interim |        |        |        |        |        |        |
| > cut-off    |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| > Full       | 311    | 309    | 271    | 268    | 582    | 577    |
| > analysis   | (      | (      | (62.3) | (62.6) | (78.0) | (78.3) |
| > set (FAS); | 100.0) | 100.0) |        |        |        |        |
| > achieve 24 |        |        |        |        |        |        |
| > weeks of   |        |        |        |        |        |        |
| > efficacy   |        |        |        |        |        |        |
| > by interim |        |        |        |        |        |        |
| > cut-off    |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| > Per        | 191    | 193    | 180    | 167    | 371    | 360    |
| > protocol   | (61.4) | (62.5) | (41.4) | (39.0) | (49.7) | (48.8) |
| > set (PPS); |        |        |        |        |        |        |
| > subset of  |        |        |        |        |        |        |
| > FAS        |        |        |        |        |        |        |
| > without    |        |        |        |        |        |        |
| > any        |        |        |        |        |        |        |
| > protocol   |        |        |        |        |        |        |
| > deviations |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+

The integrated RESIST trial population included in the interim 24-week
efficacy analyses consisted of 1159 patients, 582 randomized to TPV/r
and 577 to CPI/r. Demographic characteristics were comparable between
the two treatment groups (Table 6.3.1: 2).

Patients in the RESIST-1 trial had a lower CD4+ cell count (median 123
cells/mm^3^ in both treatment groups) than the RESIST-2 trial (median
175 cells/mm^3^ for TPV/r and 200 cells/mm^3^ for CPI/r), potentially
reflective of geographic differences in the treatment strategies of
investigators.

Table 6.3.1: 2 Baseline demographic data, HIV-1 RNA values, and CD4+
cell counts -- RESIST trials (FAS a)

+------------------+-------+-------+-------+-------+-------+-------+
|                  | RES   |       | RES   |       | Com   |       |
|                  | IST-1 |       | IST-2 |       | bined |       |
|                  |       |       |       |       | R     |       |
|                  | BI    |       | BI    |       | ESIST |       |
|                  | 11    |       | 11    |       | T     |       |
|                  | 82.12 |       | 82.48 |       | rials |       |
+==================+=======+=======+=======+=======+=======+=======+
|                  | TPV/r | CPI/r | TPV/r | CPI/r | TPV/r | CPI/r |
+------------------+-------+-------+-------+-------+-------+-------+
| Total treated    | 311   | 309   | 271   | 268   | 582   | 577   |
+------------------+-------+-------+-------+-------+-------+-------+
| Age \[years\]    |       |       |       |       |       |       |
+------------------+-------+-------+-------+-------+-------+-------+
| N                | 311   | 309   | 271   | 268   | 582   | 577   |
+------------------+-------+-------+-------+-------+-------+-------+
| Median           | 45.0  | 43.0  | 42.0  | 42.0  | 43.0  | 43.0  |
+------------------+-------+-------+-------+-------+-------+-------+
| Range            | 24-80 | 28-70 | 17-76 | 21-72 | 17-80 | 21-72 |
+------------------+-------+-------+-------+-------+-------+-------+
| > Subgroups \[N  |       |       |       |       |       |       |
| > (%)\]          |       |       |       |       |       |       |
+------------------+-------+-------+-------+-------+-------+-------+
| > \<18           | 0     | 0     | 1     | 0     | 1     | 0     |
|                  |       |       | (0.4) |       | (0.2) |       |
+------------------+-------+-------+-------+-------+-------+-------+
| > 18 -- 40       | 86    | 94    | 115   | 118   | 201   | 212   |
|                  | (     | (     | (     | (     | (     | (     |
|                  | 27.7) | 30.4) | 42.4) | 44.0) | 34.5) | 36.7) |
+------------------+-------+-------+-------+-------+-------+-------+
| > 41 -- 55       | 191   | 190   | 128   | 122   | 319   | 312   |
|                  | (     | (     | (     | (     | (     | (     |
|                  | 61.4) | 61.5) | 47.2) | 45.5) | 54.8) | 54.1) |
+------------------+-------+-------+-------+-------+-------+-------+
| > 56 -- 64       | 29    | 23    | 25    | 21    | 54    | 44    |
|                  | (9.3) | (7.4) | (9.2) | (7.8) | (9.3) | (7.6) |
+------------------+-------+-------+-------+-------+-------+-------+
| >                | 5     | 2     | 2     | 7     | 7     | 9     |
| [\>]{.underline} | (1.6) | (0.6) | (0.7) | (2.6) | (1.2) | (1.6) |
| > 65             |       |       |       |       |       |       |
+------------------+-------+-------+-------+-------+-------+-------+
| Gender \[N (%)\] |       |       |       |       |       |       |
+------------------+-------+-------+-------+-------+-------+-------+
| Male             | 278   | 287   | 225   | 229   | 503   | 516   |
|                  | (     | (     | (     | (     | (     | (     |
|                  | 89.4) | 92.9) | 83.0) | 85.4) | 86.4) | 89.4) |
+------------------+-------+-------+-------+-------+-------+-------+
| Female           | 33    | 22    | 46    | 39    | 79    | 61    |
|                  | (     | (7.1) | (     | (     | (     | (     |
|                  | 10.6) |       | 17.0) | 14.6) | 13.6) | 10.6) |
+------------------+-------+-------+-------+-------+-------+-------+
| Race \[N (%)\]   |       |       |       |       |       |       |
+------------------+-------+-------+-------+-------+-------+-------+
| White            | 241   | 235   | 189   | 179   | 430   | 414   |
|                  | (     | (     | (     | (     | (     | (     |
|                  | 77.5) | 76.1) | 69.7) | 66.8) | 73.9) | 71.8) |
+------------------+-------+-------+-------+-------+-------+-------+
| Black            | 68    | 69    | 15    | 11    | 83    | 80    |
|                  | (     | (     | (5.5) | (4.1) | (     | (     |
|                  | 21.9) | 22.3) |       |       | 14.3) | 13.9) |
+------------------+-------+-------+-------+-------+-------+-------+
| Asian            | 2     | 5     | 2     | 3     | 4     | 8     |
|                  | (0.6) | (1.6) | (0.7) | (1.1) | (0.7) | (1.4) |
+------------------+-------+-------+-------+-------+-------+-------+
| Not Collected^b^ | 0     | 0     | 65    | 75    | 65    | 75    |
|                  |       |       | (     | (     | (     | (     |
|                  |       |       | 24.0) | 28.0) | 11.2) | 13.0) |
+------------------+-------+-------+-------+-------+-------+-------+
| Median baseline  | 4.81  | 4.84  | 4.84  | 4.81  | 4.83  | 4.82  |
| HIV-1 RNA        |       |       |       |       |       |       |
| \[log~10~        |       |       |       |       |       |       |
| copies/mL\]      |       |       |       |       |       |       |
+------------------+-------+-------+-------+-------+-------+-------+
| Median baseline  | 123   | 123   | 175   | 200   | 155   | 158   |
| CD4+ cell count  |       |       |       |       |       |       |
| \[cells/mm^3^\]  |       |       |       |       |       |       |
+------------------+-------+-------+-------+-------+-------+-------+

a FAS, full analysis set of patients in 24-week efficacy analyses. The
reader is cautioned against making comparison to the Summary of Clinical
Safety Module 2.7.4 since the FAS used here includes patients who could
have achieved 24 weeks of treatment whereas the Summary of Clinical
Safety uses the all treated population.

b In France, race data collection not allowed.

Patients enrolled in the RESIST trials were highly treatment
experienced, with a history of using a median of 12 ARVs before entry
into the trial (Table 6.3.1: 3). More than 70% of patients had used four
or more PIs, although PI use was slightly lower in RESIST-2. The median
number of NRTIs that had been used was 6 (range 2-8) and the median
number of NNRTIs was 1 (range 0-3), thus representing a population of
patients with extensive ARV treatment experience and few ARV options
with which to construct a viable regimen. Enfuvirtide had been
previously used by 12% of patients. There were no differences between
treatment groups in past ARV use within the combined study population.

Table 6.3.1: 3 Number of antiretroviral agents used prior to study
randomization, by class -- RESIST trials (FAS a)

+--------------+--------+--------+--------+--------+--------+--------+
|              | RE     |        | RE     |        | Co     |        |
|              | SIST-1 |        | SIST-2 |        | mbined |        |
|              |        |        |        |        | RESIST |        |
|              | BI     |        | BI     |        | Trials |        |
|              | 1      |        | 1      |        |        |        |
|              | 182.12 |        | 182.48 |        |        |        |
+==============+========+========+========+========+========+========+
|              | TPV/r  | CPI/r  | TPV/r  | CPI/r  | TPV/r  | CPI/r  |
+--------------+--------+--------+--------+--------+--------+--------+
| Total        | 311    | 309    | 271    | 268    | 582    | 577    |
| treated      |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| Total of all |        |        |        |        |        |        |
| ARVs         |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| Median       | 12     | 12     | 12     | 12     | 12     | 12     |
+--------------+--------+--------+--------+--------+--------+--------+
| Range        | 3-19   | 4-20   | 4-18   | 3-18   | 3-19   | 3-20   |
+--------------+--------+--------+--------+--------+--------+--------+
| ENF          |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| N (%)        | 39     | 37     | 30     | 31     | 69     | 68     |
|              | (12.5) | (12.0) | (11.1) | (11.6) | (11.9) | (11.8) |
+--------------+--------+--------+--------+--------+--------+--------+
| PIs b        |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| Median       | 4      | 4      | 4      | 4      | 4      | 4      |
+--------------+--------+--------+--------+--------+--------+--------+
| Range        | 1-7    | 1-7    | 1-7    | 1-7    | 1-7    | 1-7    |
+--------------+--------+--------+--------+--------+--------+--------+
| > Subgroups\ |        |        |        |        |        |        |
| > \[N (%)\]  |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| > 1          | 2      | 6      | 3      | 4      | 5      | 10     |
|              | (0.6)  | (1.9)  | (1.1)  | (1.5)  | (0.9)  | (1.7)  |
+--------------+--------+--------+--------+--------+--------+--------+
| > 2          | 25     | 18     | 26     | 34     | 51     | 52     |
|              | (8.0)  | (5.8)  | (9.6)  | (12.7) | (8.8)  | (9.0)  |
+--------------+--------+--------+--------+--------+--------+--------+
| > 3          | 50     | 54     | 54     | 52     | 104    | 106    |
|              | (16.1) | (17.5) | (19.9) | (19.4) | (17.9) | (18.4) |
+--------------+--------+--------+--------+--------+--------+--------+
| > 4          | 87     | 77     | 76     | 66     | 163    | 143    |
|              | (28.0) | (24.9) | (28.0) | (24.6) | (28.0) | (24.8) |
+--------------+--------+--------+--------+--------+--------+--------+
| > [\>]       | 147    | 154    | 112    | 112    | 259    | 266    |
| {.underline} | (47.3) | (49.8) | (41.3) | (41.8) | (44.5) | (46.1) |
| > 5          |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| NRTIs        |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| Median       | 6      | 6      | 6      | 6      | 6      | 6      |
+--------------+--------+--------+--------+--------+--------+--------+
| Range        | 2-8    | 2-8    | 2-8    | 2-8    | 2-8    | 2-8    |
+--------------+--------+--------+--------+--------+--------+--------+
| NNRTIs       |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| Median       | 2      | 1      | 1      | 1      | 1      | 1      |
+--------------+--------+--------+--------+--------+--------+--------+
| Range        | 0-3    | 0-3    | 0-3    | 0-3    | 0-3    | 0-3    |
+--------------+--------+--------+--------+--------+--------+--------+

a FAS, full analysis set of patients in 24-week efficacy analyses

b RTV was only counted if given at a therapeutic dose.

6.3.1.1 Baseline genotypic resistance

The combined RESIST population was well balanced between treatment
groups for the frequencies of protease gene mutations, per-protocol
primary protease mutations, and number of mutations at codons 33, 82,
84, or 90 (Table 6.3.1: 4). The median number of protease gene
mutations, defined as any change deviation from the Los Alamos database
consensus sequence for HIV-1 subtype B, was 16 for the combined
population. Patients in both treatment groups in both trials had a
median of three per-protocol protease gene mutations (defined as
mutations at codons 30, 33, 46, 48, 50, 82, 84, or 90). The majority of
patients (\~65%) entering the trial had mutations at two of the key
protease mutations 33, 82, 84, or 90. Patients with three or more
mutations at these key positions could enter the companion BI 1182.51
although a small number were enrolled in the RESIST trials and were
categorized as protocol deviations and not major violations. Overall,
the mutation patterns seen in the RESIST population describe a
PI-experienced population, and one in which there was broad resistance
to the commercially available agents including available PIs.

Table 6.3.1: 4 Distribution of baseline protease gene mutations --
RESIST trials (FAS a)

+------------------+-------+-------+-------+-------+-------+-------+
|                  | RES   |       | RES   |       | Com   |       |
|                  | IST-1 |       | IST-2 |       | bined |       |
|                  |       |       |       |       | R     |       |
|                  | BI    |       | BI    |       | ESIST |       |
|                  | 11    |       | 11    |       | T     |       |
|                  | 82.12 |       | 82.48 |       | rials |       |
+==================+=======+=======+=======+=======+=======+=======+
|                  | TPV/r | CPI/r | TPV/r | CPI/r | TPV/r | CPI/r |
+------------------+-------+-------+-------+-------+-------+-------+
| Total treated    | 311   | 309   | 271   | 268   | 582   | 577   |
|                  | (1    | (1    | (1    | (1    | (1    | (1    |
|                  | 00.0) | 00.0) | 00.0) | 00.0) | 00.0) | 00.0) |
+------------------+-------+-------+-------+-------+-------+-------+
| No. of protease  |       |       |       |       |       |       |
| gene mutations b |       |       |       |       |       |       |
+------------------+-------+-------+-------+-------+-------+-------+
| Median           | 15    | 15    | 16    | 16    | 16    | 16    |
+------------------+-------+-------+-------+-------+-------+-------+
| > Subgroups \[N  |       |       |       |       |       |       |
| > (%)\]          |       |       |       |       |       |       |
+------------------+-------+-------+-------+-------+-------+-------+
| >                | 70    | 79    | 47    | 42    | 117   | 121   |
| [\<]{.underline} | (     | (     | (     | (     | (     | (     |
| > 12             | 22.5) | 25.6) | 17.3) | 15.7) | 20.1) | 21.0) |
+------------------+-------+-------+-------+-------+-------+-------+
| > 13 -- 15       | 90    | 86    | 70    | 74    | 160   | 160   |
|                  | (     | (     | (     | (     | (     | (     |
|                  | 28.9) | 27.8) | 25.8) | 27.6) | 27.5) | 27.7) |
+------------------+-------+-------+-------+-------+-------+-------+
| > 16 -- 18       | 93    | 78    | 88    | 76    | 181   | 154   |
|                  | (     | (     | (     | (     | (     | (     |
|                  | 29.9) | 25.2) | 32.5) | 28.4) | 31.1) | 26.7) |
+------------------+-------+-------+-------+-------+-------+-------+
| >                | 57    | 66    | 66    | 76    | 123   | 142   |
| [\>]{.underline} | (     | (     | (     | (     | (     | (     |
| > 19             | 18.3) | 21.4) | 24.4) | 28.4) | 21.1) | 24.6) |
+------------------+-------+-------+-------+-------+-------+-------+
| > Missing        | 1     | 0     | 0     | 0     | 1     | 0     |
|                  | (0.3) |       |       |       | (0.2) |       |
+------------------+-------+-------+-------+-------+-------+-------+
| No. of protease  |       |       |       |       |       |       |
| mutations at 33, |       |       |       |       |       |       |
| 82, 84, 90 \[N   |       |       |       |       |       |       |
| (%)\]            |       |       |       |       |       |       |
+------------------+-------+-------+-------+-------+-------+-------+
| 0                | 11    | 13    | 12    | 7     | 23    | 20    |
|                  | (3.5) | (4.2) | (4.4) | (2.6) | (4.0) | (3.5) |
+------------------+-------+-------+-------+-------+-------+-------+
| 1                | 91    | 77    | 74    | 83    | 165   | 160   |
|                  | (     | (     | (     | (     | (     | (     |
|                  | 29.3) | 24.9) | 27.3) | 31.0) | 28.4) | 27.7) |
+------------------+-------+-------+-------+-------+-------+-------+
| 2                | 192   | 204   | 182   | 174   | 374   | 378   |
|                  | (     | (     | (     | (     | (     | (     |
|                  | 61.7) | 66.0) | 67.2) | 64.9) | 64.3) | 65.5) |
+------------------+-------+-------+-------+-------+-------+-------+
| Subtotal         | 294   | 294   | 268   | 264   | 562   | 558   |
| [\<]{.underline} | (     | (     | (     | (     | (     | (     |
| 2                | 94.5) | 95.1) | 98.9) | 98.5) | 96.6) | 96.7) |
+------------------+-------+-------+-------+-------+-------+-------+
| 3                | 16    | 15    | 2     | 4     | 18    | 19    |
|                  | (5.1) | (4.9) | (0.7) | (1.5) | (3.1) | (3.3) |
+------------------+-------+-------+-------+-------+-------+-------+
| 4                | 0     | 0     | 1     | 0     | 1     | 0     |
|                  |       |       | (0.4) |       | (0.2) |       |
+------------------+-------+-------+-------+-------+-------+-------+
| Missing          | 1     | 0     | 0     | 0     | 1     | 0     |
|                  | (0.3) |       |       |       | (0.2) |       |
+------------------+-------+-------+-------+-------+-------+-------+

a FAS, full analysis set of patients in 24-week efficacy analyses

b Protease gene mutations include any deviation from Los Alamos database
consensus sequence for subtype B

6.3.1.2 Baseline phenotypic resistance

Although baseline phenotypic testing was not performed in real time and
results were therefore not available to investigators to determine
patient eligibility or to make baseline drug choices, these data were
later obtained on a randomly selected sub-set of the patients
participating in the RESIST studies. These data showed high level
phenotypic resistance of the baseline HIV-1 isolates against each of the
currently marketed PIs with the majority of isolates remaining sensitive
to TPV.

The median IC~50~ fold-change for each PI tested was:

-   Tipranavir (n=454) 1.7

-   Lopinavir (n=452) 87.4

-   Indinavir (n=423) 41.0

-   Saquinavir (n=450) 20.1

-   Amprenavir (n=445) 12.2

-   Nelfinavir (n=452) 40.7

-   Ritonavir (n=449) 194.7

-   Atazanavir (n=456) 55.3.

[]{#__RefHeading___Toc101398941 .anchor}6.3.2 Pre-selection of
comparator PI and enfuvirtide

[]{#__RefHeading___Toc101398942 .anchor}6.3.2.1 Stratification by
pre-selected PI and enfuvirtide use

In the RESIST studies, investigators had the option to pre-select a
comparator PI that was either new or ongoing. A new PI was one that was
not in use at the time of randomization, but could have been recycled
from a previous regimen. Investigators also had the option to pre-select
a genotypically available or a genotypically resistant PI. Where
possible, investigators pre-selected a genotypically available PI for
use in the CPI/r arms, but when the baseline genotype report provided an
interpretation that there was no PI that was genotypically available,
investigators could pre-select a PI that was considered genotypically
resistant.

The resistance expert consultant panel was made available to assist
investigators in interpreting the actual mutation pattern provided on
the genotype report and to select an optimal PI for use in the CPI/r arm
in context with the patient\'s treatment history.

The comparator PIs pre-selected by investigators and the use of a "new"
CPI/r is provided in Table 6.3.2.1: 1. LPV/r was the most common
comparator PI pre-selected (50.3%), followed by APV/r (25.8%), SQV/r
(20.5%), and IDV/r (3.5%). Nearly two thirds of patients had a "new"
CPI/r pre-selected, indicating that it was not the PI that the patient
had been taking at the time of randomization. Of those who actually
received treatment in the CPI/r arms, the PI used was "new" for 122/290
(42.1%) of those receiving LPV/r, 17/20 (85.0%) of those receiving
IDV/r, 97/118 (82.2%) of those receiving SQV/r, and 127/149 (85.2) of
those receiving APV/r.

**Table 6.3.2.1: 1 Summary of patient treatment with respect to PI
strata and use of a new PI -- RESIST trials (FAS)**

  ------------------------------------------------------------------------
                                       Total             
  ------------------------------------ ----------------- -----------------
                                       TPV/r             CPI/r

                                       N   (%)           N   (%)

  Total                                582 (100.0)       577 (100.0)

  PI strata                                              

  LPV                                  293 (50.3)        290 (50.3)

  IDV                                  21 (3.6)          20 (3.5)

  SQV                                  117 (20.1)        118 (20.5)

  APV                                  151 (25.9)        149 (25.8)

  New pre-selected PI                  375 (64.4)        363 (62.9)

  New pre-selected PI by strata                          

  LPV                                  128 (22.0)        122 (21.1)

  IDV                                  20 (3.4)          17 (2.9)

  SQV                                  96 (16.5)         97 (16.8)

  APV                                  131 (22.5)        127 (22.0)
  ------------------------------------------------------------------------

The pre-selected use of enfuvirtide by investigators is provided in
Table 6.3.2.1: 2. Overall, 158/582 (27.1%) of patients receiving TPV/r
also used enfuvirtide and 128/577 (22.2%) of patients receiving CPI/r
also used enfuvirtide.

**Table 6.3.2.1: 2 Summary of patient treatment with respect to
enfuvirtide use by PI strata -- RESIST trials (FAS)**

  ------------------------------------------------------------------------
                                       Total             
  ------------------------------------ ----------------- -----------------
                                       TPV/r             CPI/r

                                       N   (%)           N   (%)

  Total                                582 (100.0)       577 (100.0)

  Total ENF use                        158 (27.1)        128 (22.2)

  ENF use by strata                                      

  LPV                                  85 (14.6)         71 (12.3)

  IDV                                  8 (1.4)           3 (0.5)

  SQV                                  37 (6.4)          32 (5.5)

  APV                                  28 (4.8)          22 (3.8)
  ------------------------------------------------------------------------

It is important to note that patients who pre-selected enfuvirtide had
different baseline characteristics than those patients who did not.
Table 6.3.2.1: 3 provides the baseline data of those patients who
pre-selected enfuvirtide and those who did not. In general, patients
pre-selected enfuvirtide had higher baseline viral load, lower CD4
count, more prior ARV drug use, and more baseline drug resistance than
patients who did not pre-select enfuvirtide.

Table 6.3.2.1: 3 Baseline demographic data and HIV characteristics of
patients receiving or not receiving enfuvirtide -- RESIST trials (FAS)

+------------------------+------------+----------+---------+---------+
|                        | Receiving  |          | Not     |         |
|                        | ENF        |          | Re      |         |
|                        |            |          | ceiving |         |
|                        |            |          | ENF     |         |
+========================+============+==========+=========+=========+
|                        | TPV/r      | CPI/r    | TPV/r   | CPI/r   |
+------------------------+------------+----------+---------+---------+
| Total treated          | 158        | 128      | 424     | 449     |
+------------------------+------------+----------+---------+---------+
| Median baseline HIV-1  | 5.07       | 5.10     | 4.74    | 4.75    |
| RNA \[log~10~          |            |          |         |         |
| copies/mL\]            |            |          |         |         |
+------------------------+------------+----------+---------+---------+
| Median baseline CD4+   | 72         | 77       | 177     | 182     |
| cell count             |            |          |         |         |
| \[cells/mm^3^\]        |            |          |         |         |
+------------------------+------------+----------+---------+---------+
| Median ARV use (range) | 13 (8-19)  | 14       | 11      | 11      |
|                        |            | (4-20)   | (3-18)  | (3-19)  |
+------------------------+------------+----------+---------+---------+
| > Median prior PI use  | 5 (2-7)    | 5 (1-7)  | 4 (1-7) | 4 (1-7) |
| > (range)              |            |          |         |         |
+------------------------+------------+----------+---------+---------+
| > Median NRTI use      | 6 (3-8)    | 6 (2-8)  | 6 (2-8) | 6 (2-8) |
| > (range)              |            |          |         |         |
+------------------------+------------+----------+---------+---------+
| > Median NNRTI use     | 2 (0-3)    | 2 (0-3)  | 1 (0-3) | 1 (0-3) |
| > (range)              |            |          |         |         |
+------------------------+------------+----------+---------+---------+
| Median number of       | 17         | 17       | 15      | 15      |
| protease gene          |            |          |         |         |
| mutations a            |            |          |         |         |
+------------------------+------------+----------+---------+---------+
| Mutations at 33, 82,   |            |          |         |         |
| 84, 90 \[N, (%)\]      |            |          |         |         |
+------------------------+------------+----------+---------+---------+
| 0                      | 4 (2.5)    | 1 (0.8)  | 19      | 19      |
|                        |            |          | (4.5)   | (4.2)   |
+------------------------+------------+----------+---------+---------+
| 1                      | 31 (19.6)  | 25       | 134     | 135     |
|                        |            | (19.5)   | (31.6)  | (30.1)  |
+------------------------+------------+----------+---------+---------+
| 2                      | 114 (72.2) | 95       | 260     | 283     |
|                        |            | (74.2)   | (61.3)  | (63.0)  |
+------------------------+------------+----------+---------+---------+
| 3                      | 9 (5.7)    | 7 (5.5)  | 9 (2.1) | 12      |
|                        |            |          |         | (2.7)   |
+------------------------+------------+----------+---------+---------+
| 4                      | 0 (0.0)    | 0 (0.0)  | 1 (0.2) | 0 (0.0) |
+------------------------+------------+----------+---------+---------+

a Protease gene mutations include any deviation from Los Alamos database
consensus sequence for subtype B

2.  Use of new vs. ongoing or susceptible vs. resistant comparator PIs

Overall, most patients who randomized to the CPI/r arms (62.9%) of the
RESIST studies used a new PI, one that was not being used at the time of
randomization. These data are shown in table 6.3.2.2: 1. In contrast,
most patients who randomized to the CPI/r arms (66.7%) of the RESIST
studies used a PI that was considered "resistant" in the interpretation
of the baseline genotype report. These data are also shown in Table
6.3.2.2: 1.

Table 6.3.2.2: 1 Choice of pre-selected PI as new or ongoing and
resistance interpretation from the genotype report -- RESIST trials
(FAS)

+----------------------------------+--------+--------+-----+---------+
|                                  | TPV/r  |        | CP  |         |
|                                  |        |        | I/r |         |
+==================================+========+========+=====+=========+
|                                  | N      | (%)    | N   | (%)     |
+----------------------------------+--------+--------+-----+---------+
| Total treated                    | 582    | (      | 577 | (100.0) |
|                                  |        | 100.0) |     |         |
+----------------------------------+--------+--------+-----+---------+
| New or ongoing pre-selected PI   |        |        |     |         |
+----------------------------------+--------+--------+-----+---------+
| New PI                           | 375    | (64.4) | 363 | (62.9)  |
+----------------------------------+--------+--------+-----+---------+
| Ongoing PI                       | 207    | (35.6) | 214 | (37.1)  |
+----------------------------------+--------+--------+-----+---------+
| Resistance to pre-selected PI    |        |        |     |         |
+----------------------------------+--------+--------+-----+---------+
| Susceptible a                    | 76     | (13.1) | 80  | (13.9)  |
+----------------------------------+--------+--------+-----+---------+
| Possibly                         | 135    | (23.2) | 112 | (19.4)  |
|                                  |        |        |     |         |
| > Resistant b                    |        |        |     |         |
+----------------------------------+--------+--------+-----+---------+
| Resistant c                      | 369    | (63.4) | 385 | (66.7)  |
+----------------------------------+--------+--------+-----+---------+
| Missing                          | 2      | (0.3)  | 0   |         |
+----------------------------------+--------+--------+-----+---------+
| Genotypically available and new  | 152    | (26.1) | 140 | (24.3)  |
| pre-selected PI                  |        |        |     |         |
+----------------------------------+--------+--------+-----+---------+

> a TruGene®: No evidence of resistance. Virtual Phenotype™: within
> normal susceptibility range or resistance unlikely; for IDV
> [\<]{.underline} 3.0, for SQV [\<]{.underline} 2.5, for APV
> [\<]{.underline} 2.0, and for LPV \<10.
>
> b TruGene®: Possible resistance. Virtual Phenotype™: for LPV only 10
> to \<40.
>
> c TruGene®: Resistance. Virtual Phenotype™: resistance or resistance
> likely as defined by being above normal susceptibility range; for IDV
> \>3.0, for SQV \>2.5, for APV \>2.0, and for LPV [\>]{.underline} 40.

[]{#__RefHeading___Toc101398943 .anchor}6.3.3 Differences between RESIST
studies

There were several noteworthy differences between the RESIST trials. One
difference was a higher frequency of new pre-selected PIs in the
RESIST-2 study (70.3% for both treatment groups combined) than in the
RESIST-1 study (57.9% for both treatment groups combined). The
difference might have been a result of more patients in the RESIST-2
trial not having exhausted all of their PI options; whereas more
patients in the RESIST-1 trial had used five or more PIs before
screening. Another difference between the trials concerned the genotypic
resistance interpretation, with more patients in the RESIST-2 trial
(73.8%) than patients in the RESIST-1 trial (57.4%) testing resistant to
the pre-selected PI. This difference may be attributed to geographic
differences in treatment strategies or due to the different algorithms
used by the resistance testing laboratories, TruGene® (exclusively used
in RESIST-1) and Virtual Phenotype™ (primarily used in RESIST-2). In
addition, the VIRCO Virtual Phenotype™ interpretation used only one
cut-off for all PIs except LPV.

Enfuvirtide was used more frequently in the RESIST-1 trial (38.3% of the
TPV/r group and 34.0% of the CPI/r group) than in the RESIST-2 trial
(only 14.4% in the TPV/r group and 8.6% in the CPI/r group). In the
integrated analyses, 27.1% of TPV/r patients and 22.2% of CPI/r patients
received E concomitantly with study medication. Enfuvirtide was most
frequently co-administrated with LPV in the comparator arm. The lower
use of enfuvirtide in the RESIST-2 trial was due to the limited access
to the drug in Europe and Latin America at the time the trial was
recruiting patients. Patients taking enfuvirtide differed from patients
not taking enfuvirtide for median VL (higher), median CD4+ cell count
(lower), prior ARV medication use (more), and median number of protease
gene mutations (more). The differences between enfuvirtide and
non-enfuvirtide users were similar for TPV/r and CPI/r patients for all
of these characteristics

[]{#__RefHeading___Toc101398944 .anchor}6.3.4 Patient disposition

Of the 1,159 randomized patients, 475 (81.6%) in the TPV/r group and 247
(42.8%) in the CPI/r group completed Week 24 (Table 6.3.4: 1). This
difference between treatment groups was driven by early trial
discontinuation because of lack of virologic response in the CPI/r
group.[^18]

A higher level of patients in the CPI/r arms had missing or incomplete
data at Week 24 than in the TPV/r arms. This higher number of patients
with missing or incomplete data appears to reflect the fact that more
patients in the CPI/r discontinued than patients in the TPV/r arms.

Table 6.3.4: 1 Patient disposition -- RESIST trials (FAS)

+---------------+--------+--------+--------+-------+-------+--------+
|               | RE     |        | RE     |       | Com   |        |
|               | SIST-1 |        | SIST-2 |       | bined |        |
|               |        |        |        |       | R     |        |
|               | Trial  |        | Trial  |       | ESIST |        |
|               | BI     |        | BI     |       | T     |        |
|               | 1      |        | 1      |       | rials |        |
|               | 182.12 |        | 182.48 |       |       |        |
+---------------+--------+--------+--------+-------+-------+--------+
|               | TPV/r  | CPI/r  | TPV/r  | CPI/r | TPV/r | CPI/r  |
+---------------+--------+--------+--------+-------+-------+--------+
|               | N      | N      | N      | N (%) | N     | N      |
|               |    (%) |    (%) |    (%) |       |   (%) |    (%) |
+---------------+--------+--------+--------+-------+-------+--------+
| > Total       | 311    | 309    | 271    | 268   | 582   | 577    |
| > treated     | (      | (      | (      | (1    | (1    | (      |
|               | 100.0) | 100.0) | 100.0) | 00.0) | 00.0) | 100.0) |
+---------------+--------+--------+--------+-------+-------+--------+
| > Completing  | 263    | 151    | 212    | 96    | 475   | 247    |
| > to\         | (84.6) | (48.9) | (78.2) | (     | (     | (42.8) |
| > Week 24     |        |        |        | 35.8) | 81.6) |        |
+---------------+--------+--------+--------+-------+-------+--------+
| > Missing or  | 0      | 19     | 9      | 48    | 9     | 67     |
| > incomplete  | (0.0)  | (6.1)  | (3.3)  | (     | (1.5) | (11.6) |
| > data at     |        |        |        | 17.9) |       |        |
| > Week 24 a   |        |        |        |       |       |        |
+---------------+--------+--------+--------+-------+-------+--------+
| > Study drug  | 48     | 139    | 50     | 124   | 98    | 263    |
| >             | (15.4) | (45.0) | (18.5) | (     | (     | (45.6) |
|  discontinued |        |        |        | 46.3) | 16.8) |        |
| > prematurely |        |        |        |       |       |        |
+---------------+--------+--------+--------+-------+-------+--------+

a Missing or incomplete at Week 24 consists of two subgroups of
patients. The first subgroup had a premature discontinuation of the
study based on the end of treatment case report form page filled out
with a date up to Day 196, but no date or reason for the stop of study
medications was indicated on the protease inhibitor case report form
page. The second subgroup did neither have a documentation of a
premature discontinuation nor did it have documentation of continued use
of the study medication on the protease inhibitor case report form page
because this page was not received by BI for the Week 24 visit.

[]{#__RefHeading___Toc101398945 .anchor}6.3.5 Analysis of treatment
response: primary and secondary endpoints

[]{#__RefHeading___Toc101398946 .anchor}6.3.5.1 Treatment response

The primary endpoint for accelerated approval is treatment response
through Week 24. Treatment response is a composite primary endpoint of
the proportion of patients with two consecutive VL measurements \>1
log~10~ below baseline after 24 weeks of treatment without prior (1)
evidence of a confirmed virological failure, (2) introduction of a new
ARV to the regimen for reasons other than toxicity or intolerance to a
background drug, (3) permanent discontinuation of the study drug, (4)
death, or (5) loss to follow-up.

The primary endpoint treatment response is shown below in Table
6.3.5.1: 1. At 24 weeks, 41.2% of TPV/r patients achieved this confirmed
treatment response as compared with 18.9% of CPI/r patients (p
\<0.0001). This difference, adjusted for the stratification by PI strata
and enfuvirtide strata was 21.3%, with a lower limit of the two-sided
95% CI of 16.3% superiority (Table and Figure 6.3.2.1: 1).

The proportion of treatment responders in the TPV/r group was similar
across both the RESIST-1 and RESIST-2 studies, though a lower proportion
of CPI/r patients in RESIST-2 (14.9%) achieved a treatment response at
Week 24 than CPI/r patients in RESIST-1 (22.3%), which resulted in a
larger weighted treatment difference favoring TPV/r in RESIST-2
(Table 6.3.5.1: 1).

Table 6.3.5.1: 1 Primary endpoint treatment response (2 consecutive VL
measurements \>1 log~10~ below baseline) at Week 24 -- RESIST trials
(FAS)

  ----------------------------------------------------------------------------------------------------------------------
                        Treatment                                               Treatment Difference b          
                        Response a by                                                                           
                        Treatment Group                                                                         
  --------- ----------- ----------------- -------- ----- ------- -------- ----- ---------------------- -------- --------
                        TPV/r                            CPI/r                  Weighted               95% CI   

  Trial     Analysis    n                 (%)      N     n       (%)      N     Diff.\                 LL\      UL\
                                                                                (%)                    (%)      (%)

  1182.12   FAS (NCF)   129               (41.5)   311   69      (22.3)   309   (18.4)                 (11.4)   (25.3)

  1182.48   FASS24      111               (41.0)   271   40      (14.9)   268   (25.0)                 (17.8)   (32.2)
            (NCF)                                                                                               

  Total     FAS (NCF)   240               (41.2)   582   109     (18.9)   577   (21.3)                 (16.3)   (26.4)
  ----------------------------------------------------------------------------------------------------------------------

a Treatment response is the composite endpoint of the proportion of
patients with two consecutive VL measurements \>1 log~10~ below baseline
after 24 weeks without prior (1) evidence of a confirmed virological
failure, (2) introduction of a new ARV to the regimen for reasons other
than toxicity or intolerance to a background drug, (3) permanent
discontinuation of the study drug, (4) death, or (5) loss to follow-up

b Treatment difference and confidence interval weighted for the sizes of
ENF strata and PI strata.

n = number of responders, N = number of evaluable patients.

![](media/image4.wmf){width="5.05in" height="3.4493055555555556in"}

Figure 6.3.5.1: 1 Treatment response over time through 24 weeks --
Combined RESIST trials, (FAS \[NCF\])

24-week difference: p \<0.0001

For patients in the TPV/r treatment arms, the proportion of treatment
responders reached a peak at Week 4. At each time point the proportion
of treatment responders was larger among TPV/r patients than CPI/r
patients (p \<0.0001). At Week 24 the proportion of treatment responders
in the TPV/r group was larger than the peak proportion of responders in
the CPI/r group during the 24 weeks.

The primary reason for a lack of treatment response was lack of a
confirmed 1 log~10~ reduction below baseline, which occurred in 45.9% of
TPV/r patients and 71.4% of CPI/r patients (Table 6.3.5.1: 2). Specific
reasons that led to failure were (1) a 1 log~10~ drop from baseline
without confirmation; (2) viral load never being suppressed ;( 3)
rebound; and (4) a drug change or discontinuation due to virologic
failure. The two treatment groups differed especially for drug change or
discontinuation due to virologic failure, which occurred in 37.3% of
CPI/r patients and 6.4% of TPV/r patients and for viral rebound, which
occurred in 15.3% of TPV/r patients and 10.9% of CPI/r patients.

The higher rate of rebound in the TPV/r group is likely due to the fact
that there were more virologic responders in the TPV/r group and only
responders can show rebound.

Discontinuations of study medication due to AEs were more frequent in
the TPV/r group (8.1%) than CPI/r group (3.8%). The RESIST study design
may have contributed to this imbalance, as patients in the CPI/r arms
could leave the study to receive TPV/r in BI 1182.17 for virologic
failure, but not due to AEs. The rate of discontinuation for reasons
other than AEs (e.g., consent withdrawn, lost to follow-up) were
comparable between the two treatment groups, with 5.0% in the CPI/r
group and 3.8% in the TPV/r group.

Table 6.3.5.1: 2 Treatment outcomes at Week 24 -- RESIST trials (FAS
\[NCF\])

+-----------------+-------+-------+-------+-------+-------+-------+
|                 | RES   |       | RES   |       | Com   |       |
|                 | IST-1 |       | IST-2 |       | bined |       |
|                 |       |       |       |       | R     |       |
|                 | BI    |       | BI    |       | ESIST |       |
|                 | 11    |       | 11    |       | T     |       |
|                 | 82.12 |       | 82.48 |       | rials |       |
+=================+=======+=======+=======+=======+=======+=======+
|                 | T     | C     | T     | C     | T     | C     |
|                 | PV/r\ | PI/r\ | PV/r\ | PI/r\ | PV/r\ | PI/r\ |
|                 | N     | N     | N     | N     | N     | N     |
|                 |   (%) |   (%) |   (%) |   (%) |   (%) |   (%) |
+-----------------+-------+-------+-------+-------+-------+-------+
| Total treated   | 311   | 309   | 271   | 268   | 582   | 577   |
|                 | (1    | (1    | (1    | (1    | (1    | (1    |
|                 | 00.0) | 00.0) | 00.0) | 00.0) | 00.0) | 00.0) |
+-----------------+-------+-------+-------+-------+-------+-------+
| Primary         | 129   | 69    | 111   | 40    | 240   | 109   |
| endpoint        | (     | (     | (     | (     | (     | (     |
| treatment       | 41.5) | 22.3) | 41.0) | 14.9) | 41.2) | 18.9) |
| response at     |       |       |       |       |       |       |
| Week 24         |       |       |       |       |       |       |
+-----------------+-------+-------+-------+-------+-------+-------+
| No confirmed 1  | 140   | 209   | 127   | 203   | 267   | 412   |
| log~10~ drop    | (     | (     | (     | (     | (     | (     |
| from baseline   | 45.0) | 67.6) | 46.9) | 75.7) | 45.9) | 71.4) |
+-----------------+-------+-------+-------+-------+-------+-------+
| > 1 log~10~     | 31    | 16    | 19    | 16    | 50    | 32    |
| > drop from     | (     | (5.2) | (7.0) | (6.0) | (8.6) | (5.5) |
| > baseline      | 10.0) |       |       |       |       |       |
| > without       |       |       |       |       |       |       |
| > confirmation  |       |       |       |       |       |       |
+-----------------+-------+-------+-------+-------+-------+-------+
| Rebound a       | 51    | 39    | 38    | 24    | 89    | 63    |
|                 | (     | (     | (     | (9.0) | (     | (     |
|                 | 16.4) | 12.6) | 14.0) |       | 15.3) | 10.9) |
+-----------------+-------+-------+-------+-------+-------+-------+
| > Never         | 45    | 45    | 46    | 57    | 91    | 102   |
| > suppressed    | (     | (     | (     | (     | (     | (     |
| > through Week  | 14.5) | 14.6) | 17.0) | 21.3) | 15.6) | 17.7) |
| > 24            |       |       |       |       |       |       |
+-----------------+-------+-------+-------+-------+-------+-------+
| > Drug change   | 13    | 109   | 24    | 106   | 37    | 215   |
| > or            | (4.2) | (     | (8.9) | (     | (6.4) | (     |
| >               |       | 35.3) |       | 39.6) |       | 37.3) |
| discontinuation |       |       |       |       |       |       |
| > due to        |       |       |       |       |       |       |
| > virologic     |       |       |       |       |       |       |
| > failure b     |       |       |       |       |       |       |
+-----------------+-------+-------+-------+-------+-------+-------+
| Death c         | 5     | 3     | 1     | 2     | 6     | 5     |
|                 | (1.6) | (1.0) | (0.4) | (0.7) | (1.0) | (0.9) |
+-----------------+-------+-------+-------+-------+-------+-------+
| Study drug      | 25    | 9     | 22    | 13    | 47    | 22    |
| discontinuation | (8.0) | (2.9) | (8.1) | (4.9) | (8.1) | (3.8) |
| due to adverse  |       |       |       |       |       |       |
| events d        |       |       |       |       |       |       |
+-----------------+-------+-------+-------+-------+-------+-------+
| Study drug      | 12    | 19    | 10    | 10    | 22    | 29    |
| discontinuation | (3.9) | (6.1) | (3.7) | (3.7) | (3.8) | (5.0) |
| due to other    |       |       |       |       |       |       |
| reasons         |       |       |       |       |       |       |
+-----------------+-------+-------+-------+-------+-------+-------+
| Consent         | 3     | 3     | 3     | 2     | 6     | 5     |
| withdrawn       | (1.0) | (1.0) | (1.1) | (0.7) | (1.0) | (0.9) |
+-----------------+-------+-------+-------+-------+-------+-------+
| Loss to         | 4     | 4     | 0     | 0     | 4     | 4     |
| follow-up       | (1.3) | (1.3) |       |       | (0.7) | (0.7) |
+-----------------+-------+-------+-------+-------+-------+-------+
| Non-adherence   | 3     | 9     | 1     | 0     | 4     | 9     |
|                 | (1.0) | (2.9) | (0.4) |       | (0.7) | (1.6) |
+-----------------+-------+-------+-------+-------+-------+-------+
| Pregnancy       | 1     | 0     | 1     | 0     | 2     | 0     |
|                 | (0.3) |       | (0.4) |       | (0.3) |       |
+-----------------+-------+-------+-------+-------+-------+-------+
| Protocol        | 1     | 1     | 2     | 0     | 3     | 1     |
| violation       | (0.3) | (0.3) | (0.7) |       | (0.5) | (0.2) |
+-----------------+-------+-------+-------+-------+-------+-------+
| Other           | 0     | 2     | 3     | 8     | 3     | 10    |
|                 |       | (0.6) | (1.1) | (3.0) | (0.5) | (1.7) |
+-----------------+-------+-------+-------+-------+-------+-------+

a Confirmed loss of virologic response or loss of virologic response and
missing confirmatory visit.

b Includes premature discontinuation of the study PI due to virologic
failure and the addition of a drug to the background regimen (if not
introduced to replace a background drug discontinued due to AEs
attributable to the discontinued background drug).

c Death as primary reason for treatment failure.

d The reader is cautioned against making comparison to the Summary of
Clinical Safety Module 2.7.4 since the count used here is
discontinuation as reason for virologic failure and is based on the FAS
population whereas the Summary of Clinical Safety counts all treated
patients.

[]{#__RefHeading___Toc101398947 .anchor}6.3.5.2 Response by pre-selected
PI strata

Data from each of the two RESIST trials were combined to analyze
treatment response within each pre-selected PI stratum.

To evaluate the impact of the extensive treatment experience of patients
in the RESIST trials, analyses were conducted according to choice of the
pre-selected PI: whether the pre-selected PI was new to the study
regimen constructed at randomization (new PI), whether the virus was
susceptible to the PI or the PI was genotypically available based on
genotypic report interpretation of susceptible or possibly resistant, or
whether the PI was both new to the study regimen and virus was
susceptible or PI was genotypically available.

The TPV/r group had significantly greater treatment responses than
LPV/r, SQV/r, or APV/r groups and these data are provided in Table
6.3.5.2: 1. The IDV stratum had too few patients to make a valid
definitive comparison.

Table 6.3.5.2: 1 Treatment response at Week 24 by PI strata - RESIST
trials (FAS)

  ----------------------------------------------------------------------------------------------------------------------
                        Treatment Group                                         Treatment Difference a          
  -------- ------------ ----------------- -------- ----- ------- -------- ----- ---------------------- -------- --------
                        TPV/r                            CPI/r                  Weighted               95% CI   

  PI       Analysis     n                 (%)      N     n       (%)      N     Diff. (%)              LL\      UL\
  Strata                                                                                               (%)      (%)

  LPV      FAS (NCF)    116               (39.6)   293   62      (21.4)   290   (17.7)                 (10.5)   (25.0)

  IDV      FAS (NCF)    10                (47.6)   21    1       (5.0)    20    b                      b        b

  SQV      FAS (NCF)    51                (43.6)   117   18      (15.3)   118   (27.4)                 (16.5)   (38.3)

  APV      FAS (NCF)    63                (41.7)   151   28      (18.8)   149   (22.0)                 (12.1)   (31.9)
  ----------------------------------------------------------------------------------------------------------------------

n = Number of responders; N = Number of evaluable patients

a Treatment difference and confidence interval weighted for the size of
ENF strata and PI strata.

b Weighted difference and confidence interval not presented for the IDV
stratum due to small sample size.

**It is important for the reviewer to interpret these data cautiously.**
While the treatment response for patients receiving TPV/r was superior
to the treatment response of those receiving LPV/r, SQV/r, or APV/r, the
comparator PI being used was not always "new" and was not always
considered "genotypically available" on the baseline resistance report.
In the LPV/r stratum, for example, if the LPV/r was "new" the treatment
response was 45.3% in the TPV/r arm and 36.1% in the CPI/r arm (p=NS).
Alternatively, in the LPV/r stratum, if the LPV/r was "ongoing" the
treatment response was 35.2% in the TPV/r arm and 10.7% in the CPI/r
arm, a statistically significant result.

The response by status of pre-selected PI (new or ongoing) and whether
or not it was genotypically available[^19] *for the aggregate CPI/r
population* was examined and these data are provided in Table 6.3.5.2:
2. These data demonstrate that patients who pre-selected a "new" PI had
a superior treatment response if they received TPV/r than if they
received CPI/r. In addition, the data show that those patients who
pre-selected a "genotypically available" PI had a superior treatment
response if they received TPV/r than if they received CPI/r.

Table 6.3.5.2: 2 Treatment responses at Week 24 by choice of and
resistance to pre-selected PIs *for the aggregate CPI/r population* --
RESIST trials (FAS)

<table>
<colgroup>
<col style="width: 28%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 6%" />
<col style="width: 8%" />
<col style="width: 6%" />
<col style="width: 10%" />
<col style="width: 8%" />
<col style="width: 8%" />
</colgroup>
<thead>
<tr class="header">
<th></th>
<th colspan="6">Treatment Group</th>
<th colspan="3">Treatment Difference a</th>
</tr>
<tr class="odd">
<th></th>
<th colspan="3">TPV/r</th>
<th colspan="3">CPI/r</th>
<th>Weighted</th>
<th colspan="2">95% CI</th>
</tr>
<tr class="header">
<th></th>
<th>n</th>
<th>(%)</th>
<th>N</th>
<th>n</th>
<th>(%)</th>
<th>N</th>
<th>Diff.<br />
(%)</th>
<th>LL<br />
(%)</th>
<th>UL<br />
(%)</th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td>Pre-selected PI</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>New PI</td>
<td>165</td>
<td>(44.0)</td>
<td>375</td>
<td>88</td>
<td>(24.2)</td>
<td>363</td>
<td>(18.4)</td>
<td>(11.9)</td>
<td>(24.9)</td>
</tr>
<tr class="odd">
<td>Ongoing PI</td>
<td>75</td>
<td>(36.2)</td>
<td>207</td>
<td>21</td>
<td>(9.8)</td>
<td>214</td>
<td>(25.1)</td>
<td>(17.6)</td>
<td>(32.7)</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Resistance to pre-selected PI</p>
</blockquote></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Genotypically available a</p>
</blockquote></td>
<td>92</td>
<td>(43.6)</td>
<td>211</td>
<td>55</td>
<td>(28.6)</td>
<td>192</td>
<td>(14.2)</td>
<td>(5.0)</td>
<td>(23.3)</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Genotypically resistant</p>
</blockquote></td>
<td>147</td>
<td>(39.8)</td>
<td>369</td>
<td>54</td>
<td>(14.0)</td>
<td>385</td>
<td>(24.3)</td>
<td>(18.4)</td>
<td>(30.2)</td>
</tr>
<tr class="odd">
<td>Missing</td>
<td>1</td>
<td>(50.0)</td>
<td>2</td>
<td>0</td>
<td></td>
<td>0</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Genotypically available and new pre-selected CPI/r</td>
<td>70</td>
<td>(46.1)</td>
<td>152</td>
<td>46</td>
<td>(32.9)</td>
<td>140</td>
<td>(11.7)</td>
<td>(1.1)</td>
<td>(22.4)</td>
</tr>
</tbody>
</table>

n = number of responders, N = number of evaluable patients

a Treatment difference and confidence interval weighted for the size of
PI strata

Pre-specified secondary efficacy endpoints included viral load change
from baseline, proportion of patients with undetectable viral load (BLQ
400 copies/mL, BLQ 50 copies/mL, CD4 count change, and AIDS progression
events). These data are described in the following sections.

[]{#__RefHeading___Toc101398948 .anchor}6.3.5.3 Viral load change from
baseline at 24 weeks (FAS population)

Viral load reduction from baseline was rapid and substantial in the
TPV/r group (Figure 6.3.5.3: 1). For the TPV/r group, the peak median
change from baseline (LOCF) was ‑1.53 log~10~ copies/mL at Week 4. After
24 weeks of treatment, the median change in VL from baseline in the
combined RESIST trials was -0.80 log~10~ copies/mL for the TPV/r group
compared to -0.25 for the CPI/r group (p \<0.0001).

Table 6.3.5.3: 1 VL change from baseline at Week 24 -- RESIST trials
(FAS)

<table style="width:100%;">
<colgroup>
<col style="width: 14%" />
<col style="width: 5%" />
<col style="width: 8%" />
<col style="width: 5%" />
<col style="width: 8%" />
<col style="width: 5%" />
<col style="width: 8%" />
<col style="width: 5%" />
<col style="width: 8%" />
<col style="width: 5%" />
<col style="width: 8%" />
<col style="width: 5%" />
<col style="width: 9%" />
</colgroup>
<thead>
<tr class="header">
<th></th>
<th colspan="4"><p>RESIST-1</p>
<p>BI 1182.12</p></th>
<th colspan="4"><p>RESIST-2</p>
<p>BI 1182.48</p></th>
<th colspan="4">Combined RESIST Trials</th>
</tr>
<tr class="odd">
<th></th>
<th colspan="2">TPV/r</th>
<th colspan="2">CPI/r</th>
<th colspan="2">TPV/r</th>
<th colspan="2">CPI/r</th>
<th colspan="2">TPV/r</th>
<th colspan="2">CPI/r</th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td></td>
<td>N</td>
<td>Median</td>
<td>N</td>
<td>Median</td>
<td>N</td>
<td>Median</td>
<td>N</td>
<td>Median</td>
<td>N</td>
<td>Median</td>
<td>N</td>
<td>Median</td>
</tr>
<tr class="even">
<td>Baseline VL [log<sub>10</sub> copies/mL]</td>
<td>311</td>
<td>4.81</td>
<td>309</td>
<td>4.84</td>
<td>271</td>
<td>4.84</td>
<td>268</td>
<td>4.81</td>
<td>582</td>
<td>4.83</td>
<td>577</td>
<td>4.82</td>
</tr>
<tr class="odd">
<td>VL change (LOCF)</td>
<td>311</td>
<td>-0.88</td>
<td>309</td>
<td>-0.28</td>
<td>271</td>
<td>-0.72</td>
<td>268</td>
<td>-0.22</td>
<td>582</td>
<td>-0.80</td>
<td>577</td>
<td>-0.25</td>
</tr>
</tbody>
</table>

![](media/image5.wmf){width="5.125in" height="3.5006944444444446in"}

Figure 6.3.5.3: 1 Median log10 copies/mL change from baseline in viral
load through Week 24 in combined RESIST trials -- (FAS \[LOCF\])

24-week difference: p \<0.0001

[]{#__RefHeading___Toc101398949 .anchor}6.3.5.4 Virologic response (\<
400 and \< 50 copies/mL) and immunologic response at 24 weeks (FAS
population)

At Week 24, the proportion of patients who achieved a VL \< 400
copies/mL was greater among TPV/r patients (34.2%) than CPI/r patients
(14.9%), and the proportion of patients who achieved a VL \< 50
copies/mL was also greater among TPV/r patients (23.9%) than CPI/r
patients (9.4%) (p \<0.0001) (Table 6.3.5.4: 1; Figures 6.3.5.4: 1,
6.3.5.4: 2). Slightly larger proportions of CPI/r patients in RESIST-1
achieved responses of \< 400 copies/mL and \< 50 copies/mL compared with
CPI/r patients in RESIST-2.

Table 6.3.5.4: 1 Summary of Week 24 virologic response (\< 400 and \< 50
HIV RNA copies/mL) and immunologic response -- RESIST trials (FAS)

<table style="width:100%;">
<colgroup>
<col style="width: 15%" />
<col style="width: 5%" />
<col style="width: 8%" />
<col style="width: 5%" />
<col style="width: 8%" />
<col style="width: 5%" />
<col style="width: 8%" />
<col style="width: 5%" />
<col style="width: 8%" />
<col style="width: 5%" />
<col style="width: 8%" />
<col style="width: 5%" />
<col style="width: 8%" />
</colgroup>
<thead>
<tr class="header">
<th></th>
<th colspan="4"><p>RESIST-1</p>
<p>BI 1182.12</p></th>
<th colspan="4"><p>RESIST-2</p>
<p>BI 1182.48</p></th>
<th colspan="4">Combined RESIST Trials</th>
</tr>
<tr class="odd">
<th></th>
<th colspan="2">TPV/r</th>
<th colspan="2">CPI/r</th>
<th colspan="2">TPV/r</th>
<th colspan="2">CPI/r</th>
<th colspan="2">TPV/r</th>
<th colspan="2">CPI/r</th>
</tr>
<tr class="header">
<th></th>
<th>N</th>
<th>(%)</th>
<th>N</th>
<th>(%)</th>
<th>N</th>
<th>(%)</th>
<th>N</th>
<th>(%)</th>
<th>N</th>
<th>(%)</th>
<th>N</th>
<th>(%)</th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td>Total treated</td>
<td>311</td>
<td>(100.0)</td>
<td>309</td>
<td>(100.0)</td>
<td>271</td>
<td>(100.0)</td>
<td>268</td>
<td>(100.0)</td>
<td>582</td>
<td>(100.0)</td>
<td>577</td>
<td>(100.0)</td>
</tr>
<tr class="even">
<td>VL &lt; 400 copies/mL (NCF)</td>
<td>108</td>
<td>(34.7)</td>
<td>51</td>
<td>(16.5)</td>
<td>91</td>
<td>(33.6)</td>
<td>35</td>
<td>(13.1)</td>
<td>199</td>
<td>(34.2)</td>
<td>86</td>
<td>(14.9)</td>
</tr>
<tr class="odd">
<td>VL &lt; 50 copies/mL (NCF)</td>
<td>78</td>
<td>(25.1)</td>
<td>31</td>
<td>(10.0)</td>
<td>61</td>
<td>(22.5)</td>
<td>23</td>
<td>(8.6)</td>
<td>139</td>
<td>(23.9)</td>
<td>54</td>
<td>(9.4)</td>
</tr>
<tr class="even">
<td></td>
<td>N</td>
<td>Median</td>
<td>N</td>
<td>Median</td>
<td>N</td>
<td>Median</td>
<td>N</td>
<td>Median</td>
<td>N</td>
<td>Median</td>
<td>N</td>
<td>Median</td>
</tr>
<tr class="odd">
<td>Baseline CD4+ cell count [cells/mm<sup>3</sup>]</td>
<td>310</td>
<td>123</td>
<td>309</td>
<td>123</td>
<td>269</td>
<td>175</td>
<td>265</td>
<td>200</td>
<td>579</td>
<td>155</td>
<td>574</td>
<td>158</td>
</tr>
<tr class="even">
<td>Absolute change CD4+ cell count [cells/mm<sup>3</sup>] (LOCF)</td>
<td>310</td>
<td>36</td>
<td>309</td>
<td>6</td>
<td>269</td>
<td>31</td>
<td>265</td>
<td>1</td>
<td>579</td>
<td>34</td>
<td>574</td>
<td>4</td>
</tr>
</tbody>
</table>

![](media/image6.wmf){width="4.529861111111111in"
height="3.088888888888889in"}

Figure 6.3.5.4: 1 Virologic response (VL \< 400 copies/mL) over time
through 24 weeks in combined RESIST trials -- (FAS \[NCF\])

24-week difference: p \<0.0001

![](media/image7.wmf){width="4.981944444444444in"
height="3.4027777777777777in"}

Figure 6.3.5.4: 2 Virologic response (VL \< 50 copies/mL) over time
through 24 weeks in combined RESIST trials -- (FAS \[NCF\])

24-week difference: p \<0.0001

In the combined RESIST trials, TPV/r patients achieved a larger median
increase in CD4+ cell count (34 cells/mm^3^) than CPI/r patients (4
cells/mm^3^) at Week 24 (p \<0.0001) (Figure 6.3.5.4: 3). The mean
increase in the patients receiving TPV/r was 52 cells/mm^3^.

![](media/image8.wmf){width="5.155555555555556in"
height="3.5215277777777776in"}

Figure 6.3.5.4: 3 Median change from baseline in CD4+ cell count
(cells/mm^3^) in combined RESIST trials -- (FAS \[LOCF\])

24-week difference: p \<0.0001

[]{#__RefHeading___Toc101398950 .anchor}6.3.5.5 New onset of AIDS events

In the combined RESIST study population, the proportion of patients who
developed a new AIDS event was a secondary efficacy endpoint. The
frequency of AIDS events was 3.4% for patients in the TPV/r arms and
4.6% for patients in the CPI/r arms, despite a greater duration of
exposure in the TPV/r group. This difference did not achieve statistical
significance, an anticipated result as the study was not powered to
discriminate between treatment arms for this outcome.

[]{#__RefHeading___Toc101398951 .anchor}**6.3.6 Impact of active
background antiretroviral drugs**

The OBR of patients in the RESIST trials consisted predominantly of two
NRTIs, although some patients received up to 5 NRTIs. Overall, 52-57% of
the patients in the RESIST trials had 2 or more genotypically available
background ARVs to support the RTV-boosted protease (tipranavir or
comparator) in the regimen.

The genotypic sensitivity score (GSS) was the total number of drugs in
the OBR to which a patient's viral isolate showed genotypic sensitivity
according to the algorithmic interpretations of the TruGene® or *Virtual
Phenotype*™. By pre-established definition, enfuvirtide was always
considered genotypically available, even if enfuvirtide had been
previously administered, and it therefore counts in the calculation of
GSS for those patients who chose to use it as part of their ARV regimen.

Table 6.3.6: 1 Genotypic sensitivity score of the background regimen in
patients treated -- RESIST trials (FAS)

  ------------------------------------------------------------------------
                                             Total          
  ------------------------------------------ -------------- --------------
                                             TPV/r          CPI/r

  Total treated                              582            577

  Genotypic sensitivity score for OBR        N (%)          N (%)

  0                                          61 (10.5)      77 (13.3)

  1                                          190 (32.6)     186 (32.2)

  2                                          236 (40.5)     206 (35.7)

  [\>]{.underline} 3                         95 (16.3)      108 (18.7)
  ------------------------------------------------------------------------

As noted previously, enfuvirtide use was declared by investigators prior
to randomization and it could not be added after study treatment had
already been initiated. A total of 286 patients in the RESIST studies
used enfuvirtide in their treatment regimen; 27.1% in the TPV/r group
(158 of 582) and 22.2% in the CPI/r group (128 of 577).

For patients who used enfuvirtide, there was a higher treatment response
than for those who did not use it. The treatment response increased to
58.2% for those on TPV/r who used enfuvirtide and to 25.8% for those on
CPI/r who used the drug. For those not taking enfuvirtide, the
proportion of treatment responders was also twice as high in the TPV/r
group (34.9%) than in the CPI/r group (16.9%).

Even in the absence of enfuvirtide, a treatment response was achieved
with TPV/r in more than 40% of patients when used with 2 or more
background ARV drugs that were considered genotypically available at
baseline to the patient. A comparable response in patients treated with
CPI/r was achieved when the CPI/r drug was used with at least three
other genotypically available ARVs (GSS [\>]{.underline} 3).

Table 6.3.6: 2 Treatment responses at Week 24 according to enfuvirtide
use and number of sensitive background ARVs - RESIST trials (FAS
\[NCF\])

  -----------------------------------------------------------------------------------------------------------------
                     ENF                                                                                      
                     strata                                                                                   
  ------------------ -------- -------- ----- ------- -------- ----- --------- -------- ----- ------- -------- -----
                     With ENF                                       Without                                   
                                                                    ENF                                       

                     TPV/r                   CPI/r                  TPV/r                    CPI/r            

                     n        (%)      N     n       (%)      N     n         (%)      N     n       (%)      N

  Total              92       (58.2)   158   33      (25.8)   128   148       (34.9)   424   76      (16.9)   449

  Genotypic                                                                                                   
  sensitivity score                                                                                           
  for OBR a                                                                                                   

  0                  34       (57.6)   59    6       (13.6)   44    8         (13.1)   61    7       (9.1)    77

  1                  37       (55.2)   67    10      (23.8)   42    37        (28.2)   131   18      (12.7)   142

  2                  17       (68.0)   25    12      (38.7)   31    72        (42.6)   169   31      (18.9)   164

  [\>]{.underline} 3 4        (57.1)   7     5       (45.5)   11    31        (49.2)   63    20      (30.3)   66
  -----------------------------------------------------------------------------------------------------------------

n = number of responders, N = number of evaluable patients.

a ENF not counted; always considered susceptible.

Co-administration of enfuvirtide influenced other categories of
virologic response. Within both treatment groups, patients taking
enfuvirtide had higher proportions of responders achieving a reduction
in VL [\>]{.underline} 1 log~10~, a VL of \< 400 copies/mL, or a VL \<
50 copies/mL than patients not taking enfuvirtide.

Changes in VL and CD4+ cell count from baseline to Week 24 were also
influenced by enfuvirtide use even though these patients had a higher
baseline VL and lower CD4+ cell count. For patients taking enfuvirtide,
the median reduction in VL at Week 24 was -2.06 log~10~ copies/mL in the
TPV/r group and -0.40 log~10~ copies/mL in the CPI/r group; and for
patients not taking enfuvirtide the median reduction in VL at Week 24
was -0.57 log~10~ copies/mL in the TPV/r group and -0.20 log~10~
copies/mL in the CPI/r group. TPV/r patients taking enfuvirtide had a
median increase of 55 cells/mm^3^, while TPV/r patients not taking
enfuvirtide had a median increase of 27 cells/mm^3^; and CPI/r patients
taking enfuvirtide had a median increase of 6 cells/mm^3^, while CPI/r
patients not taking enfuvirtide had a median increase of 3 cells/mm^3^.

Table 6.3.6: 3 Summary of secondary efficacy endpoints at Week 24
according to enfuvirtide use - RESIST trials (FAS)

  -----------------------------------------------------------------------------------------------------
  Endpoint /\         ENF  Strata                                                              
  Genotypic                                                                                    
  sensitivity\                                                                                 
  score a                                                                                      
  ------------------- ------------- -------- -------- -------- ------------- -------- -------- --------
                      With ENF                                 Without ENF                     

                      TPV/r                  CPI/r             TPV/r                  CPI/r    

                      n/N           (%)      n/N      (%)      n/N           (%)      n/N      (%)

  VL [\>]{.underline} 93/158        (58.9)   35/128   (27.3)   161/424       (38.0)   83/449   (18.5)
  1 log~10~ reduction                                                                          
  (NCF)                                                                                        

  0                   0                      0                 9/61          (14.8)   7/77     (9.1)

  1                   34/59         (57.6)   6/44     (13.6)   41/131        (31.3)   19/142   (13.4)

  2                   38/67         (56.7)   10/42    (23.8)   79/169        (46.7)   35/164   (21.3)

  [\>]{.underline} 3  21/32         (65.6)   19/42    (45.2)   32/63         (50.8)   22/66    (33.3)

  VL \< 400 copies/mL 71/158        (44.9)   26/128   (20.3)   128/424       (30.2)   60/449   (13.4)
  (NCF)                                                                                        

  0                   0                      0                 7/61          (11.5)   4/77     (5.2)

  1                   24/59         (40.7)   5/44     (11.4)   31/131        (23.7)   13/142   (9.2)

  2                   28/67         (41.8)   9/42     (21.4)   66/169        (39.1)   24/164   (14.6)

  [\>]{.underline} 3  19/32         (59.4)   12/42    (28.6)   24/63         (38.1)   19/66    (28.8)

  VL \< 50 copies/mL  48/158        (30.4)   16/128   (12.5)   91/424        (21.5)   38/449   (8.5)
  (NCF)                                                                                        

  0                   0                      0                 3/61          (4.9)    2/77     (2.6)

  1                   18/59         (30.5)   4/44     (9.1)    21/131        (16.0)   9/142    (6.3)

  2                   16/67         (23.9)   3/42     (7.1)    48/169        (28.4)   16/164   (9.8)

  [\>]{.underline} 3  14/32         (43.8)   9/42     (21.4)   19/63         (30.2)   11/66    (16.7)

                      N             Median   N        Median   N             Median   N        Median

  Baseline VL         158           5.07     128      5.10     424           4.74     449      4.75
  \[log~10~                                                                                    
  copies/mL\]                                                                                  

  VL change \[log~10~ 158           -2.06    128      -0.40    424           -0.57    449      -0.20
  copies/mL\] (LOCF)                                                                           

  Baseline CD4+ cell  158           72       127      77       421           177      447      182
  count                                                                                        
  \[cells/mm^3^\]                                                                              

  Absolute change in  158           55       127      6        421           27       447      3
  CD4+ cell count                                                                              
  \[cells/mm^3^\]                                                                              
  (LOCF)                                                                                       
  -----------------------------------------------------------------------------------------------------

a ENF not counted; always considered susceptible.

The number of patients with prior enfuvirtide treatment experience was
69/582 (11.9%) in the TPV/r arms and 68/577 (11.8%) in the CPI/r arms. A
greater percentage of those patients without prior enfuvirtide
experience achieved a treatment response.

The greatest response was seen in patients who were enfuvirtide naïve
and received the combination of TPV/r and enfuvirtide where nearly 70%
achieved a treatment response.

Table 6.3.6: 4 Treatment response by prior enfuvirtide use

  --------------- --------- ---------- ------- ------- ------------ --------
                  TPV/r                        CPI/r                

  ENF Use         N         \%         N       N       \%           N

  ENF Naive       80        69.6%      115     27      28.7%        94

  ENF Experienced 12        27.9%      43      6       17.6%        34

  No ENF Use                                                        

  ENF Naive       146       36.7%      398     73      17.6%        415

  ENF Experienced 2         7.7%       26      3       8.8%         34
  --------------- --------- ---------- ------- ------- ------------ --------

For most participants in the RESIST trials enfuvirtide was a drug from a
new class of antiretroviral agents. To characterize the relative
contribution of the different components of the regimen started after
randomization into RESIST, an ANOVA analysis of the Week 24 viral load
change considering treatment group, preselected PI, enfuvirtide use, and
genotypic susceptibility to background drugs (other than enfuvirtide)
was performed. This analysis confirmed the superiority of TPV/r compared
to CPI/r after adjustment for the other factors. The Week 24 viral load
reduction attributable to TPV/r over and above the Week 24 viral load
reduction attributable to CPI/r was 0.64 log~10~ copies/mL. Similarly,
after controlling for other factors including treatment group, the
magnitude of Week 24 viral load reduction attributable to a new class of
drug (enfuvirtide) was of approximately the same order of magnitude as
that for TPV/r, i.e., 0.67 log~10~ copies/mL.

[]{#__RefHeading___Toc101398952 .anchor}**6.3.7 Impact of baseline viral
load and CD4+ count**

In the TPV/r group, the proportion with a treatment response increased
from 34.9% in patients with high baseline VL (\>100,000-1,000,000
copies/mL) to 56.3% in patients with low baseline VL (1,000-10,000
copies/mL). In the CPI/r group, the proportion of patients with a
treatment response was 13.7% and 31.5% in patients with high and low
baseline viral loads respectively. In the TPV/r group, the proportion of
patients with a treatment response increased from 26.3% for patients in
the \< 50 cells/mm3 baseline CD4+ group to 46.0% for patients in the
\>350 cells/mm3 group. In the CPI/r group, the response rate increased
from 9.5% for patients in the \< 50 cells/mm3 baseline CD4+ group to
21.2% for patients in the \>350 cells/ mm3 group.

[]{#__RefHeading___Toc101398953 .anchor}6.3.8 Sensitivity analyses

Multiple sensitivity analyses were conducted to evaluate the potential
for bias. One sensitivity analysis explored the influence of protocol
violations on the Week 24 treatment responses (PPS \[NCF\]). In this
analysis, only patients who did not have protocol violations or relevant
protocol deviations[^20] (PPS) were considered in the assessment of Week
24 treatment responses. Consistent with the primary analysis, this
analysis showed that a larger proportion of TPV/r patients (44.7%)
achieved a treatment response than did CPI/r patients (22.5%). The
weighted difference in the proportion of treatment responders was 21.3%
and the lower bound of the 95% CI was 14.7% superiority, which again
indicated a large treatment effect.

Table 6.3.8: 1 Sensitivity analyses of treatment response at Week 24 --
RESIST trials (FAS and PPS[^21])

  ------------------------------------------------------------------------------------------------------------------------
                          Treatment Group                                         Treatment Difference            
  --------- ------------- ----------------- -------- ----- ------- -------- ----- ---------------------- -------- --------
                          TPV/r                            CPI/r                  Weighted               95% CI   

  Trial     Analysis      n                 (%)      N     n       (%)      N     Diff.\                 LL\      UL\
                                                                                  (%)                    (%)      (%)

  1182.12   FAS (NCC)     129               (42.3)   305   69      (23.7)   291   (17.7)                 (10.5)   (24.8)

            FAS\          129               (41.5)   311   69      (23.7)   291   (17.0)                 (9.9)    (24.1)
            TPV/r (NCF)\                                                                                          
            CPI/r (NCC)                                                                                           

            PPS24 (NCF)   86                (45.0)   191   50      (25.9)   193   (18.5)                 (9.3)    (27.6)

  1182.48   FASS24, (NCC) 111               (42.4)   262   40      (15.3)   261   (26.1)                 (18.7)   (33.4)

            FAS\          111               (41.0)   271   40      (15.3)   261   (24.6)                 (17.4)   (31.9)
            TPV/r (NCF)\                                                                                          
            CPI/r (NCC)                                                                                           

            PPSS24 (NCF)  80                (44.4)   180   31      (18.6)   167   (24.6)                 (15.4)   (33.8)

  Total     FAS (NCC)     240               (42.3)   567   109     (19.7)   552   (21.4)                 (16.3)   (26.6)

            FAS\          240               (41.2)   582   109     (19.7)   552   (20.4)                 (15.3)   (25.5)
            TPV/r (NCF)\                                                                                          
            CPI/r (NCC)                                                                                           

            PPS (NCF)     166               (44.7)   371   81      (22.5)   360   (21.3)                 (14.7)   (27.8)
  ------------------------------------------------------------------------------------------------------------------------

[]{#__RefHeading___Toc101398954 .anchor}6.4 Efficacy RESULTS IN SPECIAL
POPULATIONS

Within the TPV/r clinical development program, the highly treatment
experienced adult patients in BI 1182.51, who by design harbored more
resistant virus (more than 2 mutations at codons 33, 82, 84, or 90),
represent an important treatment population. Efficacy results for this
trial are summarized here. Direct comparison to the RESIST trials cannot
be made, however, due to the fact that different primary endpoints were
used. BI 1182.51 was primarily a PK and safety trial with 2- and 4-week
efficacy results. Patients in BI 1182.51 were allowed to have background
medication adjustments at 4 weeks (after completing the PK portion of
the trial), thus interpretation of 24-week efficacy results is limited.

Patients who screened for either of the two RESIST studies but were not
able to enrol because they had more than 2 key mutations at codons 33,
82, 84, or 90 in the protease gene were offered TPV/r in a study
evaluating the safety and pharmacokinetics of TPV/r of dual boosted PI
regimens. Of those who failed screening for the RESIST studies, 315
patients were randomized into BI 1182.51 and received at least one dose
of study medication.

At baseline, all patients received an individually selected OBR and were
randomized to receive either TPV/r (n = 67) or LPV/r (n = 83), SQV/r
(n = 82), or APV/r (n = 83). Fourteen percent of patients pre-selected
enfuvirtide as part of the background regimen.

After 2 weeks using one of the four single RTV-boosted regimens, TPV/r
was added to patients in the LPV/r, SQV/r, and APV/r treatment arms;
patients in the TPV/r control arm either maintained their same drug
regimen or had a second PI added to their treatment regimen although the
primary trial objective was to evaluate the safety and pharmacokinetics
of dual boosted PI regimens the first 4 weeks of the trial allow for
comparison of intrinsic activity of the individual PIs.

Patients in BI 1182.51 tended to have a lower baseline CD4+ count
(median 138 compared with 155 cells/mm^3^ in the TPV/r group of the
combined RESIST trials), a higher baseline viral load (4.97 compared
with 4.83 log~10~ copies/mL in the TPV/r group of the combined RESIST
trials), and had been exposed to more antiretroviral agents (13 compared
with 12 in the TPV/r group of the combined RESIST trials).

During the first 2 weeks of therapy in which patients received a single
boosted PI, the median viral load reduction among patients randomized to
TPV/r was 1.06 log~10~ copies/mL, while it was below 0.4 log~10~
copies/mL in the 3 other arms (Table 6.4.1: 1 and Figure 6.4.1: 1).

Table 6.4.1: 1 Median Baseline VL \[log~10~ copies/mL\] change in BI
1182.51 - FAS (LOCF/NCF)

  --------------- ------------- ------------- ------------- -------------
                  TPV/r a       LPV/r b       SQV/r b       APV/r b

  Week            N = 67        N = 83        N = 82        N = 83

  Baseline VL     4.78          4.97          5.02          4.99

  2               -1.06         -0.38         -0.19         -0.15

  4 c             -1.27         -1.19         -0.96         -1.12

  8               -0.76         -0.63         -0.54         -0.69

  24              -0.28         -0.43         -0.24         -0.47
  --------------- ------------- ------------- ------------- -------------

a Enrollment into the TPV/r arm was halted when the trial monitoring
team found that \>25% of patients on the TPV/r arm had at Week 4 VL
reduction below 0.5 log~10~. Since the sample size for the primary PK
objective was 60, enrollment into the TPV/r arm was stopped.

b TPV/r added after 2 weeks.

c Patients were allowed to switch both background ARVs and PIs after
Week 4.

At Week 2, TPV/r was added to the individual PIs and, the virologic
response at Week 4 was similar for each of the four treatment arms to
that seen for TPV alone during the first 2 weeks of the study. After
Week 4, the virologic response began to decay across all treatment arms
and after 8 weeks of therapy, there was no significant difference in
virologic response across all four treatment arms. Viral load responses
diminish after 4 weeks due to a combination of impaired TPV activity and
limited active background drugs available to support the TPV/r resulting
in the development of viruses resistant to TPV. (Figure 6.4.1: 1).

![](media/image9.wmf){width="5.48125in" height="3.734722222222222in"}

Figure 6.4.1: 1 Reduction in HIV-1 viral load from baseline in each of
the four treatment arms in BI 1182.51 during the single boosted and dual
boosted PI treatment phases (Weeks 0-8)

[]{#__RefHeading___Toc101398955 .anchor}6.5 EFFICACY CONCLUSIONS

-   TPV/r has proved to be a potent PI in patients who have been
    previously exposed to 2 or more PI-containing antiretroviral
    regimens.

-   In multiple PI-experienced patients, TPV/r was virologically and
    immunologically superior to CPI/r across multiple efficacy analyses
    confirmed by sensitivity analyses of the overall results and for
    individual randomized CPI comparisons.

-   For patients with PI-resistant virus, superior efficacy was
    demonstrated for TPV/r compared to the best available alternate
    ritonavir-boosted PI.

-   The superior virological and immunological responses seen with TPV/r
    at 24 weeks were associated with a nonsignificant decrease in AIDS
    progression events in patients with PI-resistant HIV-1.

-   The antiviral effect seen with regimens containing TPV/r is greater
    in regimens with additional active ARVs (e.g. other genotypically
    available background drugs, for example enfuvirtide). TPV/r had
    potent early antiviral responses despite high-level protease
    inhibitor resistance, but to obtain a durable response with TPV/r
    additional active background drugs are needed.

-   Consistent with established NIH and IAS guidelines for the use of
    ARV drugs in treatment-experienced patients, knowledge of baseline
    resistance can be used to choose the optimal background regimen to
    combine with TPV/r to obtain a durable antiviral response.

[]{#__RefHeading___Toc101398956 .anchor}7. RESISTANCE

[]{#__RefHeading___Toc101398957 .anchor}7.1 Development Of Tipranavir
Resistance *In Vitro*

The development of resistance to tipranavir *in vitro* is slow and
complex. In one *in vitro* resistance experiment starting with wild type
HIV-1, an HIV-1 isolate that was 87-fold resistant to tipranavir was
selected after 9 months and contained 10 mutations in the protease:
L10F, I13V, V32I, L33F, M36I, K45I, I54V/T, A71V, V82L, I84V as well as
a mutation in the gag polyprotein CA/P2 cleavage site. Reverse genetic
experiments showed that the presence of 6 mutations in the protease
(I13V, V32I, L33F, K45I, V82L, I84V) was required to confer \>10-fold
resistance to tipranavir while the full 10-mutation genotype conferred
69‑fold resistance to tipranavir.

*In vitro*, there is an inverse correlation between the degree of
resistance to tipranavir and the capacity of viruses to replicate.
Recombinant viruses showing [\>]{.underline} 3-fold resistance to
tipranavir grow at less than 1% of the rate detected for wild type HIV-1
in the same conditions. Tipranavir-resistant viruses which emerged *in
vitro* from wild-type HIV-1 showed decreased susceptibility to the
protease inhibitors amprenavir, atazanavir, indinavir, lopinavir,
nelfinavir and ritonavir but remained sensitive to saquinavir.

[]{#__RefHeading___Toc101398958 .anchor}7.2 Clinical Resistance (*In
Vivo)*

Current treatment of HIV-1 infection involves the concomitant
administration of at least three ARV medications among the classes of
non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside
reverse transcriptase inhibitors (NRTIs), PIs, and to a lesser extent
HIV entry inhibitors. There are currently eight PIs approved for the
treatment of HIV infection. Varying degrees of cross resistance among
the PIs approved for HIV therapy have been observed and have resulted in
limited options for patients with PI-resistant virus. There is clearly a
need for novel PIs with activity against PI-resistant HIV-1 and distinct
patterns of PI cross resistance. Tipranavir (TPV) demonstrates unique
resistance characteristics that offer potential therapeutic advantages
to PI-experienced patients. In a study of 105 highly PI‑resistant
viruses at VIRCO, Larder, et. al. showed that 90% remained sensitive to
TPV (\< 4-fold WT) while only 2% showed high level resistance (\>
10-fold WT).[^22]

Experiments by Larder, et al also demonstrated that clinical HIV-1
strains resistant to TPV had a high frequency of mutations V82T and
I84V. Specifically, two clusters of mutation patterns were identified:
V82T with I84V and I84V with L90M (both with numerous secondary
mutations). In Phase II and III clinical trials, 276 patients with
on-treatment genotypes have demonstrated that the predominant emerging
mutations with TPV/r treatment are L33F/I/V, V82T/L and I84V.
Combination of all three of these mutations is usually required for
reduced TPV susceptibility. Mutations at position 82 occur via two
pathways: one from pre-existing mutation 82A selecting to 82T, the other
from V82-wild type selecting to 82L.

These *in vitro* observations led BI to emphasize analyses of patient
responses according to the presence of multiples of mutations at four
protease codons: 33, 82, 84, and 90 which were associated with decreased
viral load responses to TPV/r in Phase II studies and broad, high level
resistance to other available PIs in *in vitro* studies. At various
times, these positions have been called \"key TPV-associated
mutations\", \"universal protease-associated mutations\" (UPAMs), or
\"protease resistance-associated mutations\" (PRAMs). This section will
provide a comprehensive review of resistance data obtained from all TPV
clinical trials, including evaluation of effect of the genotype on
susceptibility phenotype and genotype or phenotype on antiviral
responses.

[]{#__RefHeading___Toc101398959 .anchor}7.3 GENOTYPIC SCORES

HIV drug susceptibility genotyping and phenotyping are the two methods
currently in use to determine whether an HIV-1 isolate has decreased
susceptibility to ARV agents. With either of these methods, physicians
can construct regimens for treatment-experienced patients that provide
enhanced antiviral response compared with regimens designed using
treatment history alone.

In the context of the RESIST trials, genotypic resistance testing was
performed at screening for all patients. Phenotyping was conducted in a
subset of 500 randomly selected baseline plasma samples (400 for
patients randomized to TPV/r and 100 for patients randomized to CPI/r).
A total of 454 paired genotypic and phenotypic results of screening
samples were available for analyses of the relationship between protease
mutations and phenotype (phenotyping was unsuccessful for 46 samples).
To broaden the range of TPV susceptibilities evaluated, 356 samples from
patients in the Phase II program (Trials BI 1182.52 and 1182.51) were
added to some analyses. Virologic responses of patients on the 500/200
mg dose of TPV/r in Phase II trials were also included in some response
analyses.

To examine the relationship between protease mutations detected by
genotypic resistance testing and TPV phenotypic susceptibility results,
several patterns of protease inhibitor resistance mutations were
investigated:

-   *Key protease mutations*: *protease codons* 33, 82, 84, 90

-   *TPV score mutations: protease codons* 10V, 13V, 20M/R/V, 33F, 35G,
    36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D, 84V

-   *FDA protease mutations: protease codons 30, 32, 36, 46, 47, 48, 50,
    53, 54, 82, 84, 88, 90*

[]{#__RefHeading___Toc101398960 .anchor}7.3.1 Key protease mutations
(HIV protease codons 33, 82, 84 and 90)

The relationship between the presence of key mutations (mutations at
HIV-1 protease codons 33, 82, 84, and 90) and associated change in
phenotypic susceptibility to available protease inhibitors was evaluated
using the clinical samples from the TPV development program (Table
7.3.1: 1). HIV-1 isolates with one key mutation showed resistance to
lopinavir, indinavir, nelfinavir, ritonavir and atazanavir, and
decreased susceptibility to saquinavir and amprenavir while TPV had a
median susceptibility of 1.1-fold WT. HIV-1 isolates with 2 key
mutations demonstrated high level resistance to all currently available
PIs but remained susceptible to TPV with a median susceptibility of
1.7-fold WT. Tipranavir susceptibility was decreased (
[\>]{.underline} 3-fold WT) for HIV-1 with protease enzymes containing 3
key mutations and high level resistance ( [\>]{.underline} 10-fold WT)
usually requires 4 key mutations to be present.

Table 7.3.1: 1 Comparative phenotype of all protease inhibitors tested
in Phase II and III TPV trials according to number of key protease
mutations

  ------------ ----- ----------- ------- ------ ------ ------ ------ ------- -------
                     Protease                                                
                     inhibitor                                               
                     median                                                  
                     IC~50~ fold                                             
                     WT                                                      

  Number of    N     TPV         LPV     IDV    SQV    APV    NFV    RTV     TAZ
  key                                                                        
  mutations\                                                                 
  33, 82, 84,                                                                
  90                                                                         

  0            82    0.7         1.0     1.1    0.9    0.6    2.3    1.1     1.8

  1            232   1.1         49.7    12.2   4.4    4.6    32.4   43.9    13.4

  2            371   1.7         90.6    43.5   33.2   15.1   41.8   199.1   76.6

  3            112   3.4         102.8   53.9   42.2   30.9   43.1   361.0   102.9

  4            13    12.0        100.1   36.7   46.2   32.3   41.7   361.0   95.8
  ------------ ----- ----------- ------- ------ ------ ------ ------ ------- -------

[]{#__RefHeading___Toc101398961 .anchor}7.3.2 Tipranavir score

Through a series of multiple stepwise regression analyses of baseline
and on-treatment genotypes from all clinical studies, mutations at 16
protease codons have been associated with reduced tipranavir
susceptibility and/or reduced 2 or 24-week viral load responses: 10V,
13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P,
82L/T, 83D and 84V. As shown in Figure 7.3.2: 1, a number of TPV score
mutations have not been previously associated with resistance to other
PIs -- at codons 13, 35, 43, 58, 69, 74, and 83. Similarly, many IAS-USA
mutations are not associated with resistance to TPV -- at codons 24, 30,
32, 48, 50, 53, 88, and 90. This may explain the low level of cross
resistance between TPV and other currently available protease
inhibitors.

![](media/image10.wmf){width="6.206944444444445in"
height="1.7340277777777777in"}

Figure 7.3.2: 1 Comparison of TPV Score Mutations with IAS-USA Mutations
for Currently Available Protease Inhibitors

The accumulation of greater than 4 protease mutations among the 16
TPV-associated codons is required to predict decreased phenotypic TPV
susceptibility ( [\>]{.underline} 3-fold WT) and decreased antiviral
responses to TPV. High level resistance to TPV ( [\>]{.underline} 10
fold WT) usually requires \> 7 TPV-associated mutations. The mutation
L90M does not appear to be related to decreased TPV susceptibility or
decreased antiviral responses to TPV. V82A, the most common mutation at
codon 82 selected by currently available PIs, also does not appear
related to TPV susceptibility. L90M when combined with mutations at
codons 82 or 84 may be a marker for viruses with multiple associated
protease resistance mutations.

[]{#__RefHeading___Toc101398962 .anchor}7.3.3 FDA protease gene
mutations

The FDA protease mutation score was determined by counting any
alteration at codons 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84, 88, 90
in HIV-1 protease as defined by the FDA.

[]{#__RefHeading___Toc101398963 .anchor}7.4 Relationship of Genotype to
Phenotype

During the course of the Tipranavir Phase II/III clinical development
program genotypic resistance testing was performed at screening in all
participants. The data presented in this section concern the results of
paired genotypic and phenotypic resistance screening sample results for
810 participants. To examine the relationship between protease mutations
detected by genotypic resistance testing and TPV phenotypic
susceptibility results, the three categories of mutations were used
(Table 7.4: 1).

Table 7.4: 1 Median IC~50~ fold change from wild type for TPV by number
of mutations in the protease gene among participants in Phase II and III
TPV trials

+-------------------------+-----------+--------------------------------+
| Number of mutations     | N         | Median TPV Fold Change (IQR)   |
+-------------------------+-----------+--------------------------------+
| FDA Protease gene       |           |                                |
| mutations1              |           |                                |
+-------------------------+-----------+--------------------------------+
| 0 - 1                   | 75        | 0.9 (0.5, 1.1)                 |
+-------------------------+-----------+--------------------------------+
| 2 - 3                   | 179       | 1.0 (0.6, 1.9)                 |
+-------------------------+-----------+--------------------------------+
| 4 - 5                   | 417       | 1.8 (0.9, 3.7)                 |
+-------------------------+-----------+--------------------------------+
| 6+                      | 139       | 2.6 (1.0, 6.0)                 |
+-------------------------+-----------+--------------------------------+
| Key protease mutations2 |           |                                |
+-------------------------+-----------+--------------------------------+
| 0                       | 82        | 0.7 (0.4, 1.0)                 |
+-------------------------+-----------+--------------------------------+
| 1                       | 232       | 1.1 (0.7, 2.1)                 |
+-------------------------+-----------+--------------------------------+
| 2                       | 371       | 1.7 (0.9, 3.7)                 |
+-------------------------+-----------+--------------------------------+
| 3                       | 112       | 3.4 (1.9, 8.4)                 |
+-------------------------+-----------+--------------------------------+
| 4                       | 13        | 12.0 (2.5, 16.6)               |
+-------------------------+-----------+--------------------------------+
| TPV score mutations3    |           |                                |
+-------------------------+-----------+--------------------------------+
| > 0                     | 80        | 0.7 (0.4, 1.0)                 |
+-------------------------+-----------+--------------------------------+
| > 1                     | 105       | 0.9 (0.6, 1.4)                 |
+-------------------------+-----------+--------------------------------+
| > 2                     | 118       | 1.1 (0.6, 1.9)                 |
+-------------------------+-----------+--------------------------------+
| > 3                     | 159       | 1.4 (0.7, 2.6)                 |
+-------------------------+-----------+--------------------------------+
| > 4                     | 153       | 2.0 (1.0, 4.1)                 |
+-------------------------+-----------+--------------------------------+
| > 5                     | 114       | 3.1 (1.7, 7.0)                 |
+-------------------------+-----------+--------------------------------+
| > 6                     | 49        | 3.3 (1.6, 8.7)                 |
+-------------------------+-----------+--------------------------------+
| > 7                     | 25        | 3.9 (2.7, 12.5)                |
+-------------------------+-----------+--------------------------------+
| > 8                     | 6         | 14.7 (4.9, 19.8)               |
+-------------------------+-----------+--------------------------------+
| > 9                     | 1         | 52.5 (52.5, 52.5)              |
+-------------------------+-----------+--------------------------------+

> 1 FDA protease mutation: 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84,
> 88, 90
>
> 2 Key protease mutations: 33, 82, 84, and 90.
>
> 3 TPV score mutations: L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T,
> M46L, I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D, and I84V.

In general, as the number of mutations in the protease gene increased,
TPV susceptibility progressively decreased.

In summary, among the 810 screening isolates with paired genotype and
phenotype resistance testing from participants in the TPV Phase II and
III programs, an increased number of FDA protease mutations were
associated with decreased TPV phenotypic susceptibility but despite the
presence of a large number of these mutations in the protease gene, the
change in TPV phenotypic susceptibility was modest. Counting TPV score
mutations or key protease mutations appeared the best predictors of
changes in TPV phenotypic susceptibility.

Table 7.4: 2 Relationship of different protease gene scores to TPV
susceptibility

  --------------------- ---------------- ----------------- -----------------
  Fold-change at        FDA Mutation     Key Mutation      Tipranavir Score
  baseline in           Score            Score\            
  tipranavir IC~50~                      (33, 82, 84, 90)  

  0 to \< 3             1 to 6+          0 to 2            0 to 4

  3 to \<10             N.A.             3                 5 to 7

  [\>]{.underline} 10   N.A              4                 8+
  --------------------- ---------------- ----------------- -----------------

[]{#__RefHeading___Toc101398964 .anchor}7.5 Impact of Genotype on
Virologic Response

The relationship between screening genotype and VL response was examined
for 810 participants on the 500/200 mg dose of TPV/r in the TPV clinical
development program with data available at baseline. Virologic responses
were evaluated at 2 weeks (for TPV/r antiviral activity) and 24 weeks
(for the durability of TPV/r-containing regimens). A problem
complicating these analyses is that patients with viruses with higher
levels of TPV resistance had very limited options for active background
drugs. Thus, lower GSS scores were correlated with higher TPV scores.

Three mutation scores (i.e., FDA protease mutations, TPV score
mutations, and key protease mutations) are presented in this section.
All response analyses were ITT using all patients with complete data
available for the analysis.

Table 7.5: 1 Change in viral load at Weeks 2 and 24 according to
baseline genotypic mutations among participants in all Phase II and III
trials using the TPV/r 500/200 mg dose

  ------------------ ---------------------- -------- --------------- -- ------- -------- ---------------
  Mutation Category  TPV/r                                                               
  and Count          Change in Viral Load                                                
                     from Baseline                                                       

                     Week 2 (OT)                                        Week 24          
                                                                        (LOCF            
                                                                        d)               

                     N                      Median   (IQR)              N       Median   (IQR)

  FDA Protease a                                                                         

  0 - 1              31                     -1.09    (-0.58, -1.61)     24      -0.64    (-0.12, -2.34)

  2 - 3              162                    -1.40    (-0.83, -1.76)     132     -1.65    (-0.47, -2.65)

  4 - 5              466                    -1.36    (-0.66, -1.86)     397     -0.63    (-0.11, -2.29)

  6 +                147                    -1.37    (-0.43, -1.85)     135     -0.48    (-0.05, -2.28)

  Key proteaseb                                                                          

  [\<]{.underline} 1 255                    -1.35    (-0.77, -1.86)     205     -1.27    (-0.24, -2.62)

  2                  473                    -1.39    (-0.67, -1.83)     402     -0.78    (-0.14, -2.42)

  3                  68                     -1.25    (-0.26, -1.68)     71      -0.24    (0.13 -1.87)

  4                  10                     -1.08    (-0.33, -1.54)     10      -0.33    (-0.14, -0.66)

  TPV scorec                                                                             

  [\<]{.underline} 1 135                    -1.25    (-0.91, -1.78)     114     -2.10    (-0.82, -2.77)

  2                  112                    -1.38    (-0.87, -1.83)     91      -1.30    (-0.31, -2.54)

  3                  177                    -1.36    (-0.72, -1.83)     151     -0.64    (-0.16, -2.29)

  4                  190                    -1.42    (-0.64, -1.87)     156     -0.60    (-0.11, -2.39)

  5                  112                    -1.38    (-0.37, -1.89)     104     -0.30    (0.13 -1.54)

  6                  56                     -1.35    (-0.23, -1.81)     50      -0.51    (-0.05, -1.44)

  7                  20                     -1.06    (-0.18, -1.79)     18      -0.49    (0, -2.84)

  8                  4                      -0.33    (0.11, -0.83)      4       -0.08    (0.01, -0.18)
  ------------------ ---------------------- -------- --------------- -- ------- -------- ---------------

> a FDA protease mutations: 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84,
> 88, 90
>
> b Key mutations: 33, 82, 84, and 90.
>
> c TPV score mutations: L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T,
> M46L, I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D, and I84V.
>
> d LOCF: last observation carried forward.

For all three analyses TPV/r-containing regimens showed a median 1.1 to
1.4 log~10~ copies/mL response except for mutation score cells with very
few patients at 2 weeks (Table 7.5: 1). The clearest relationship with
reduced HIV RNA responses at 24 weeks was seen with increasing scores
with either the key mutations or the TPV score. None-the-less, \>25% of
patients had a durable 1 log or greater response to TPV-containing
regimens, even with 3 key mutations or a TPV score of 7. These results
are confirmed in the RESIST trials for viral endpoints of \<
400 copies/ml or \< 50 copies/ml in Table 7.5: 2 below.

Table 7.5: 2 Summary of TPV/r 24-week virologic response according to
baseline genotypic categories in Combined RESIST Trials

  ------------------ ------------- ------------- ------------- -------------
  Mutation Category  \% \< 400     \% \< 50      \% 1 log10    \% 0.5 log10
  and Count          Copies\       Copies\       Drop from     Drop from
                     (NCF)\        (NCF)\        Baseline\     Baseline\
                     n/Na (%)      n/Na (%)      (NCF)\        (OT)\
                                                 n/Na (%)      n/Na (%)

  Key (33, 82, 84,                                             
  90)                                                          

  [\<]{.underline} 1 74 / 188      50 / 188      87 / 188      97 / 144
                     (39.4)        (26.6)        (46.3)        (67.4)

  2                  121 / 374     86 / 374      161 / 374     192 / 324
                     (32.4)        (23.0)        (43.0)        (59.3)

  3                  4 / 18 (22.2) 3 / 18 (16.7) 6 / 18 (33.3) 5 / 15 (33.3)

  4                  0 / 1 (0.0)   0 / 1 (0.0)   0 / 1 (0.0)   

  TPV scoreb                                                   

  [\<]{.underline} 1 59 / 104      45 / 104      70 / 104      75 / 89
                     (56.7)        (43.3)        (67.3)        (84.3)

  2                  29 / 80       25 / 80       34 / 80       42 / 62
                     (36.3)        (31.3)        (42.5)        (67.7)

  3                  38 / 127      26 / 127      48 / 127      56 / 10
                     (29.9)        (20.5)        (37.8)        (54.4)

  4                  44 / 139      22 / 139      58 / 139      68 / 123
                     (31.7)        (15.8)        (41.7)        (55.3)

  5                  17 / 83       13 / 83       24 / 83       30 / 67
                     (20.5)        (15.7)        (28.9)        (44.8)

  6                  7 / 36 (19.4) 4 / 36 (11.1) 13 / 36       16 / 29
                                                 (36.1)        (55.2)

  7                  5 / 12 (41.7) 4 / 12 (33.3) 7 / 12 (58.3) 7 / 10 (70.0)
  ------------------ ------------- ------------- ------------- -------------

a N = number within the specified genotypic category; n = number (out of
N) of patients who achieved the respective virologic response.

b TPV score mutations: L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T,
M46L, I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D, and I84V.

[]{#__RefHeading___Toc101398965 .anchor}7.6 Impact of Phenotype on
Virologic Response

For the RESIST trials, the relationship between the change in TPV
phenotypic susceptibility at baseline and Week 2 and Week 24 virologic
responses was analyzed.

Analyses of treatment response at 24 weeks and viral load responses at 2
and 24 weeks show apparent TPV breakpoints at 3-fold and 10-fold wild
type with the clearest dose response relationship in patients who did
not receive enfuvirtide (Tables 7.6: 1 and 7.6: 2). In all
susceptibility strata, addition of enfuvirtide improved the virologic
response seen with TPV/r, especially in the patients with high level TPV
resistance.

Table 7.6: 1 Treatment Response ^a^ at Week 24 for TPV/r by Baseline
Tipranavir Susceptibility, Stratified by Enfuvirtide Use, in Combined
RESIST Trials

  --------------------- ------------------------- -----------------------
  Enfuvirtide Use       Fold-change at baseline   TPV/r treatment
                        in TPV IC~50~             response

  No                    0 to \< 3                 75/193 (38.9%)

                        3 to \< 10                10/53 (18.9%)

                        [\>]{.underline} 10       0/12 (00.0%)

  Yes                   0 to \< 3                 45/61 (73.8%)

                        3 to \< 10                12/32 (37.5%)

                        [\>]{.underline} 10       5/10 (50.0%)
  --------------------- ------------------------- -----------------------

a Treatment response is the composite endpoint of the proportion of
patients with two consecutive VL measurements \>1 log~10~ below baseline
after 24 weeks without prior (1) evidence of a confirmed virological
failure, (2) introduction of a new ARV to the regimen for reasons other
than toxicity or intolerance to a background drug, (3) permanent
discontinuation of the study drug, (4) death, or (5) loss to follow-up.

Table 7.6: 2 HIV Viral Load Response at Weeks 2 and 24 for TPV/r by
Baseline Tipranavir Susceptibility, Stratified by Enfuvirtide Use, in
Combined RESIST trials

  ------------------ ---------- -------- ------------ -------- -------- --------------
                     TPV/r\                                             
                     Change in                                          
                     Viral Load                                         
                     from                                               
                     Baseline                                           

                     2 weeks                          24 weeks          
                     (OT)                             (LOCF)            

  Fold-change at     N          Median   (IQR)        N        Median   (IQR)
  baseline in                                                           
  tipranavir IC~50~                                                     

  **No Enfuvirtide                                                      
  Use**                                                                 

  1 to \< 3          176        -1.39    (-0.81,      193      -0.66    (-0.16, -2.24)
                                         -1.87)                         

  3 to \< 10         50         -0.67    (-0.21,      53       -0.32    (+0.03, -0.64)
                                         -1.61)                         

  [\>]{.underline}   11         -0.52    (+0.21,      12       -0.15    (+0.10, -0.72)
  10                                     -1.03)                         

  **Enfuvirtide                                                         
  included in                                                           
  regimen**                                                             

  1 to \< 3          59         -1.72    (-1.27,      61       -2.57    (-1.21, -3.16)
                                         -2.22)                         

  3 to \< 10         30         -1.85    (-0.15,      32       -0.85    (+0.02, -2.78)
                                         -2.38)                         

  [\>]{.underline}   10         -1.70    (-1.07,      10       -0.94    (-0.27, -2.77)
  10                                     -2.12)                         
  ------------------ ---------- -------- ------------ -------- -------- --------------

[]{#__RefHeading___Toc101398966 .anchor}7.7 Predictors OF VIRAL Load
RESPONSE at 24 Weeks

A multivariate analysis was conducted of factors that were associated
with the viral load responses seen at 24 weeks on TPV/r-containing
regimens. Factors associated with an increased viral load reduction were
TPV/r, addition of Enfuvirtide, and each additional active NRTI/NNRTI in
the regimen. Increasing TPV mutation scores were associated with
decreased antiviral responses with each mutation reducing the 24 week
viral load response by 0.2 log (Table 7.7: 1).

Table 7.7: 1 Predictors of viral load responses at 24 weeks to
TPV/r-containing regimens

  -------------------------------------------- -------------- -----------
                                               24 weeks       

  Parameter                                    Estimate       P-value

  Tipranavir/r                                 -1.25          \<0.01

  Enfuvirtide use                              -0.91          \<0.01

  Per available NRTI/NNRTI in background       -0.24          \<0.01

  Per TPV score mutation                       0.17           \<0.01
  -------------------------------------------- -------------- -----------

[]{#__RefHeading___Toc101398967 .anchor}7.8 RESISTANCE Conclusions

-   TPV/r is virologically active against the majority of HIV-1 with
    broad PI resistance.

-   There is a high genetic barrier to resistance with TPV. It takes 3
    key protease gene mutations or \> 4 TPV-associated mutations to
    produce decreased susceptibility ([\>]{.underline} 3‑fold WT) *in
    vitro* or reduced antiviral responses in the clinic. High level TPV
    resistance ([\>]{.underline} 10-fold WT) was seen when all 4 key
    mutations or \> 7 TPV-associated mutations were present.

-   Key mutations at PI codons 33, 82, 84, 90 can produce high level
    resistance to currently available PIs. Viruses with 3 or more key
    mutations showed [\>]{.underline} 3‑fold resistance to TPV/r.

-   In viruses from PI-experienced patients, many of the mutations which
    produce resistance to TPV are different than the mutations that
    produce drug resistance to currently available PIs. This may explain
    the diminished cross resistance seen between TPV and other currently
    available protease inhibitors.

-   The predominant emerging mutations with virologic failure in
    PI-experienced patients receiving TPV/r are 33F/I/V, 82T/L, and 84V.

-   The drug resistance pattern which will result from treatment of drug
    naïve patients is still being evaluated.

-   The TPV score, enfuvirtide use, and available NRTI/NNRTI in
    background are all strong predictors of sustained 24 week virologic
    response. The associated contribution to VL response was:

```{=html}
<!-- -->
```
-   Tipranavir/r: 1.25 log~10~ copies/mL increase

-   Enfuvirtide: 0.9 log~10~ copies/mL increase

-   Per active NRTI/NNRTI in OBR\
    increase: 0.2 log~10~ copies/mL                            

-   Per TPV score mutation: 0.2 log~10~ copies/mL decrease

[]{#__RefHeading___Toc101398968 .anchor}8. SAFETY

Safety data from the Safety Update utilizing a 30 September 2004 cut-off
date are summarized in this section.

[]{#__RefHeading___Toc101398969 .anchor}8.1 EXPOSURE

Overall, a total of 3,367 HIV-positive patients and 769 HIV‑negative
subjects have been exposed to TPV/r in clinical trials. Adult
HIV-positive patients have been treated with TPV/r in Phase II
dose-finding trials (n=579), in a Phase IIb PK/Safety Trial BI 1182.51
(n=315), Phase III RESIST trials (n=748), the rollover Trial BI 1182.17
(n=772) and the Emergency Use/Expanded Access Program (n=879).
Seventy-four pediatric HIV-positive patients from Trial BI 1182.14 have
also been treated with TPV/r. A total of 1,411 patients have been
treated with the TPV/r 500/200 mg dose, and of these 1,206 patients have
been exposed for at least 24 weeks.

In the subsequent sections, safety observations from early Phase I and
II trials will be summarized, followed by comprehensive comparative
analyses of adverse events, serious adverse events, and laboratory
abnormalities for the Phase III RESIST trials.

[]{#__RefHeading___Toc101398970 .anchor}8.2 SAFETY DATA FROM EARLY
CLINICAL TRIALS

In Phase I drug interaction studies HIV-negative subjects who were
exposed to TPV/r for between 1 to 32 days, 88.3% reported any adverse
event, 0.3% (2 subjects) reported any serious adverse event, and 11.1%
discontinued due to adverse events. The most common adverse events
reported in Phase I and II trial participants were diarrhea, nausea,
vomiting, abdominal pain, flatulence, headache, and fatigue. This was
found to be consistent with Phase II and III trials, although the
frequency of some adverse events was higher in the Phase II trials. The
slightly higher frequency of adverse events reported in Phase I and II
trials are likely related to lower tolerability thresholds and
non-induced hepatic 3A enzyme systems in HIV-negative subjects and the
use of an hard filled capsule formulation and higher doses of TPV/r (up
to TPV/r 1250/100 mg) in early trials of HIV-positive patients.

Five TPV Phase I studies were conducted prior to full development of QTc
regulatory guidance documents. The ECG data collected in these trials
were analyzed to understand the potential for ECG abnormalities. No
evidence of QTc prolongation was observed in nearly 200 subjects
administered TPV/r for up to 32 days.

In a drug interaction study of TPV/r co-administered with ethinyl
estradiol and norethindrone, female healthy volunteers experienced rash
and arthralgias that resolved upon discontinuation of these medications.
This observation of non-serious rash occurring in women receiving
ethinyl estradiol with TPV/r was confirmed in Phase III trials of
HIV‑positive women. Women using estrogens may have an increased risk of
non-serious rash.

In Phase II trials in HIV-positive patients who received at least one
dose of TPV/r, 85.1% reported any adverse event, 10.8% reported any
serious adverse event, and 7.8% discontinued treatment due to adverse
events.

The most common laboratory abnormalities noted in Phase I and II trials
were elevations in serum transaminases and plasma lipids. An analysis of
these trials combining TPV/r doses into groups of TPV/r \<500/200 mg,
500/200 mg, and \>500/200 mg revealed a dose-related increase in Grade 3
and 4 abnormalities for ALT: 0.8%, 5.7% and 11.8% respectively. Values
for AST showed a similar dose dependent pattern (0.8%, 3.3%, 4.9%,
respectively). The dose-finding Trial BI 1182.52 showed KM estimated
probabilities of Grade 3 or 4 ALT and/or AST abnormalities through 24
weeks of TPV/r treatment for 7.5% of patients treated with TPV/r 500/100
mg, for 11.3% of patients treated with TPV/r 500/200 mg, and for 24.5%
of patients treated with TPV/r 750/200 mg. At a constant dose of TPV
(500 mg bid), a dose-related risk of Grade 3 or 4 ALT and/or AST
abnormalities is apparent with 7.5% of patients treated with RTV 100 mg
bid developing Grade 3 or 4 ALT and/or AST abnormalities as compared to
11.3% of patients treated with RTV 200 mg bid for at least 24 weeks. At
a constant dose of RTV (200 mg bid), a dose-related risk of Grade 3 or 4
ALT and/or AST abnormalities is apparent with 11.3% of patients treated
with TPV 500 mg bid developing Grade 3 or 4 ALT and/or AST abnormalities
as compared to 24.5% of patients treated with TPV 750 mg bid for at
least 24 weeks. Most of the hepatic transaminase and plasma lipid
elevations were mild and not associated with clinical symptoms, and
resolved spontaneously or with treatment discontinuation. No TPV dose
relationship with elevated plasma lipid levels was observed in these
trials.

The safety signals identified in the Phase I and II TPV/r studies were
gastrointestinal adverse events including nausea, vomiting and diarrhea,
skin rash, and abnormalities of hepatic transaminases and elevated
plasma lipids. The findings also were observed in the Phase III trials.

[]{#__RefHeading___Toc101398971 .anchor}8.3 CLINICAL SAFETY DATA OF
PIVOTAL, ACTIVE-CONTROLLED TRIALS (RESIST-1 AND RESIST-2)

While efficacy analyses focused on RESIST trial patients who reached the
Week 24 timepoint cut-off for NDA submission for accelerated approval,
safety analyses include all treated patients. For efficacy, 582 patients
in the TPV/r group and 577 patients in the CPI/r group were included.
Overall however, a total 748 patients received TPV/r 500/200 mg and 737
received CPI/r in the RESIST trials (mainly due to RESIST-2 patients who
had reached 16 weeks for European analyses but not 24 weeks for the FDA
analyses). For the CPI/r group, doses were as follows: LPV/r 400/100 mg
(n=358), IDV/r 800/100 mg (n=23), SQV/r 1000/100 mg or 800/200 mg
(n=162), and APV/r 600/100 mg (n=194). All doses were administered twice
daily.

A number of factors in the design of the RESIST trials complicate
analyses of safety including: the open-label design, the selection of
comparator PI based on ARV medication history in addition to resistance
data, and the differential dropout from the study arms. The design of
the RESIST trials, which allowed patients with documented virological
failure -- but not adverse events - to leave the CPI/r arm of the study
after 8 weeks, confounds comparison of safety between the treatment
arms. For the NDA submission analyses at Week 24, 85.7% (639 of 746)
patients remained in the TPV/r arm as compared to 48.4% (357 of 737) in
the CPI/r arm. This difference continues to increase and at the cut-off
for the Safety Update, 70.1% (524 of 748) patients in the TPV/r group as
compared to 31.3% (231 of 737) patients in the CPI/r group remained in
the study (Table 8.3: 1).

Table 8.3: 1 Disposition of RESIST trial patients

+----------------------+------------+----------+----------+----------+
|                      | NDA        |          | Safety   |          |
|                      | Submission |          | Update   |          |
+======================+============+==========+==========+==========+
| Disposition:         | TPV/r      | CPI/ra   | TPV/r    | CPI/ra   |
+----------------------+------------+----------+----------+----------+
| Total Treated        | 746        | 737      | 748      | 737      |
|                      | (100.0)    | (100.0)  | (100.0)  | (100.0)  |
+----------------------+------------+----------+----------+----------+
| Currently Continuing | 639 (85.7) | 357      | 524      | 231      |
| in Trials            |            | (48.4)   | (70.1)   | (31.3)   |
+----------------------+------------+----------+----------+----------+
| Prematurely          | 107 (14.3) | 380      | 224      | 506      |
| Discontinued         |            | (51.6)   | (29.9)   | (68.7)   |
+----------------------+------------+----------+----------+----------+
| > Adverse Event      | 56 (7.5)   | 27 (3.7) | 78       | 35 (4.7) |
|                      |            |          | (10.4)   |          |
+----------------------+------------+----------+----------+----------+
| > Non-compliant with | 8 (1.1)    | 15 (2.0) | 16 (2.1) | 22 (3.0) |
| > Protocol           |            |          |          |          |
+----------------------+------------+----------+----------+----------+
| > Lost to Follow-up  | 5 (0.7)    | 4 (0.5)  | 5 (0.7)  | 5 (0.7)  |
+----------------------+------------+----------+----------+----------+
| > Consent Withdrawn  | 6 (0.8)    | 5 (0.7)  | 8 (1.1)  | 6 (0.8)  |
+----------------------+------------+----------+----------+----------+
| > Lack of Efficacy   | 22 (2.9)   | 248      | 68 (9.1) | 316      |
|                      |            | (33.6)   |          | (42.9)   |
+----------------------+------------+----------+----------+----------+
| > Other              | 7 (0.9)    | 18 (2.4) | 15 (2.0) | 29 (3.9) |
+----------------------+------------+----------+----------+----------+
| > Missing            | 3 (0.4)    | 63 (8.5) | 34 (4.5) | 93       |
|                      |            |          |          | (12.6)   |
+----------------------+------------+----------+----------+----------+

> a CPI/r = LPV/r 400/100, IDV/r 800/100, SQV/r 1000/100 or SQV/r
> 800/200, and APV/r 600/100; all doses in mg.

Of the 43% (316 of 737) of patients who left the comparator arm of the
RESIST trials, 298 (94%) rolled over into Trial BI 1182.17 and received
TPV/r. Patients leaving the CPI/r arm of the trial due to virological
failure had lower median CD4+ counts (117 cells/mm3) and higher viral
loads (4.8 log~10~ copies/mL) compared to patients remaining in the
trial on CPI/r (median CD4+ count of 238 cells/mm3; viral load 3.7
log~10~ copies/mL). Thus, patients remaining in the comparator arm of
the study were more immune competent, on average, than patients
originally randomized into the RESIST trials, or patients remaining on
TPV/r. As a result, comparisons of TPV/r and CPI/r safety data beyond
the first 8 weeks of treatment should be interpreted cautiously.

The number of patients stopping trial participation due to an adverse
event was twice as frequent in the TPV/r group (10.4%) as in the CPI/r
group (4.7%). However, these data may have been influenced by entry
criteria that allowed patients with virological failure, but not adverse
events leading to CPI/r discontinuation, to rollover to Trial BI
1182.17.

[]{#__RefHeading___Toc101398972 .anchor}8.3.1 Exposure and disposition

In the Safety Update, exposure for the TPV/r group represents 615.0
person exposure years (PEY) while exposure for the CPI/r group
represents 405.7 PEY, an exposure difference of 50%. The large
difference exposure after 8 weeks between the TPV/r and CPI/r treatment
groups occurred largely from patients who virologically failed the CPI/r
regimen and exited the trial to receive TPV/r in the open label rollover
Trial BI 1182.17 (Table 8.3: 1 and Figure 8.3.1: 1). Nearly 50% of TPV/r
patients have been treated for at least 48 weeks, although not all
patients have had the opportunity to achieve the 48 week milestone by
the Safety Update cut-off (Table 8.3.1: 1).

Table 8.3.1: 1 Treatment exposure to trial medication in the RESIST
trials at time of NDA submission and in Safety Update

  -----------------------------------------------------------------------
  Duration:            NDA Submission             Safety      
                                                  Update      
  -------------------- -------------- ----------- ----------- -----------
                       TPV/r          CPI/ra      TPV/r       CPI/ra

  Total treated \[N    746 (100.0)    737 (100.0) 748 (100.0) 737 (100.0)
  (%)\]                                                       

  [\>]{.underline} 8   713 (95.6)     703 (95.4)  715 (95.6)  703 (95.4)
  weeks                                                       

  [\>]{.underline} 16  665 (89.1)     526 (71.4)  683 (91.3)  536 (72.7)
  weeks                                                       

  [\>]{.underline} 24  385 (51.6)     245 (33.2)  645 (86.2)  395 (53.6)
  weeks                                                       

  [\>]{.underline} 32  \--            \--         576 (77.0)  285 (38.7)
  weeks                                                       

  [\>]{.underline} 48  \--            \--         354 (47.3)  135 (18.3)
  weeks                                                       

  Median \[days\]      168.0          124.0       330.0       172.0

  Range \[days\]       1 - 274        1 -- 313    1 - 523     1 - 511

  Total person         300.3          264.6       615.0       405.7
  exposure yearsb                                             
  -----------------------------------------------------------------------

> a CPI/r = LPV/r 400/100, IDV/r 800/100, SQV/r 1000/100 or SQV/r
> 800/200, and APV/r 600/100; all doses in mg.
>
> b Definition of total person exposure years \[PEY\]: (sum of total
> duration across all patients)/365.25.

![](media/image11.wmf){width="4.455555555555556in"
height="3.079861111111111in"}

Figure 8.3.1: 1 Patients remaining in the RESIST trials by treatment
group up to 48 weeks

[]{#__RefHeading___Toc101398973 .anchor}8.3.2 Adverse Events in RESIST
trials

In the following sections, comparative frequencies of the most commonly
reported adverse events as reported in the Safety Update for TPV/r and
CPI/r patients in the RESIST trials are displayed. The order of
presentation is: (1) adverse events of any severity considered related
to study treatment, (2) serious adverse events, and (3) adverse events
leading to study drug discontinuation.

[Adverse events of any severity in RESIST trials]{.underline}

According to BI standards, intensity of adverse events was collected
using a mild, moderate, severe scale. Investigators were provided the
DAIDS grading scale and graded adverse events as follows: mild = DAIDS
Grade 1, moderate = Grade 2, severe = Grade 3 or 4.

The TPV/r group had a higher overall percentage of patients reporting
study drug-related adverse events of any severity: 41.7% compared with
27.8% in the CPI/r group. In general, for study drug-related adverse
events, no major differences were observed between the 2 treatment
groups. The only adverse events with \>2% differences between TPV/r and
CPI/r were diarrhea, nausea, and headache.

Table 8.3.2: 1 Study drug-related adverse events occurring in 1% or more
of RESIST trial patients in either treatment group in the Safety Update

+---------------------+----------+-----------+-----------+-----------+
|                     | Un       |           | Crude     |           |
|                     | adjusted |           | adjusted  |           |
|                     | Rate     |           | rate per  |           |
|                     |          |           | 100 PEY   |           |
+---------------------+----------+-----------+-----------+-----------+
| SOC / Preferred     | TPV/r a  | CPI/r a   | TPV/r     | CPI/r     |
| Term                |          |           |           |           |
+---------------------+----------+-----------+-----------+-----------+
| Total Treated or    | 748      | 737       | 615 PEY   | 405.7 PEY |
| Total Exposure      | (100.0)  | (100.0)   |           |           |
+---------------------+----------+-----------+-----------+-----------+
| **Total with Any    | **361    | **220     | **361     | **220     |
| AE**                | (48.3)** | (29.9)**  | (58.7)**  | (54.2)**  |
+---------------------+----------+-----------+-----------+-----------+
| **Gastrointestinal  | **233    | **161     | **233     | **161     |
| Disorders**         | (31.1)** | (21.8)**  | (37.9)**  | (39.7)**  |
+---------------------+----------+-----------+-----------+-----------+
| > Diarrhea          | 109      | 84 (11.4) | 109       | 84 (20.7) |
|                     | (14.6)   |           | (17.7)    |           |
+---------------------+----------+-----------+-----------+-----------+
| > Nausea            | 93       | 62 (8.4)  | 93 (15.1) | 62 (15.3) |
|                     | (12.4)   |           |           |           |
+---------------------+----------+-----------+-----------+-----------+
| > Vomiting          | 32 (4.3) | 23 (3.1)  | 32 (5.2)  | 23 (5.7)  |
+---------------------+----------+-----------+-----------+-----------+
| > Abdominal Pain    | 19 (2.5) | 20 (2.7)  | 19 (3.1)  | 20 (4.9)  |
+---------------------+----------+-----------+-----------+-----------+
| > Flatulence        | 23 (3.1) | 15 (2.0)  | 23 (3.7)  | 15 (3.7)  |
+---------------------+----------+-----------+-----------+-----------+
| > Abdominal         | 20 (2.7) | 13 (1.8)  | 20 (3.3)  | 13 (3.2)  |
| > Distension        |          |           |           |           |
+---------------------+----------+-----------+-----------+-----------+
| > Abdominal Pain    | 8 (1.1)  | 8 (1.1)   | 8 (1.3)   | 8 (2.0)   |
| > Upper             |          |           |           |           |
+---------------------+----------+-----------+-----------+-----------+
| > Loose Stools      | 12 (1.6) | 9 (1.2)   | 12 (2.0)  | 9 (2.2)   |
+---------------------+----------+-----------+-----------+-----------+
| > Dyspepsia         | 8 (1.1)  | 6 (0.8)   | 8 (1.3)   | 6 (1.5)   |
+---------------------+----------+-----------+-----------+-----------+
| **Nervous System    | **53     | **39      | **53      | **39      |
| Disorders**         | (7.1)**  | (5.3)**   | (8.6)**   | (9.6)**   |
+---------------------+----------+-----------+-----------+-----------+
| > Headache          | 28 (3.7) | 9 (1.2)   | 28 (4.6)  | 9 (2.2)   |
+---------------------+----------+-----------+-----------+-----------+
| > Dizziness         | 11 (1.5) | 7 (0.9)   | 11 (1.8)  | 7 (1.7)   |
+---------------------+----------+-----------+-----------+-----------+
| **General           | **49     | **32      | **49      | **32      |
| Disorders**         | (6.6)**  | (4.3)**   | (8.0)**   | (7.9)**   |
+---------------------+----------+-----------+-----------+-----------+
| > Fatigue           | 34 (4.5) | 19 (2.6)  | 34 (5.5)  | 19 (4.7)  |
+---------------------+----------+-----------+-----------+-----------+
| **Metabolism and    | **61     | **30      | **61      | **30      |
| Nutrition**         | (8.2)**  | (4.1)**   | (9.9)**   | (7.4)**   |
+---------------------+----------+-----------+-----------+-----------+
| > Anorexia          | 8 (1.1)  | 7 (0.9)   | 8 (1.3)   | 7 (1.7)   |
+---------------------+----------+-----------+-----------+-----------+
| > H                 | 24 (3.2) | 6 (0.8)   | 24 (3.9)  | 6 (1.5)   |
| ypertriglyceridemia |          |           |           |           |
+---------------------+----------+-----------+-----------+-----------+
| > Hyperlipidemia    | 17 (2.3) | 4 (0.5)   | 17 (2.8)  | 4 (1.0)   |
+---------------------+----------+-----------+-----------+-----------+
| **Skin**            | **46     | **27      | **46      | **27      |
|                     | (6.1)**  | (3.7)**   | (7.5)**   | (6.7)**   |
+---------------------+----------+-----------+-----------+-----------+
| > Rash              | 13 (1.7) | 7 (0.9)   | 13 (2.1)  | 7 (1.7)   |
+---------------------+----------+-----------+-----------+-----------+
| > Pruritus          | 11 (1.5) | 3 (0.4)   | 11 (1.8)  | 3 (0.7)   |
+---------------------+----------+-----------+-----------+-----------+
| **Investigations**  | **48     | **10      | **48      | **10      |
|                     | (6.4)**  | (1.4)**   | (7.8)**   | (2.5)**   |
+---------------------+----------+-----------+-----------+-----------+
| > ALT increased     | 17 (2.3) | 1 (0.1)   | 17 (2.8)  | 1 (0.2)   |
+---------------------+----------+-----------+-----------+-----------+
| > AST increased     | 12 (1.6) | 1 (0.1)   | 12 (2.0)  | 1 (1.2)   |
+---------------------+----------+-----------+-----------+-----------+
| > GGT increased     | 13 (1.7) | 1 (0.1)   | 13 (2.1)  | 1 (0.2)   |
+---------------------+----------+-----------+-----------+-----------+
| > Triglycerides     | 9 (1.2)  | 4 (0.5)   | 9 (1.5)   | 4 (1.0)   |
| > increased         |          |           |           |           |
+---------------------+----------+-----------+-----------+-----------+

> a BID Doses: TPV/r 500/200; CPI/r: LPV/r 400/100, IDV/r 800/100, SQV/r
> 1000/100 or 800/200, APV/r 600/100.

The frequency of adverse events for each of the individual protease
inhibitors in the CPI/r group was examined and the highest percentage of
patients with study drug-related adverse events was 34.6% in the SQV/r
group compared with 25.3% in the APV/r group and 25.1% in the LPV/r
groups. There were only 23 patients in the IDV/r group, thus no
comparisons for this group were made. The SQV/r group had the highest
percentage of patients with study drug-related gastrointestinal adverse
events: 26.5% compared with 19.1% and 19.0% in the APV/r and LPV/r
groups, respectively. In addition, the SQV/r group had the highest
percentage of patients with study drug-related nervous system disorder
adverse events: 7.4% compared with 6.2% and 3.6% in the APV/r and LPV/r
groups, respectively. The APV/r group had the highest percentage of
patients (4.6%) with study drug-related skin and subcutaneous disorder
adverse events (1.1% in the LPV/r group and 2.5% in the SQV/r group).

Diarrhea was self-limiting, manageable, and similar across both
treatment arms in the RESIST studies. Frequencies of patients with
diarrhea were higher in the Phase II trials likely due to the higher
doses of TPV used in early Phase II trials.

Although individual variability in the type and frequency of adverse
events was observed in evaluation of adverse events by age, gender, race
and geographic location, clinically, no unusual adverse event patterns
or other safety concerns were identified in the RESIST trials that would
suggest that TPV/r should be restricted or have the dose adjusted based
on these factors.

[Severe adverse events in RESIST trials\
]{.underline}Severe adverse events (DAIDS Grade 3 to 4) were reported in
16.1% of the 1483 patients; the most frequently reported severe adverse
event was diarrhea (TPV/r, 1.3%; CPI/r, 1.8%).

[]{#__RefHeading___Toc101398974 .anchor}8.3.3 Serious adverse events

[SAEs in the RESIST trials\
]{.underline}In the Safety Update of RESIST trials, 18.9% of patients in
the TPV/r arm as compared to 14.7% of patients in the CPI/r arm
experienced SAEs, regardless of causality. The most frequently observed
SAEs were in the infections and infestations system organ class (SOC).
Most events were associated with advanced HIV disease and were
comparable between the two treatment groups. Many of the excess SAEs
seen with TPV/r are no longer present after exposure adjustment. The
SAEs which remain more prevalent with TPV/r are in the general
disorders, metabolism and investigations SOC (Table 8.3.3: 1).

Table 8.3.3: 1 Any Serious Adverse Events occurring in 0.5% or more of
RESIST trial patients in the Safety Update

+------------------------+----------+---------+-----------+----------+
| SOC / Preferred Term   | Un       |         | Crude     |          |
|                        | adjusted |         | adjusted  |          |
|                        | Rate     |         | rate per  |          |
|                        |          |         | 100 PEY   |          |
+------------------------+----------+---------+-----------+----------+
|                        | TPV/ra   | CPI/ra  | TPV/r     | CPI/r    |
+------------------------+----------+---------+-----------+----------+
| Total Treated or Total | 748      | 737     | 615 PY    | 405.7 PY |
| Exposure               | (100.0)  | (100.0) |           |          |
+------------------------+----------+---------+-----------+----------+
| **Total with Any SAE** | **141    | **108   | **141     | **108    |
|                        | (18.9)** | (       | (22.9)**  | (26.6)** |
|                        |          | 14.7)** |           |          |
+------------------------+----------+---------+-----------+----------+
| **Infections and       | **53     | **49    | **53      | **49     |
| Infestations**         | (7.1)**  | (6.6)** | (8.6)**   | (12.1)** |
+------------------------+----------+---------+-----------+----------+
| > Pneumonia            | 10 (1.3) | 5 (0.7) | 10 (1.6)  | 5 (1.2)  |
+------------------------+----------+---------+-----------+----------+
| > Gastroenteritis      | 4 (0.5)  | 1 (0.1) | 4 (0.7)   | 1 (0.2)  |
+------------------------+----------+---------+-----------+----------+
| > CMV Chorioretinitis  | 4 (0.5)  | 2 (0.3) | 4 (0.7)   | 2 (0.5)  |
+------------------------+----------+---------+-----------+----------+
| > Esophageal           | 4 (0.5)  | 5 (0.7) | 4 (0.7)   | 5 (1.2)  |
| > Candidiasis          |          |         |           |          |
+------------------------+----------+---------+-----------+----------+
| > *PCP* Pneumonia      | 4 (0.5)  | 3 (0.4) | 4 (0.7)   | 3 (0.7)  |
+------------------------+----------+---------+-----------+----------+
| > PML                  | 1 (0.1)  | 4 (0.5) | 1 (0.2)   | 4 (1.0)  |
+------------------------+----------+---------+-----------+----------+
| **General Disorders**  | **30     | **18    | **30      | **18     |
|                        | (4.0)**  | (2.4)** | (4.9)**   | (4.4)**  |
+------------------------+----------+---------+-----------+----------+
| > Pyrexia              | 17 (2.3) | 11      | 17 (2.8)  | 11 (2.7) |
|                        |          | (1.5)   |           |          |
+------------------------+----------+---------+-----------+----------+
| > Rigors               | 4 (0.5)  | 0 (0.0) | 4 (0.7)   | 0 (0.0)  |
+------------------------+----------+---------+-----------+----------+
| **Gastrointestinal     | **27     | **18    | **27      | **18     |
| Disorders**            | (3.6)**  | (2.4)** | (4.4)**   | (4.4)**  |
+------------------------+----------+---------+-----------+----------+
| > Diarrhea             | 9 (1.2)  | 5 (0.7) | 9 (1.5)   | 5 (1.2)  |
+------------------------+----------+---------+-----------+----------+
| > Pancreatitis         | 4 (0.5)  | 0 (0.0) | 4 (0.7)   | 0 (0.0)  |
+------------------------+----------+---------+-----------+----------+
| > Abdominal Pain       | 4 (0.5)  | 1 (0.1) | 4 (0.7)   | 1 (0.2)  |
+------------------------+----------+---------+-----------+----------+
| > Vomiting             | 4 (0.5)  | 3 (0.4) | 4 (0.7)   | 3 (0.7)  |
+------------------------+----------+---------+-----------+----------+
| **Metabolism and       | **14     | **7     | **14      | **7      |
| Nutrition**            | (1.9)**  | (0.9)** | (2.3)**   | (1.7)**  |
+------------------------+----------+---------+-----------+----------+
| > Dehydration          | 8 (1.1)  | 3 (0.4) | 8 (1.3)   | 3 (0.7)  |
+------------------------+----------+---------+-----------+----------+
| **Respiratory          | **14     | **10    | **14      | **10     |
| Disorders**            | (1.9)**  | (1.4)** | (2.3)**   | (2.5)**  |
+------------------------+----------+---------+-----------+----------+
| > Dyspnea              | 3 (0.4)  | 4 (0.5) | 3 (0.5)   | 4 (1.0)  |
+------------------------+----------+---------+-----------+----------+
| **Nervous System       | **13     | **14    | **13      | **14     |
| Disorders**            | (1.7)**  | (1.9)** | (2.1)**   | (3.5)**  |
+------------------------+----------+---------+-----------+----------+
| > Headache             | 5 (0.7)  | 2 (0.3) | 5 (0.8)   | 2 (0.5)  |
+------------------------+----------+---------+-----------+----------+
| **Investigations**     | **11     | **5     | **11      | **5      |
|                        | (1.5)**  | (0.7)** | (1.8)**   | (1.2)**  |
+------------------------+----------+---------+-----------+----------+
| > ALT Increased        | 5 (0.7)  | 0 (0.0) | 5 (0.8)   | 0 (0.0)  |
+------------------------+----------+---------+-----------+----------+
| **Renal and Urinary    | **11     | **5     | **11      | **5      |
| Disorders**            | (1.5)**  | (0.7)** | (1.8)**   | (1.2)**  |
+------------------------+----------+---------+-----------+----------+
| > Renal Failure Acute  | 5 (0.7)  | 2 (0.3) | 5 (0.8)   | 2 (0.5)  |
+------------------------+----------+---------+-----------+----------+
| **Psychiatric          | **4      | **8     | **4       | **8      |
| Disorders**            | (0.5)**  | (1.1)** | (0.7)**   | (2.0)**  |
+------------------------+----------+---------+-----------+----------+
| > Depression           | 1 (0.1)  | 5 (0.7) | 1 (0.2)   | 5 (1.2)  |
+------------------------+----------+---------+-----------+----------+
| **Blood and Lymphatic  | **8      | **10    | **8       | **10     |
| System**               | (1.1)**  | (1.4)** | (1.3)**   | (2.5)**  |
+------------------------+----------+---------+-----------+----------+
| > Anemia               | 4 (0.5)  | 7 (0.9) | 4 (0.7)   | 7 (1.7)  |
+------------------------+----------+---------+-----------+----------+

> a BID Doses: TPV/r 500/200; CPI/r: LPV/r 400/100, IDV/r 800/100, SQV/r
> 1000/100 or 800/200, APV/r 600/100.

Based on the data in the comparative RESIST trials, there are no
indications that TPV/r therapy contributes to more SAEs or has a unique
safety profile compared with other ritonavir-boosted PIs.

[]{#__RefHeading___Toc101398975 .anchor}8.3.4 Adverse events leading to
discontinuation of treatment

In the RESIST trials, 12.3% of patients in the TPV/r group and 4.9% of
patients in the CPI/r group experienced adverse events which led to
study drug discontinuation (Table 8.3.4: 1).

The SOC with the highest percentage of patients with adverse events
leading to discontinuation of study medication was the gastrointestinal
disorders SOC (4.5% TPV/r and 3.0% CPI/r).

The percentages of patients with adverse events leading to
discontinuation of study medication were consistently higher in the
TPV/r group. While numbers were small, it should be noted that the TPV/r
group had many more patients discontinuing with events in the SOC of
investigations (TPV/r 2.7%, CPI/r 0.1%), and this difference between
treatment groups remained with crude adjustment for exposure. The
investigations SOC includes laboratory test abnormality events which are
discussed in detail in the laboratory data section.

The most frequently reported adverse events leading to discontinuation
of study medication in the RESIST trials consisted of the following:
nausea (1.7% TPV/r, 1.1% CPI/r), diarrhea (1.7% TPV/r, 1.1% CPI/r),
vomiting (1.1% in both TPV/r and CPI/r groups), and increased ALT (0.9%
TPV/r, 0.0% CPI/r). All other adverse events leading to discontinuation
of study medication occurred in 0.5% of all patients ([\<]{.underline} 4
patients).

Table 8.3.4: 1 Adverse events leading to discontinuation of study
medication in 3 or more RESIST trial patients in the Safety Update

+-----------------------+-----------+----------+-----------+-----------+
|                       | U         |          | Crude     |           |
|                       | nadjusted |          | adjusted  |           |
|                       | rate      |          | rate per  |           |
|                       |           |          | 100 PEY   |           |
+-----------------------+-----------+----------+-----------+-----------+
|                       | TPV/ra    | CPI/ra   | TPV/r     | CPI/r     |
+-----------------------+-----------+----------+-----------+-----------+
| Total Treated or      | 748       | 737      | 615 PY    | 405.7 PY  |
| Total Exposure        | (100.0)   | (100.0)  |           |           |
+-----------------------+-----------+----------+-----------+-----------+
| **Total with Any AE   | **92      | **47     | **92      | **47      |
| Leading to            | (12.3)**  | (6.4)**  | (15.0)**  | (11.6)**  |
| Discontinuation**     |           |          |           |           |
+-----------------------+-----------+----------+-----------+-----------+
| **Gastrointestinal    | **34      | **22     | **34      | **22      |
| Disorders**           | (4.5)**   | (3.0)**  | (5.5)**   | (5.4)**   |
+-----------------------+-----------+----------+-----------+-----------+
| > Nausea              | 13 (1.7)  | 8 (1.1)  | 13 (2.1)  | 8 (2.0)   |
+-----------------------+-----------+----------+-----------+-----------+
| Vomiting              | 8 (1.1)   | 8 (1.1)  | 8 (1.3)   | 8 (2.0)   |
+-----------------------+-----------+----------+-----------+-----------+
| > Diarrhea            | 13 (1.7)  | 8 (1.1)  | 13 (2.1)  | 8 (2.0)   |
+-----------------------+-----------+----------+-----------+-----------+
| > Abdominal Pain      | 2 (0.3)   | 4 (0.5)  | 2 (0.3)   | 4 (1.0)   |
+-----------------------+-----------+----------+-----------+-----------+
| **Investigations**    | **20      | **1      | **20      | **1       |
|                       | (2.7)**   | (0.1)**  | (3.3)**   | (0.2)**   |
+-----------------------+-----------+----------+-----------+-----------+
| > ALT Increased       | 7 (0.9)   | 0 (0.0)  | 7 (1.1)   | 0 (0.0)   |
+-----------------------+-----------+----------+-----------+-----------+
| > AST Increased       | 3 (0.4)   | 0 (0.0)  | 3 (0.5)   | 0 (0.0)   |
+-----------------------+-----------+----------+-----------+-----------+
| > GGT Increased       | 4 (0.5)   | 0 (0.0)  | 4 (0.7)   | 0 (0.0)   |
+-----------------------+-----------+----------+-----------+-----------+
| > Hepatic Enzyme      | 3 (0.4)   | 0 (0.0)  | 3 (0.5)   | 0 (0.0)   |
| > Increased           |           |          |           |           |
+-----------------------+-----------+----------+-----------+-----------+
| > Triglycerides       | 3 (0.4)   | 0 (0.0)  | 3 (0.5)   | 0 (0.0)   |
| > Increased           |           |          |           |           |
+-----------------------+-----------+----------+-----------+-----------+
| **General Disorders** | **15      | **7      | **15      | **7       |
|                       | (2.0)**   | (0.9)**  | (2.4)**   | (1.7)**   |
+-----------------------+-----------+----------+-----------+-----------+
| > Fatigue             | 4 (0.5)   | 1 (0.1)  | 4 (0.7)   | 1 (0.2)   |
+-----------------------+-----------+----------+-----------+-----------+
| > Pyrexia             | 4 (0.5)   | 3 (0.4)  | 4 (0.7)   | 3 (0.7)   |
+-----------------------+-----------+----------+-----------+-----------+
| **Metabolism and      | **11      | **6      | **11      | **6       |
| Nutrition**           | (1.5)**   | (0.8)**  | (1.8)**   | (1.5)**   |
+-----------------------+-----------+----------+-----------+-----------+
| > Anorexia            | 4 (0.5)   | 1 (0.1)  | 4 (0.7)   | 1 (0.2)   |
+-----------------------+-----------+----------+-----------+-----------+
| **Hepatobiliary       | **9       | **1      | **9       | **1       |
| Disorders**           | (1.2)**   | (0.1)**  | (1.5)**   | (0.2)**   |
+-----------------------+-----------+----------+-----------+-----------+
| > Cytolytic Hepatitis | 2 (0.3)b  | 0 (0.0)  | 2 (0.3)   | 0 (0.0)   |
+-----------------------+-----------+----------+-----------+-----------+
| **Skin Disorders**    | **7       | **5      | **7       | **5       |
|                       | (0.9)**   | (0.7)**  | (1.1)**   | (1.2)**   |
+-----------------------+-----------+----------+-----------+-----------+
| > Rash                | 4 (0.5)   | 1 (0.1)  | 4 (0.7)   | 1 (0.2)   |
+-----------------------+-----------+----------+-----------+-----------+

> a BID Doses: TPV/r 500/200; CPI/r: LPV/r 400/100, IDV/r 800/100, SQV/r
> 1000/100 or 800/200, APV/r 600/100.

The rate of discontinuation from the trial is slightly higher in the
TPV/r group than the CPI/r group, but this rate is offset by the high
rate of discontinuations due to virologic failure in the CPI/r group,
leaving a disproportionately higher number of patients on TPV/r
treatment in the RESIST trials.

There were no new or unexpected events identified that lead to
discontinuation of study medication in the RESIST trials; data are
consistent to early Phase II findings.

[]{#__RefHeading___Toc101398976 .anchor}8.3.5 Exploratory analyses of
medically selected terms

An exploratory analysis of adverse events was conducted to evaluate
PI-specific class effects (e.g., fat redistribution), events warranting
evaluation because of preclinical or early clinical experience with
TPV/r (e.g., hepatitis, bleeding, rash), or identified as issues of
concern for the development of any drug product or effects of concern
for the development of any drug product (e.g., QTc prolongation). For
this analysis, a broad range of preferred terms were included to
comprise each medically selected term (MST); the MST name is a
descriptor of the preferred terms and only one of the collection of
preferred terms, thus the MST name is used with quotes (" ") around the
term.

Figure 8.3.5: 1 summarizes the relative risk of individual Medically
Selected Terms observed with TPV/r as compared to CPI/r in the NDA
Summary of Clinical Safety (SCS) and in the Safety Update. In the Safety
Update population there was no overall increased risk for TPV/r compared
to the CPI/r of "hyperglycemia," "ischemic heart disease,"
"pancreatitis", "rash", "renal failure" and "QTc prolongation" events.
The relative risk (RR) of these MSTs ranged from 0.44 to 1.00, however,
these measures were moderately precise.

![](media/image12.wmf){width="5.963888888888889in"
height="4.045138888888889in"}

Figure 8.3.5: 1 Relative risk of medically selected term adverse events
between treatment groups in RESIST trials: Comparison of NDA Summary of
Clinical Safety and Safety Update populations

a Relative risk = TPV/r to CPI/r.

The overall relative risk of "bleeding" events decreased from 1.98 (95%
CI = 1.03, 3.80) in the Summary of Clinical Safety population to 1.19
(95% CI = 0.67, 2.12) in the Safety Update population. There appears to
be no consistent pattern of "bleeding" events. There are no notable
differences between treatment groups in Grade 3 or 4 laboratory
parameters for decreased hemoglobin, decreased platelets, or prolonged
PT (see laboratory section). Overall, there seems to be normalization of
the relative risk of bleeding between the TPV/r and CPI/r arm with the
Safety Update.

The RESIST trials evaluated a highly PI-experienced patient population,
with many patients entering the trials with significant lipodystrophy.
In the Safety Update, TPV/r patients continue to have a greater risk of
"fat redistribution" than CPI/r patients. The ultimate impact of TPV/r
on "fat redistribution" will need to be assessed with longer term data
from the RESIST trials and a metabolic substudy including DEXA exams in
Trial BI 1182.33 of treatment naïve HIV-positive patients.

Elevated liver enzymes (ALT/AST) and clinical "hepatitis" were more
common in patients receiving TPV/r than patients receiving CPI/r. This
will be described in the laboratory section below.

"Hyperlipidemia" was more common in TPV/r patients than CPI/r patients.
These lipid elevations were not associated with increased rates of
"pancreatitis" or "ischemic heart disease". Given the short duration of
follow-up, it is not possible to draw definitive conclusions regarding
risk of potential long term sequelae of elevated plasma lipids, e.g.
ischemic heart disease. Long term follow-up data will be needed to
adequately assess this potential risk.

Treatment with TPV/r does not appear to increase the risk of "rash"
compared to other ritonavir-boosted PIs. However, based on the signal
from the Phase I drug interaction study of oral contraceptive use in
women and analyses conducted on the Phase III RESIST data, patients with
lower CD4+ counts and women using estrogens appear to be at greater risk
of developing non-serious rashes.

[]{#__RefHeading___Toc101398977 .anchor}8.4 LABORATORY EVALUATIONS OF
PIVOTAL, ACTIVE-CONTROLLED TRIALS (RESIST-1 AND RESIST-2)

An evaluation of DAIDS Grade 3 and 4 laboratory abnormalities, including
assessments of risk factors and patterns of elevations, is presented in
this section.

**8.4.1 Overview of DAIDS Grade 3 and 4 Laboratory Abnormalities in the
Safety Update**

For the hematology parameters, with the exception of Grade 3 or 4
decreased WBC in 4.9% of TPV/r patients and 5.5% of CPI/r patients, few
patients had hematology abnormalities (Table 8.4.1: 1). For most
chemistry analytes, Grade 3 or 4 abnormalities were relatively few and
similar between treatment groups, with the exception of ALT, AST, total
cholesterol and triglycerides.

Table 8.4.1: 1 DAIDS Grade 3 or 4 laboratory abnormalities in the RESIST
trials, reported in the Safety Update

+-----------------+---------+--------+--------+-------+-------+-------+
|                 | TPV/r   |        |        | CPI/r |       |       |
|                 |         |        |        |       |       |       |
|                 | N=733   |        |        | N=737 |       |       |
+-----------------+---------+--------+--------+-------+-------+-------+
| Laboratory Test | Grade 3 | Grade  | Total  | Grade | Grade | Total |
|                 |         | 4      |        | 3     | 4     |       |
+-----------------+---------+--------+--------+-------+-------+-------+
| Hematology      |         |        |        |       |       |       |
+-----------------+---------+--------+--------+-------+-------+-------+
| > Haemoglobin   | 2 (0.3) | 1      | 3      | 2     | 0     | 2     |
|                 |         | (0.1)  | (0.4)  | (0.3) | (0.0) | (0.3) |
+-----------------+---------+--------+--------+-------+-------+-------+
| > WBC Count     | 34      | 2      | 36     | 32    | 8     | 40    |
| > (decrease)    | (4.6)   | (0.3)  | (4.9)  | (4.4) | (1.1) | (5.5) |
+-----------------+---------+--------+--------+-------+-------+-------+
| > Platelets     | 5 (0.7) | 3      | 8      | 6     | 1     | 7     |
|                 |         | (0.4)  | (1.1)  | (0.8) | (0.1) | (1.0) |
+-----------------+---------+--------+--------+-------+-------+-------+
| > Prothrombin   | 6 (0.8) | 2      | 8      | 6     | 2     | 8     |
| > Time          |         | (0.3)  | (1.1)  | (0.8) | (0.3) | (1.1) |
+-----------------+---------+--------+--------+-------+-------+-------+
| Chemistry       |         |        |        |       |       |       |
+-----------------+---------+--------+--------+-------+-------+-------+
| > ALT           | 38      | 28     | 66     | 12    | 4     | 16    |
|                 | (5.2)   | (3.8)  | (9.0)  | (1.7) | (0.6) | (2.2) |
+-----------------+---------+--------+--------+-------+-------+-------+
| > AST           | 34      | 10     | 44     | 11    | 3     | 14    |
|                 | (4.6)   | (1.4)  | (6.0)  | (1.5) | (0.4) | (1.9) |
+-----------------+---------+--------+--------+-------+-------+-------+
| > ALT and/or    | 44      | 28     | 72     | 17    | 5     | 22    |
| > AST           | (6.0)   | (3.8)  | (9.8)  | (2.3) | (0.7) | (3.0) |
+-----------------+---------+--------+--------+-------+-------+-------+
| > Bilirubin,    | 3 (0.4) | 2      | 5      | 3     | 1     | 4     |
| > Total         |         | (0.3)  | (0.7)  | (0.4) | (0.1) | (0.6) |
+-----------------+---------+--------+--------+-------+-------+-------+
| > Alkaline      | 3 (0.4) | 0      | 3      | 1     | 1     | 2     |
| > phosphatase   |         | (0.0)  | (0.4)  | (0.1) | (0.1) | (0.3) |
+-----------------+---------+--------+--------+-------+-------+-------+
| > Amylase       | 40      | 2      | 42     | 45    | 5     | 50    |
|                 | (5.5)   | (0.3)  | (5.7)  | (6.2) | (0.7) | (6.9) |
+-----------------+---------+--------+--------+-------+-------+-------+
| > Lipase        | 17      | 2      | 19     | 15    | 3     | 18    |
|                 | (2.3)   | (0.3)  | (2.6)  | (2.1) | (0.4) | (2.5) |
+-----------------+---------+--------+--------+-------+-------+-------+
| > Total         | 22      | 7      | 29     | 2     | 1     | 3     |
| > Cholesterol   | (3.0)   | (1.0)  | (4.0)  | (0.3) | (0.1) | (0.4) |
+-----------------+---------+--------+--------+-------+-------+-------+
| > Triglycerides | 117     | 53     | 170    | 59    | 30    | 89    |
|                 | (16.0)  | (7.2)  | (23.2) | (8.1) | (4.1) | (     |
|                 |         |        |        |       |       | 12.2) |
+-----------------+---------+--------+--------+-------+-------+-------+
| > Glucose       | 11      | 2      | 13     | 7     | 1     | 8     |
| > (increase)    | (1.5)   | (0.3)  | (1.8)  | (1.0) | (0.1) | (1.1) |
+-----------------+---------+--------+--------+-------+-------+-------+
| > Glucose       | 0 (0.0) | 0      | 0      | 0     | 3     | 3     |
| > (decrease)    |         | (0.0)  | (0.0)  | (0.0) | (0.4) | (0.4) |
+-----------------+---------+--------+--------+-------+-------+-------+
| > Creatinine    | 2 (0.3) | 0      | 2      | 1     | 0     | 1     |
|                 |         | (0.0)  | (0.3)  | (0.1) | (0.0) | (0.1) |
+-----------------+---------+--------+--------+-------+-------+-------+

a Total number of patients with Grade 3 or 4 elevations as worst
intensity during 24 weeks. For inclusion in this analysis both a
baseline and at least one on-treatment lab value had to be present.

b Grade (DAIDS or BI) and lab value units: ALT or AST Grade 3 = \>5.0 -
10.0 x ULN or 201 -- 400 U/L; Grade 4 = \>10.0 x ULN or \>400 U/L; Total
bilirubin Grade 3 = \>2.5 -- 5.0 x ULN or \>3.0 -- 6.0 mg/dl; Grade 4 =
\>5.0 x ULN or \>6.0 mg/dl; Total cholesterol Grade 3 = 400 -- 500
mg/dl; Grade 4 - \>500 mg/dl; Fasting triglycerides Grade 3 = 751‑1200
mg/dl; Grade 4 = \>1200 mg/dl.

**8.4.2 Hepatic transaminase elevations in the Safety Update**

8.4.2.1 Evaluation of ALT and/or AST abnormalities

In the Safety Update, Grade 3 or 4 ALT and/or AST combined (ALT/AST)
abnormalities were found in 72 (9.8%) of 733 patients in the TPV/r group
compared to 26 (3.6%) of 727 patients in the CPI/r group. Two additional
patients in the TPV/r group were found to have Grade 3 total bilirubin.
Grade 4 ALT/AST abnormalities were found in 28 (3.8%) of 733 patients in
the TPV/r group compared to 5 (0.7%) of 727 patients in the CPI/r group.

The relative risk of Grade 3 or 4 ALT/AST abnormalities (Table
8.4.2.1: 1), adjusted for patient exposure years to study medication,
was higher in the TPV/r group compared to CPI/r group (RR=2.41, 95% CI
1.49, 3.88).

The Kaplan-Meier (K-M) estimates of the time to first Grade 3 or 4
ALT/AST laboratory abnormalities up to 48 weeks are shown in
Figure 8.4.2.1: 1. The K‑M cumulative probability for Grade 3 or 4
ALT/AST in the TPV/r group was 10.3% at 48 weeks; while the cumulative
probability for Grade 3 or 4 ALT/AST in the CPI/r group was 3.9% at 48
weeks (p = 0.0002, log rank test).

The K-M cumulative probability of developing Grade 4 ALT/AST
abnormalities at 48 weeks was 4.2% in the TPV/r group compared to 0.9%
in the CPI/r group (p = 0.0014, log rank test).

Table 8.4.2.1: 1 Number and cumulative probability of DAIDS Grade 3 or 4
ALT or AST abnormalities in RESIST trials

  ------------ -------------- -------------- --------------- -------------
  Weeks in     TPV/r                         CPI/r           
  Trial                                                      

               No. (%)        No. Patients   No. (%)         No. Patients
               Patients with  Entering       Patients with   Entering
               Grade 3 or 4   Interval       Grade 3 or 4    Interval

  \< 0 - 2     7 (0.9)        748            0 (0.0)         737

  \> 2 - 4     9 (2.2)        733            6 (0.8)         729

  \> 4 - 8     6 (3.0)        714            4 (1.4)         711

  \> 8 - 16    7 (4.0)        696            5 (2.1)         693

  \> 16 - 24   13 (5.9)       659            2 (2.6)         524

  \> 24 - 32   11 (7.7)       613            3 (3.4)         384

  \> 32 - 40   9 (9.4)        539            0 (3.4)         276

  \> 40 - 48   4 (10.3)       445            1 (3.9)         201
  ------------ -------------- -------------- --------------- -------------

![](media/image13.png){width="6.21875in"
height="3.6979166666666665in"}Figure 8.4.2.1: 1 Kaplan-Meier estimates
for time to onset of DAIDS Grade 3 or 4 ALT or AST abnormalities up to
48 weeks in RESIST trials

8.4.2.2 Multivariable analysis for risk of LFT elevations

A Cox regression multivariable analysis was performed to identify
factors predicting the risk of liver laboratory test abnormality for
TPV/r and CPI/r patients (Table 8.4.2.2: 1). Liver laboratory test
abnormalities were defined as any Grade 3 or 4 ALT, AST, or total
bilirubin elevation during treatment as these three parameters are
deemed to be reflective of potential liver injury.

The analysis considered treatment group, age, gender, race, CD4+ cell
count at baseline, HIV RNA count at baseline, Center for Disease Control
(CDC) HIV infection classification category, time since first diagnosis
of HIV infection, use of NRTIs with the potential for hepatotoxicity
(ddI, d4T, or ddC), HBV or HCV co-infection, number of prior ARV
medications, NNRTI usage, the maximum baseline Grade for ALT, AST and
total bilirubin, and elevated baseline triglycerides.

The model identified TPV/r treatment as a significant risk factor
associated with the development of liver test abnormalities (RR=2.4, 95%
CI =1.5-3.8). Other risk factors were elevated baseline liver tests,
co-infection with HBV and/or HCV, and CD4+ cell count \>200 cell/mm^3^.
The risk posed by TPV/r treatment is similar to that of elevated
baseline liver function tests.

Table 8.4.2.2: 1 Cox regression assessing risk a for Grade 3 or 4 ALT,
AST or total bilirubin abnormalities

+----------------------------------------+-------------+--------------+
| Factor/Comparison                      | > Risk      | > 95% CI     |
|                                        | > Ratio     |              |
+----------------------------------------+-------------+--------------+
| Baseline ALT, AST total bilirubin:     | 2.5         | 1.3-4.8      |
|                                        |             |              |
| > Grade 2 or 3 vs Grade 0 to 1:        |             |              |
+----------------------------------------+-------------+--------------+
| Treatment Group:                       | 2.4         | 1.5-3.8      |
|                                        |             |              |
| > TPV/r vs CPI/r                       |             |              |
+----------------------------------------+-------------+--------------+
| CD4+ Cell Count at Baseline            | 2.0         | 1.3-2.5      |
| (cells/mm3):                           |             |              |
|                                        |             |              |
| > ≥200 vs \<200                        |             |              |
+----------------------------------------+-------------+--------------+
| HBV or HCV Co-infection:               | 2.3         | 1.4-3.7      |
|                                        |             |              |
| > Co-infected vs not co-infected       |             |              |
+----------------------------------------+-------------+--------------+

> a Risk factors for Grade 3-4 ALT/AST are similar in TPV/r and CPI/r

8.4.2.3 Actions taken with LFT abnormalities

Following the onset of Grade 3 or 4 ALT, AST or total bilirubin liver
test abnormalities, investigators in the RESIST trials had protocol
management guidelines, but were able to continue, interrupt or
discontinue a patient\'s study medication. Most patients who developed
Grade 3 or 4 liver test abnormalities remained on treatment or
temporarily interrupted treatment without permanent discontinuation as
detailed below:

**Among patients treated with TPV/r, 74 who had Grade 3/4 liver test
abnormalities:**

-   57 (77.0%) of the 74 TPV/r patients with Grade 3 or 4 liver test
    abnormalities continued TPV/r treatment:

    -   46 (62.2%) patients continued treatment without interruption:

        -   7 (9.5%) patients had Grade 3 or 4 liver test abnormalities
            at their last observed visit and were not discontinued;

        -   30 (40.5%) patients continued study treatment, and the liver
            test abnormalities returned to values of Grade 2 or less;

        -   8 (10.8%) patients continued study treatment, and the liver
            test abnormalities remained stable (Grade 3 or higher);

        -   1 (1.4%) patient continued study treatment, and a Grade 3
            elevated ALT/AST/bilirubin level increased to Grade 4.

    -   11 (14.8%) of the 74 TPV/r patients had a treatment interruption
        associated with Grade 3 or 4 liver test abnormalities that
        subsequently returned to Grade 2 or less

-   17 (23.0%) of the 74 TPV/r patients had study medication
    discontinued due to a liver test abnormalities. The reason for
    discontinuation was directly related to transaminase elevation
    and/or a liver-related AE preferred term.

**Among patients treated with CPI/r, 26 who had Grade 3/4 liver test
abnormalities:**

-   26 (100.0%) of the 26 CPI/r patients with Grade 3 or 4 liver test
    abnormalities continued CPI/r treatment without permanent
    discontinuation.

    -   23 (88.5%) of the 26 CPI/r patients with Grade 3 or 4 liver test
        abnormalities continued treatment without interruption:

        -   5 (19.2%) patients had Grade 3 or 4 liver test abnormalities
            at their last observed visit and were not discontinued;

        -   18 (69.2%) patients continued study treatment, and the Grade
            3 or 4 liver test abnormalities returned to values of Grade
            2 or less;

    -   3 (11.5%) of the 26 CPI/r patients had a treatment interruption
        associated with a Grade 3 or 4 liver test abnormalities that
        subsequently returned to Grade 2 or less;

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-   There were no patients in the CPI/r group who had study medication
    discontinued due to a Grade 3 or 4 liver test abnormalities.

    8.4.2.4 Clinical hepatic adverse events

In an evaluation of clinical hepatic adverse events associated with
Grade 3 or 4 LFT abnormalities (ALT, AST, or total bilirubin), each of
the 74 patients treated with TPV/r and 26 patients treated with CPI/r
were reviewed and categorized as having (1) adverse events potentially
related to liver injury, i.e., hepatobiliary disorders, investigations
indicative of an elevation in a liver test reported as an adverse event,
or infection associated with HBV or HCV; or (2) other adverse events not
attributable to liver injury (Table 8.4.2.4: 1).

Of the 74 TPV/r patients with Grade 3 or 4 LFT elevations, 39 (52.7%)
patients had liver-related adverse events compared with 5 (19.2%) of the
26 patients in the CPI/r group. Serious adverse events in any SOC were
reported in 22 (29.7%) of the 74 TPV/r patients with Grade 3 or 4 liver
test elevations as compared with 5 (19.2%) of the 26 patients in the
CPI/r group. There were 8 (10.8%) liver-related SAEs in the TPV/r group
and no liver-related SAEs in the CPI/r group.

Thirty (40.5%) of 74 TPV/r patients and 18 (69.2%) of 26 CPI/r patients
discontinued treatment for any reason. Of all patients with Grade 3 or 4
test abnormalities who discontinued study drug, 17 (23.0%) of the 30
patients in the TPV/r group and none of the 18 patients in the CPI/r
group were discontinued due to a liver-related adverse event.

Three TPV/r treated patients in the RESIST trials who died had a hepatic
event reported as part of the clinical course prior to their death.
These patients are discussed in the context of mortality observed in the
entire TPV development program in Section 8.5.

Table 8.4.2.4: 1 Potential liver-related clinical events associated with
Grade 3 or 4 liver test abnormalities in the RESIST trials

+-------------------------------------------+------------+------------+
|                                           | TPV/r      | CPI/r      |
+-------------------------------------------+------------+------------+
| Total Treated                             | 748        | 737        |
|                                           | (100.0)    | (100.0)    |
+-------------------------------------------+------------+------------+
| Total with Laboratory Informationa        | 735 (98.3) | 728 (98.8) |
+-------------------------------------------+------------+------------+
| Total with Grade 3 or 4 ALT, AST, or      | 74 (10.1)  | 26 (3.6)   |
| Total Bilirubin Event                     |            |            |
+-------------------------------------------+------------+------------+
| > Total with Any SAE                      | 22 (29.7)  | 5 (19.2)   |
+-------------------------------------------+------------+------------+
| > Total with Liver-related SAE            | 8 (10.8)   | 0          |
+-------------------------------------------+------------+------------+
| > Total Discontinued for Any Reason       | 30 (40.5)  | 18 (69.2)  |
+-------------------------------------------+------------+------------+
| > Total Discontinued for Liver-related    | 17 (23.0)  | 0          |
| > Event                                   |            |            |
+-------------------------------------------+------------+------------+
| > Clinical Events                         | 72 (97.39) | 23 (88.5)  |
+-------------------------------------------+------------+------------+
| > Hepatobiliary Disordersb                | 17 (23.0)  | 0          |
+-------------------------------------------+------------+------------+
| > Investigationsc                         | 26 (35.1)  | 5 (19.2)   |
+-------------------------------------------+------------+------------+
| > Infections and Infestationsd            | 1 (1.4)    | 1 (3.8)    |
+-------------------------------------------+------------+------------+
| > Other System Organ Classes              | 66 (89.2)  | 23 (88.5)  |
+-------------------------------------------+------------+------------+
| > Total of Hepatobiliary, Investigations, | 39 (52.7)  | 5 (19.2)   |
| > and Infections and Infestations         |            |            |
+-------------------------------------------+------------+------------+

> a All on-treatment laboratory test values used, regardless of whether
> baseline value was available.
>
> b Preferred terms: cholestasis, cytolytic hepatitis, hepatitis toxic,
> hyperbilirubinemia, jaundice, and liver disorder.
>
> c Preferred terms: alanine aminotransferase (ALT) increased, aspartate
> aminotransferase (AST) increased, hepatic enzyme increased, liver
> function test abnormal, and transaminase increased.
>
> d Preferred terms: Hepatitis B and Hepatitis C.

8.4.2.5 Summary of Hepatic Findings

During the Phase I and II trials, a dose related increase in Grade 3/4
elevations in ALT or AST was observed. Most of the hepatic transaminase
elevations were mild; not associated with clinical symptoms; and
resolved spontaneously or with treatment discontinuation. These findings
were confirmed in the Phase III RESIST trials. The majority of TPV/r
patients with Grade 3/4 elevated ALT or AST continued TPV/r treatment
without permanent discontinuation.

A Cox regression model identified treatment with TPV/r, elevated
baseline LFTs (Grade 2/3), CD4+ cell count [\>]{.underline} 200 and
co-infection with Hepatitis B or C as risk factors for developing Grade
3/4 elevations in hepatic transaminases.

An exploratory analysis of medically selected hepatic terms from the
RESIST trials, laboratory and clinical outcomes, suggested that TPV/r
treated patients were at greater risk of developing laboratory or
clinical hepatic events compared to CPI/r.

**8.4.3 Fasting lipid elevations**

8.4.3.1 Triglyceride elevations

Grade 3 or Grade 4 triglyceride elevations occurred in 23.2% patients in
the TPV/r group and 12.2% patients in the CPI/r group. These
abnormalities continued to develop in both treatment groups through 48
weeks. The Kaplan-Meier estimates of time to first Grade 3 or 4
triglyceride abnormality are shown in Figure 8.4.3.1: 1. The estimated
probability of a Grade 3 or 4 triglyceride elevation was higher in the
TPV/r group (7.7%) than in the CPI/r group (5.4%) at 4 weeks and
increased with time (p \<0.0001, log rank test). At 48 weeks the
probability was 25.2% in the TPV/r group compared with 15.6% in the
CPI/r group.

Patients have had longer median duration of exposure to TPV/r than with
CPI/r study medication (330.0 days and 172.0 days, respectively).
Adjusting for patient exposure, the relative risk of Grade 3 or 4
triglyceride elevations with TPV/r is higher than with CPI/r (RR=1.53,
95% CI 1.19, 1.97).

![](media/image14.png){width="6.1875in" height="3.7125in"}

Figure 8.4.3.1: 1 Kaplan-Meier estimates for time to onset of Grade 3 or
4 triglyceride abnormalities in RESIST trial patients

Adverse events related to ischemic heart disease (IHD) were reported in
38 (5.1%) of 748 patients treated with TPV/r and 35 (4.7%) of 737
patients treated with CPI/r. Eight (21.1%) of the 38 TPV/r patients, and
8 (22.9%) of the 35 CPI/r patients with IHD adverse events, had Grade 3
or 4 triglyceride abnormalities.

In the TPV/r group, 27.3% of patients with Grade 3 or 4 triglycerides
abnormalities had study medication discontinued, compared to 49.5%
patients in the CPI/r group. Discontinuation of study medication due to
IHD adverse events was observed in 3 (7.9%) of the 38 TPV/r group
patients and 0 (0.0%) of the 35 CPI/r group patients.

The most clinically relevant potential risk factors for the occurrence
of Grade 3 or 4 triglyceride abnormalities are elevated triglyceride
levels at baseline, male gender, and age.

8.4.3.2 Cholesterol elevations

Grade 3 or Grade 4 total cholesterol elevations occurred in 4.0%
patients in the TPV/r group and 0.4% patients in the CPI/r group.

In the TPV/r group, the risk of Grade 3 or 4 total cholesterol
elevations continued through 48 weeks, while it remained flat in the
CPI/r group. The Kaplan-Meier estimates of time to first Grade 3 or 4
total cholesterol elevation are shown in Figure 8.4.3.2: 1. The
estimated probability of a Grade 3 or 4 total cholesterol elevation was
higher in the TPV/r group (1.5%) than in the CPI/r group (0.0%) at 8
weeks and increased with time (p \<0.0001, log rank test). At 48 weeks
the probability was 4.4% in the TPV/r group compared with 0.5% in the
CPI/r group.

Patients have had longer median duration of exposure to TPV/r than with
CPI/r study medication (330.0 days and 172.0 days, respectively).
Adjusting for patient exposure, the relative risk of Grade 3 or 4 total
cholesterol elevations with TPV/r is significantly higher than with
CPI/r (RR=7.07, 95% CI 2.15, 23.2), although associated with a low
frequency.

Adverse events related to ischemic heart disease (IHD) were reported in
38 (5.1%) of 748 patients treated with TPV/r and 35 (4.7%) of 737
patients treated with CPI/r. Four (10.5%) of the 38 TPV/r patients, and
0 (0.0%) of the 35 CPI/r patients with IHD adverse events, had Grade 3
or 4 total cholesterol abnormalities.

In the TPV/r group, 44.8% of patients with Grade 3 or 4 total
cholesterol abnormalities had study medication discontinued, compared to
none of the patients in the CPI/r group. Discontinuation of study
medication due to IHD adverse events was observed in 3 (7.9%) of the 38
TPV/r group patients and 0 (0.0%) of the 35 CPI/r group patients.
![](media/image15.png){width="6.2347222222222225in"
height="3.8694444444444445in"}

Figure 8.4.3.2: 1 Kaplan-Meier estimates for time to onset of Grade 3 or
4 total cholesterol abnormalities in RESIST trials

**8.5 MORTALITY AND AIDS PROGRESSION**

**8.5.1 Deaths in all TPV trials**

From the beginning of the TPV program through 30 September 2004, 131
patients died in clinical trials of HIV-positive patients. There have
been 13 deaths that occurred in the screening period, prior to beginning
trial medication. This underlines the advanced disease status of the
patients studied. There have been a total of 104 deaths across all
trials among 3,367 HIV-positive patients treated with TPV/r, for an
overall incidence of 3.1%. With the exception of the two RESIST trials,
one Phase II Trial BI 1182.4, and the naïve Trial BI 1182.33, the TPV
development program has been non-comparative. There have been 14 deaths
among patients randomized to a comparator PI. The comparative incidence
of CPI/r deaths is described in the context of the RESIST trials in
detail in the following sections. There have been no deaths as of
September 30^th^ in HIV-negative subjects, the pediatric Trial BI
1182.14 or the naïve Trial BI 1182.33.

Each fatal case in the TPV program was reviewed by BI Medical Officers
and classified if it was associated with an AIDS-defining opportunistic
illness (OI) as defined by the Center for Disease Control, an
AIDS-related illness (an illness clearly attributable to
immunosuppression or that is known to occur in excess among HIV-positive
patients) or both as the cause of death or contributing to the death
(Table 8.5.2: 1). For all fatal cases, the overwhelming majority (81.7%)
were attributable to HIV disease: 38.2% AIDS-defining OI, 26.7% AIDS
related illness and 16.8% both.

Table 8.5.2: 1 Classification of fatal cases as attributable to
Opportunistic Infections, an AIDS-related illness, or both in all
HIV-positive patients

  ---------------- -------------- --------------- --------------- ----------------
  Trial Number     Pre-exposure   Post-exposure   Post-exposure   Total (%)
                                  TPV/r           CPI/r           

  Patient deaths   13             104             14              131 (100.0)

  AIDS-defining OI 3              40              7               50 (38.2)

  AIDS-related     5              29              1               35 (26.7)
  illness                                                         

  Both             0              19              3               22 (16.8)

  Neither          5              16              3               24 (18.3)
  ---------------- -------------- --------------- --------------- ----------------

**8.5.2 AIDS progression events in RESIST Trials**

Using the methodology established to classify fatal outcomes, BI Medical
Officers retrospectively reviewed treatment emergent outcomes in both
treatment arms in order to assess AIDS progression events occurring in
the RESIST trials. Outcomes were classified as treatment emergent AIDS
progression events if they met the following criteria: AIDS-defining
opportunistic illness (OI) as defined by the Center for Disease Control,
or an AIDS-related illness (an illness clearly attributable to
immunosuppression or that is known to occur in excess among HIV-positive
patients). In the RESIST trials, the proportion of patients who
developed a new AIDS-progression event was less in the TPV/r group
(3.4%) than in the CPI/r group (4.6%). This finding did not reach
statistical significance; the RESIST trials were not powered to detect
differences in AIDS progression events.

8.5.3 Deaths in RESIST trials

As of 30 September 2004, there were 39 deaths in the RESIST trials: 25
(3.3%) in patients receiving TPV/r, and 14 (1.9%) in patients receiving
CPI/r. Table 8.5.3: 1 summarizes the duration of therapy in days that
patients received study medication prior to their death in the RESIST
trials. Fifty percent (50.0%) of CPI/r deaths occurred within 90 days of
randomization compared with 38.0% of TPV/r patient deaths. In addition,
48.0% of TPV/r deaths occurred in patients exposed to TPV/r for \>180
days compared with 14.3% of the CPI/r patient deaths.

Table 8.5.3: 1 Summary of duration of therapy in days for patients that
died in RESIST trials

  -------------- ---------- ---------- ------------ ------------ -----------
  Treatment      Median     0-30 days  31-90 days   91-180 days  \>180 days
                 (days)                                          

  Patient deaths 134.5      4          10           12           13

  CPI/r (n=14)   95.0       1 (7.1%)   6 (42.9%)    5 (35.7%)    2 (14.3%)

  TPV/r (n=25)   156.0      3 (12.0%)  4 (16.0%)    6 (24.0%)    12 (48.0%)
  -------------- ---------- ---------- ------------ ------------ -----------

Table 8.5.3: 2 summarizes the number of days after study medication was
discontinued until the patient died. The majority of deaths (87.2%, 34
of 39 deaths) occurred within 30 days of stopping study medication.
However, in all presentations of fatalities, the deaths occurring \>30
days beyond stopping study therapy have been included. Greater than 50%
of TPV/r patients and \>70% of CPI/r patients died within 7 days after
stopping their study medication.

Table 8.5.3: 2 Summary of days off of study medication until death in
RESIST Trials

  ---------------- ----------- ------------- ------------- ----------------
  Treatment        0-7 days    8-30 days     \>30 days     Total

  Patient deaths   24          10            5             39

  CPI/r            10 (71.4%)  2 (14.3%)     2 (14.3%)     14

  TPV/r            14 (56.0%)  8 (32.0%)     3 (12.0%)     25
  ---------------- ----------- ------------- ------------- ----------------

**8.5.4 Adjustment for exposure in RESIST trials**

As of September 30, 2004, the mortality rates in the RESIST trials were
4.1 deaths per 100 years exposure for patients receiving TPV/r and 3.5
deaths per 100 years exposure for patients receiving a CPI/r. A
Kaplan-Meier curve of mortality in the RESIST trials reveals no
significant difference (log rank p = 0.64) between the two treatment
arms (Figure 8.5.4: 1). This finding is not unanticipated given the fact
that the RESIST trials were not powered to detect differences in
mortality between the two treatment groups.

![](media/image16.wmf){width="6.175in" height="4.214583333333334in"}

Figure 8.5.4: 1 Mortality in RESIST trials

A comparison of the causes of death, as identified by investigators, for
patients in the RESIST trials revealed the majority, in either treatment
arm, were attributable to progression of underlying HIV disease or HIV
related opportunistic complications (Table 8.5.4: 1).

Table 8.5.4: 1 Comparison of mortality in the RESIST clinical program

+--------------------------------+-------------------------------------+
| TPV/r                          | CPI/r                               |
|                                |                                     |
| (n=25)                         | (n=14)                              |
+--------------------------------+-------------------------------------+
| AIDS / Infections (9)          | AIDS / Infections (4)               |
|                                |                                     |
| Lymphoma (4)                   | Lymphoma (4)                        |
|                                |                                     |
| Neoplasm (2)                   | Neoplasm (2)                        |
|                                |                                     |
| General medical:               | General medical:                    |
|                                |                                     |
| Respiratory (4)                | Cardiac (2)                         |
|                                |                                     |
| Cardiac (1)                    | Multi-organ failure (1)             |
|                                |                                     |
| Hepatorenal (1)                | Unknown (1)                         |
|                                |                                     |
| Sepsis (2)                     |                                     |
|                                |                                     |
| Unknown (2)                    |                                     |
+--------------------------------+-------------------------------------+

This finding is consistent with the fact that the median CD4+ cell count
of the patients who died in the RESIST trials was 17 cells/mm3 for TPV/r
patients and 53 cells/mm3 for CPI/r patients.

**8.5.5 Analysis of patients who rolled over to Trial BI 1182.17 from
the CPI/r arm of RESIST trials and died**

As noted in Section 8.3, at the cut-off for the Safety Update, 43% of
patients (316 out of 737) left the comparator arm of the RESIST trials
due to virologic failure Of the 316 patients, 298 (94%) rolled over into
the BI 1182.17 study and received TPV/r. Patients leaving the CPI/r arm
of the trial due to virologic failure had lower CD4+ counts (117
cells/mm^3^) and higher viral loads (4.8 log~10~ copies/mL) compared to
patients remaining in the trial on CPI/r (CD4+ counts of 238 cells/mm^3^
and viral load of 3.7 log~10~ copies/mL). Of the patients who rolled
over into BI 1182.17 from the CPI/r arm of the RESIST trials, 14
patients died. This finding is consistent with the fact that the median
CD4+ cell count of the CPI/r RESIST trial rollover patients who died in
BI 1182.17 after receiving TPV/r was 10 cells/mm3. An overview of the
cause of death for these patients is shown in Table 8.5.5: 1; details of
each case are listed in Appendix 4.

Table 8.5.5: 1 Mortality in the CPI/r rollover patients from the RESIST
trials

+------------------------------------+---------------------------------+
| RESIST trials                      | Rollover Trial 1182.17          |
|                                    |                                 |
| CPI/r                              | CPI/r to TPV/r                  |
|                                    |                                 |
| (n=14)                             | (n=14)                          |
+------------------------------------+---------------------------------+
| AIDS / Infections (4)              | AIDS / Infections (9)           |
|                                    |                                 |
| Lymphoma (4)                       | Neoplasm (1)                    |
|                                    |                                 |
| Neoplasm (2)                       | General medical:                |
|                                    |                                 |
| General medical:                   | Cardiopulmonary (2)             |
|                                    |                                 |
| Cardiac (2)                        | Hepatic failure (1)             |
|                                    |                                 |
| Multi-organ failure (1)            | Renal failure (1)               |
|                                    |                                 |
| Unknown (1)                        |                                 |
+------------------------------------+---------------------------------+

[]{.mark}

**8.5.6 Contrast of deaths in the rollover study: patients from RESIST
clinical program compared to patients from other TPV trials**

Additional support of the advanced disease status of CPI/r patients with
virologic failure who rolled into Trial BI 1182.17 is evidenced by
comparing these patients to those who entered the rollover study from
other trials. As of 30 September 2004, there were 27 deaths among 772
patients (3.5%) in Trial BI 1182.17. Of these deaths, 13 were among 474
patients who rolled over into BI 1182.17 from a prior study in which
they had received TPV/r, and 14 were among 298 patients (4.7%) who were
CPI/r virologic failures in the RESIST trials receiving TPV/r for the
first time in BI 1182.17.

The difference in the duration of TPV/r therapy that patients received
prior to their death in BI 1182.17 was notable, comparing those CPI/r
patients who rolled over from RESIST studies and the remaining patients
who have died in BI 1182.17 (Table 8.5.6: 1). 50% of the mortality in
the CPI/r rollover patients occurred within 90 days of starting TPV/r
therapy compared with no patients who had been receiving TPV/r in a
previous study. The median days of therapy was 100 days for those
patients who were CPI/r virologic failures receiving TPV/r in Trial BI
1182.17 compared with 335 days for patients who were receiving TPV/r in
a previous study and are now in Trial BI 1182.17.

Table 8.5.6: 1 Summary of duration of therapy in days for patients that
died in Trial BI 1182.17

  ----------------- -------- ---------- ---------- ---------- -------------
  Treatment         Median   0-30 days  31-90 days 91-180     \>180 days
                    (days)                         days       

  Patient deaths    205      2          5          6          14
  (n=27)                                                      

  CPI/r virologic   100      2 (14.3%)  5 (35.7%)  5 (35.7%)  2 (14.3%)
  failures from                                               
  RESIST that have                                            
  died in 1182.17                                             
  (n=14)                                                      

  TPV/r patients    335      0          0          1 (7.7%)   12 (92.3%)
  that have died in                                           
  1182.17 that were                                           
  previously on                                               
  TPV/r in trials                                             
  1182.4, 1182.51                                             
  or 1182.52 (n=13)                                           
  ----------------- -------- ---------- ---------- ---------- -------------

8.5.7 Review of hepatic deaths

In the TPV clinical development program there have been a limited number
of cases of clinical hepatitis or death due to hepatic failure; these
have generally occurred in patients with advanced HIV disease taking
multiple concomitant medications, often in the setting of underlying
chronic hepatitis or cirrhosis. Through September 30, 2004, 5 fatal
cases out of 131 total deaths (3.8%) had a hepatic event reported as
part of the clinical course prior to the patient's death. All five fatal
cases were reported in patients exposed to TPV/r, 3 from the RESIST
trials and 2 rollover patients to BI 1182.17 (one patient from the
RESIST trials and one patient from the dual boosted Trial BI 1182.51).
Two of the five cases occurred in patients co-infected with Hepatitis B.
The causes of death for the 5 cases were: liver failure, multi-organ
failure, hepatorenal syndrome, AIDS and B-cell lymphoma.

During the three month period from 1 October 2004 through 31 December
2004, 2 additional fatal cases with a hepatic event were reported.
During this same period, a total of 39 additional fatal cases were
reported. Therefore, through 31 December 2004, a total of 7 fatal cases
with liver events were reported out of a total of 170 fatal cases,
(4.1%). The two additional cases occurred in patients treated with
TPV/r, one patient rolled over from the RESIST trials to BI 1182.17 and
one patient was entered into the Expanded Access Program. One of the two
patients was co-infected with Hepatitis C. The cause of death for the
patient who rolled over from the RESIST trials to BI 1182.17 was end
stage multidrug-resistant HIV, liver biopsy consistent with drug-induced
hepatitis. The cause of death for the patient from the Expanded Access
Program was Burkitt's lymphoma. This patient was co-infected with
Hepatitis C. Table 8.5: 7 provides brief clinical synopses of each of
the fatal cases with liver events.

Table 8.5: 7 Clinical Summary of Fatal Cases with a Hepatic Event

+----+------+-------+-------------+----------------+-----+-----------+
| ** | **   | **H   | **History** | **Intercurrent | **  | **Cause   |
|  T | Age, | epati |             | Events**       | Nea | of        |
| ri | g    | tis** |             |                | res | Death**   |
| al | ende |       |             |                | t** |           |
|  - | r,** | *     |             |                |     | (Days on  |
| P  |      | *Co-i |             |                | **  | TPV and   |
| at | *    | nfect |             |                | CD4 | Days to   |
| ie | *HIV | ion** |             |                | +** | Death)    |
| nt | Stat |       |             |                |     |           |
| nu | us** |       |             |                | **V |           |
| mb |      |       |             |                | L** |           |
| er |      |       |             |                |     |           |
| ** |      |       |             |                |     |           |
+----+------+-------+-------------+----------------+-----+-----------+
| ** |      |       |             |                |     |           |
| RE |      |       |             |                |     |           |
| SI |      |       |             |                |     |           |
| ST |      |       |             |                |     |           |
| Tr |      |       |             |                |     |           |
| ia |      |       |             |                |     |           |
| ls |      |       |             |                |     |           |
| ** |      |       |             |                |     |           |
+----+------+-------+-------------+----------------+-----+-----------+
| 11 | 43   | HBs   | Wasting,    | ↑liver/spleen, | 14  | **Hepa    |
| 82 | yo   | Ag(+) | ↑lipids,    | ↑nodes, fever, |     | torenal** |
| .1 | WM   |       | pa          | dehydration,   | 3.4 |           |
| 2- |      |       | ncreatitis, | SOB, renal     | l   | (245 and  |
| 20 | HIV+ |       | neuropathy  | failure        | og~ | 268 days) |
| 52 |      |       |             |                | 10~ |           |
+----+------+-------+-------------+----------------+-----+-----------+
| 11 | 36   | HBs   | Hyperbil    | Cholestasis    | 49  | **AIDS**  |
| 82 | yo   | Ag(+) | irubinemia, | (?itraconazole |     |           |
| .1 | BM   |       | End-AIDS,   | related),      | 3.0 | (346 and  |
| 2- |      |       | MAC, PCP,   | renal and      | l   | 364 days) |
| 22 | HIV+ |       | neuropathy, | liver failure  | og~ |           |
| 72 |      |       | diabetes    |                | 10~ |           |
+----+------+-------+-------------+----------------+-----+-----------+
| 11 | 63   |       | PCN         | Fever, liver   | 45  | **B-cell  |
| 82 | yo   |       | Allergy,    | biopsy: B-cell |     | L         |
| .4 | WM   |       | ↑lipids,    | lymphoma,      | 3.3 | ymphoma** |
| 8- |      |       | lip         | i              | l   |           |
| 41 | HIV+ |       | odystrophy, | ntra-abdominal | og~ | (85 and   |
| 68 |      |       | neuropathy  | bleed; liver   | 10~ | 91 days)  |
|    |      |       |             | failure        |     |           |
|    |      |       |             | post-chemo     |     |           |
+----+------+-------+-------------+----------------+-----+-----------+
| ** |      |       |             |                |     |           |
| Ro |      |       |             |                |     |           |
| ll |      |       |             |                |     |           |
| ov |      |       |             |                |     |           |
| er |      |       |             |                |     |           |
| a  |      |       |             |                |     |           |
| nd |      |       |             |                |     |           |
| Ex |      |       |             |                |     |           |
| pa |      |       |             |                |     |           |
| nd |      |       |             |                |     |           |
| ed |      |       |             |                |     |           |
| Ac |      |       |             |                |     |           |
| ce |      |       |             |                |     |           |
| ss |      |       |             |                |     |           |
| Tr |      |       |             |                |     |           |
| ia |      |       |             |                |     |           |
| ls |      |       |             |                |     |           |
| ** |      |       |             |                |     |           |
+----+------+-------+-------------+----------------+-----+-----------+
| 11 | 39   |       | Steat       | Hepatic        | 34  | **Liver   |
| 82 | yo   |       | ohepatitis, | Failure        |     | Failure** |
| .1 | WM   |       | AIDS, MAC,  |                | 4.6 |           |
| 7- |      |       | wasting     |                | l   | (143 and  |
| 12 | HIV+ |       |             |                | og~ | 143 days) |
| 10 |      |       |             |                | 10~ |           |
| 25 |      |       |             |                |     |           |
+----+------+-------+-------------+----------------+-----+-----------+
| 11 | 49   |       | Ischemic    | Drug-induced   | 3   | **End     |
| 82 | yo   |       | stroke,     | hepatitis      |     | stage     |
| .1 | BM   |       | diabetes    |                | 4.6 | HIV**     |
| 7- |      |       | mellitus,   |                | l   |           |
| 48 | HIV+ |       | herpes      |                | og~ | (71 and   |
| 26 |      |       | labialis    |                | 10~ | 118 days) |
| 21 |      |       |             |                |     |           |
+----+------+-------+-------------+----------------+-----+-----------+
| 11 | 58   |       | Hyperbi     | Jaundice, knee | 135 | **Mu      |
| 82 | yo M |       | lirubinemia | pain, severe   |     | lti-organ |
| .1 |      |       | , allergy   | leg edema,     | 4.6 | failure** |
| 7- | HIV+ |       | to          | mild ectasia   | l   |           |
| 51 |      |       | saquinavir, | bile ducts, no | og~ | (218 and  |
| 03 |      |       | diabetes    | DVT, general   | 10~ | 218 days) |
| 61 |      |       | mellitus,   | worsening with |     |           |
|    |      |       | peripheral  | lactic         |     |           |
|    |      |       | edema       | acid-190mg/mL  |     |           |
+----+------+-------+-------------+----------------+-----+-----------+
| 1  | 43   | HCV   | Cirrhosis,  | Decompensation | 140 | **        |
| 18 | yo M | R     | chronic HCV | of Cirrhosis   |     | Burkitt's |
| 2. |      | NA(+) |             |                | 2.9 | L         |
| 67 | HIV+ |       |             |                | l   | ymphoma** |
| -T |      |       |             |                | og~ |           |
| AL |      |       |             |                | 10~ | (67 and   |
|    |      |       |             |                |     | 74 days)  |
+----+------+-------+-------------+----------------+-----+-----------+

**8.5.8 Summary of deaths**

In all TPV studies from program inception to the 30 September 2004, 131
HIV-positive patients have died. Among these, 13 deaths have occurred
pre-treatment prior to exposure to study medication which underlines the
advanced disease status of patients in the TPV development program.

Patients who entered the RESIST trials were highly treatment-experienced
with advanced HIV disease. As of 30 September 2004, there were 39 deaths
in the RESIST trials: 25 (3.3%) in patients receiving TPV/r, and 14
(1.9%) in patients receiving CPI/r. The exposure adjusted mortality
rates in the RESIST trials were 4.1 deaths per 100 years exposure for
patients receiving TPV/r and 3.5 deaths per 100 years exposure for
patients receiving a CPI/r. This difference was not statistically
significant. The majority of the patients who died in the RESIST trials
experienced progression of their HIV-disease or an HIV-related
opportunistic infection as the underlying cause of death. The mortality
rates in the RESIST trials are similar to the mortality rates seen in
other treatment experienced patient populations, e.g. the mortality
rates in the CPCRA 064 trials (6.1 and 6.5 per 100 patient years) and in
the PLATO[^23] cohort (overall mortality 5.5 per 100 patient years).

The majority (94%) of patients who experienced virologic failure in the
CPI/r arm transferred to the TPV rollover study (BI 1182.17). Patients
leaving the CPI/r arm of the trial due to virologic failure had lower
CD4+ counts (117 cells/mm^3^) and higher viral loads (4.8 log~10~
copies/mL) compared to patients remaining in the trial on CPI/r, CD4+
238, viral load 3.7 log~10~ copies/mL~.~ Of the patients who rolled over
into BI 1182.17 from the CPI/r arm of the RESIST trials, 14 patients
died. A comparison of the causes of death, as identified by
investigators, for patients who died in the RESIST trials and the RESIST
CPI/r rollover patients to 1187.17 were similar, HIV disease,
AIDS-related illnesses or AIDS-related opportunistic infections. This is
consistent with the low median CD4+ cell counts for the patients who
died in the RESIST trials, 17 cells/mm3 for TPV/r patients and 53
cells/mm3 for CPI/r patients or who died after rolling over from CPI/r
into BI 1182.17, median CD4+ cell count 10 cells/mm3.

Across the various trials conducted as part of the TPV/r development
program, including the EUP and EAP programs and the BI 1182.17 roll over
trial, more than 80% of deaths were attributable to an AIDS-defining OI
or an AIDS-related illness. This is consistent with the highly treatment
experienced HIV-positive patient population treated with TPV/r.

**8.6 SAFETY RESULTS IN SPECIAL POPULATIONS**

**8.6.1 Long-term safety from rollover Trial BI 1182.17**

Long-term data in HIV-positive patients is provided from patients that
entered Trial BI 1182.17 (rollover extension from Phase II/III trials).
In the NDA submission, safety data for 570 patients who were exposed to
TPV/r for \>24 weeks, 372 at the intended market dose of TPV/r 500
mg/200 mg, were reported (Table 8.6.1: 1). Because the TPV treatment in
the initial trials varied with respect to TPV/r dose, formulation and
patient experience, 3 patient Groups were designated to evaluate
long-term safety data.

-   Group 1 (n = 518): Data from early TPV trials with various dose
    regimens and formulations) and data from dose-finding studies with
    multiple regimens;

-   Group 2 (n = 308): Data from Trial BI 1182.51 in which most were
    receiving a dual-boosted PI regimen containing TPV/r 500 mg/200 mg;

-   Group 3 (n = 284[^24]): Patients who failed virologically on the
    comparator-PI arm during RESIST trials and began TPV/r 500 mg/200 mg
    in Trial BI 1182.17.

A total of 220 patients (47 at the 500 mg/200 mg dose) have \>48 weeks
exposure, and 39 patients (none at the 500 mg/200 mg dose) have been
exposed to TPV for over 3 years. The maximum exposure to TPV/r was 259.9
weeks, or almost 5 years. It is noted that nearly all patients in the BI
1182.17 trial who were on doses other than the 500 mg/200 mg dose from
their prior trial have been switched to the TPV/r 500 mg/200 mg dose as
of March 2003.

Table 8.6.1: 1 Summary of long-term exposure to TPV by HIV-positive
patients, by trial grouping, from Trials BI 1182.2, 1182.4, 1182.6,
1182.17, 1182.51 and 1182.52

+------------------+----------+-------------+-------------+------------+
| Number (%) of    |          |             |             |            |
| patients         |          |             |             |            |
+------------------+----------+-------------+-------------+------------+
|                  | Group 1a | Group 2b    | Group 3c    | Total      |
+------------------+----------+-------------+-------------+------------+
| Total treated    | 518      | 308 (100.0) | 284 (100.0) | 1110       |
|                  | (100.0)  |             |             | (100.0)    |
+------------------+----------+-------------+-------------+------------+
| Exposure         |          |             |             |            |
| durationd        |          |             |             |            |
+------------------+----------+-------------+-------------+------------+
| 1 day            | 518      | 308 (100.0) | 284 (100.0) | 1110       |
|                  | (100.0)  |             |             | (100.0)    |
+------------------+----------+-------------+-------------+------------+
| \> 4 weeks       | 323      | 301 (97.7)  | 256 (90.1)  | 880 (79.3) |
|                  | (62.4)   |             |             |            |
+------------------+----------+-------------+-------------+------------+
| \> 24 weeks      | 253      | 248 (80.5)  | 69 (24.3)   | 570 (51.4) |
|                  | (48.8)   |             |             |            |
+------------------+----------+-------------+-------------+------------+
| \> 48 weeks      | 214      | 6 (1.9)     | 0 (0.0)     | 220 (19.8) |
|                  | (41.3)   |             |             |            |
+------------------+----------+-------------+-------------+------------+
| \> 72 weeks      | 185      | 0 (0.0)     | 0 (0.0)     | 185 (16.7) |
|                  | (35.7)   |             |             |            |
+------------------+----------+-------------+-------------+------------+
| \> 96 weeks      | 66       | 0 (0.0)     | 0 (0.0)     | 66 (5.9)   |
|                  | (12.7)   |             |             |            |
+------------------+----------+-------------+-------------+------------+
| \> 144 weeks     | 39 (7.5) | 0 (0.0)     | 0 (0.0)     | 39 (3.5)   |
+------------------+----------+-------------+-------------+------------+
| \> 168 weeks     | 32 (6.2) | 0 (0.0)     | 0 (0.0)     | 32 (2.9)   |
+------------------+----------+-------------+-------------+------------+
| a Group 1 =      |          |             |             |            |
| Patients from    |          |             |             |            |
| Trials 1182.2,   |          |             |             |            |
| 1182.4, 1182.6   |          |             |             |            |
| and 1182.52.     |          |             |             |            |
| Patient          |          |             |             |            |
| 1182_0004/003154 |          |             |             |            |
| rolled over from |          |             |             |            |
| the SQV arm into |          |             |             |            |
| 1182.17. Two     |          |             |             |            |
| patients in the  |          |             |             |            |
| TPV/r arm of the |          |             |             |            |
| RESIST trials    |          |             |             |            |
| who rolled over  |          |             |             |            |
| into 1182.17 are |          |             |             |            |
| also included.   |          |             |             |            |
|                  |          |             |             |            |
| b Group 2 =      |          |             |             |            |
| Patients from    |          |             |             |            |
| Trial 1182.51.   |          |             |             |            |
|                  |          |             |             |            |
| c Group 3 =      |          |             |             |            |
| CPI/r virologic  |          |             |             |            |
| failure patients |          |             |             |            |
| from Trials      |          |             |             |            |
| 1182.12 and      |          |             |             |            |
| 1182.48          |          |             |             |            |
|                  |          |             |             |            |
| d Total exposure |          |             |             |            |
| is defined as    |          |             |             |            |
| exposure in the  |          |             |             |            |
| prior trial plus |          |             |             |            |
| exposure from    |          |             |             |            |
| Trial 1182.17,   |          |             |             |            |
| when applicable. |          |             |             |            |
|                  |          |             |             |            |
| Note: This table |          |             |             |            |
| includes data on |          |             |             |            |
| all patients     |          |             |             |            |
| from Trials      |          |             |             |            |
| 1182.2, 1182.4,  |          |             |             |            |
| 1182.6, 1182.51  |          |             |             |            |
| and 1182.52 and  |          |             |             |            |
| data for         |          |             |             |            |
| patients in      |          |             |             |            |
| Trial 1182.17    |          |             |             |            |
| entering from    |          |             |             |            |
| those patients   |          |             |             |            |
| who entered      |          |             |             |            |
| Trial 1182.17    |          |             |             |            |
| and were         |          |             |             |            |
| receiving TPV/r  |          |             |             |            |
| for the first    |          |             |             |            |
| time in Trial    |          |             |             |            |
| 1182.17.         |          |             |             |            |
+------------------+----------+-------------+-------------+------------+
|                  |          |             |             |            |
+------------------+----------+-------------+-------------+------------+

Evaluation of events over time revealed that patients experienced nausea
and diarrhea more frequently in the 0-4 week time interval compared to
later time intervals. No events appeared later in the course of therapy
(\>24 weeks) that were not present earlier during therapy (24 weeks).
Lipodystrophy, an event known to be associated with chronic
administration of NRTI agents and PIs, was present in Groups 1 and 2 in
a higher percentage of patients during later exposure periods, although
the overall frequency was small (\<3%). For other events, there did not
appear to be an association with time.

The frequency of discontinuation of study medication due to adverse
events appeared highest in Group 1, the patients with longest exposure
to TPV/r, followed by Group 3 and then Group 2. Overall, the most
frequently reported adverse events leading to discontinuation were
nausea, diarrhea, and increased ALT. In Group 1, the only group that had
exposure data beyond Week 48, gastrointestinal events leading to
discontinuation of study medication occurred primarily in the first 24
weeks of exposure. Increased liver enzymes resulted in premature
discontinuations of study medication at less than 3% per year across the
different time intervals. While these long-term data may suggest that
the risk of persistent Grade 3/4 ALT and/or AST elevations does not
increase significantly over time, additional data are required before
this conclusion may be reached.

The type and frequency of serious adverse events were similar across the
3 patient Groups. The most commonly experienced SAEs were anemia,
abdominal pain, diarrhea and pyrexia. There were no SAEs predominantly
seen during a certain interval of time during TPV/r exposure, although
Group 3, who initiated therapy with TPV/r in BI Trial 1182.17, had a
higher overall frequency of SAEs in the first 4 weeks of exposure to
TPV/r.

To date, the data suggest that long-term exposure to TPV/r treatment
presents no new safety concerns, and is consistent with the already
established TPV safety profile at 24 weeks.

**8.6.2 Pediatric Trial BI 1182.14**

Initial safety data from a multicenter, multiple-dose, open-label,
randomised, safety and pharmacokinetic study of TPV in combination with
low-dose RTV in HIV-infected children and adolescent patients (ages 2-18
years) was reported in the NDA submission. This 48-week trial was
initiated in early 2004, and was fully accrued with 100 HIV-infected
pediatric patients in October 2004.

Of the data for 37 patients available for safety evaluation, 18 were
randomised to the TPV/r low dose group (TPV/r 290 mg/m2/115 mg/m^2^
BID), and 19 patients were randomised to the TPV/r high dose group
(TPV/r 375 mg/m^2^/150 mg/m^2^ BID). Patients were receiving TPV as the
liquid formulation and RTV, as either the liquid or capsule formulation.

Overall, 70.3 % (26/37) of patients reported at least 1 adverse event,
with 66.1% (11/18) in the TPV/r low dose group and 78.9% (15/19) in
TPV/r high dose group. As seen in trials in HIV-positive adult patients,
the highest percentages of pediatric patients reported adverse events in
the gastrointestinal disorders SOC (43.2%, (16/37), with nausea and
vomiting being the 2 most frequently reported adverse events: 27.0% of
patients (10/37) and 21.6% (8/37) of patients, respectively. Both nausea
and vomiting occurred more frequently in the TPV/r high dose group than
in the TPV/r low dose group: nausea, 31.6% compared with 22.2%; and
vomiting, 26.3% compared to 16.7%, respectively.

Three patients (8.1%) discontinued from the study due to adverse events,
2 in the TPV/r high dose group and 1 in the TPV/r low dose group.
Adverse events leading to discontinuation consisted of: abdominal pain,
nausea and vomiting in 1 patient; retching and vomiting in 1 patient;
and gastrointestinal discomfort and retching in 1 patient.

There were 3 SAEs reported: abdominal pain and nausea considered related
to the study drugs in 1 patient; pyrexia in 1 patient, and oesophageal
candidiasis in 1 patient both considered not to be related to study
drug. There were no significant adverse events reported, as defined in
the protocol, and no patients have died during the study.

**8.6.3 Emergency Use and Expanded Access Programs**

The objective of the BI Open Label Emergency Use Program (EUP) is to
provide highly treatment-experienced patients who were unable to
participate in the RESIST clinical trial program access to TPV/r
treatment. Overall, 15 countries are participating in the EUP. The
information presented is from the period of 01 May 2003 to 04 May 2004.

With the exception of the United States and France, both conducting the
EUP as an Open Label Safety Study (OLSS), all other participating
countries are conducting the EUP on a Named Patient Use (NPU) basis. The
EUP opened accrual in May 2003 (3 months after the first patients were
entering RESIST-1 and 2) and will close recruitment for adult patients
once the Expanded Access Program has opened in each particular country.

In order to be eligible for the program, patients initially had to
fulfill the following key entry criteria: CD4+ cell count \< 50 cells
per mm3 and HIV RNA count \>10,000 copies/mL. In January 2004, the
baseline CD4+ cell count was increased from \< 50 cells/mm3 to \< 100
cells/mm3 providing a larger number of patients access to the program.
Safety collection varied from program to program depending upon local
collection/reporting requirements. Following local regulatory
requirements to conduct a NPU Program, only in 6 (US, France, Denmark,
Greece, Belgium, and Switzerland) of the 15 participating countries
could CRFs be utilised for systematic data collection in the EUP.

A total of 451 patients have entered the EUP. A total of 450 patients
received at least 1 dose of TPV/r 500 mg/200 mg. Overall, 51 patients
discontinued TPV/r therapy; 19 patients died. A total patient exposure
of 131 patient years was estimated.

Demographic characteristic data were available for 266 patients. The
EUP/OLSS population was predominantly male (89.5%); the mean age was
43.7 years. The mean baseline HIV-1 RNA value was 5.2 log10 copies /mL.
Of the 266 patients, 54.9% showed a baseline HIV-1 RNA concentration
between 100,000 and 1,000,000 copies/mL, and 5.3% had a viral load
\>1,000,000 copies/mL. Baseline information for CD4+ cell count was
available for 263 patients. The mean baseline CD4+ count was 27.3
cells/mm3 (median 18 cells/mm3), with 84.8% of the patients having a
CD4+ cell count \< 50 cells/mm3.

Details on the ARV treatment history were available for 264 patients.
The mean number of ARV drugs each patient previously had received who
entered the EUP/OLSS was 5.0 PIs, 5.8 NRTIs and 1.6 NNRTI. Previous
exposure to an average of 12 ARV agents indicates that the number of
drugs left to construct a viable regimen in this patient population was
very limited.

Overall, 87 case reports, including 150 adverse events, were received in
the EUP program at the time of the Summary of Clinical Safety
submission. Nineteen of the 87 patients had a fatal outcome. Of the 150
adverse events received, 137 were serious and 13 were non-serious.
Within the EUP, only SAEs and drug discontinuations were systematically
collected. In addition to the 87 cases received in the time period, 7
SAE reports that occurred during the pre-treatment phase of the program
were reported.

The incidence, as well as the type of SAEs reported in the EUP for the
individual SOCs, was comparable to that seen in other trials conducted
to date. The higher proportion of SAEs reported in the EUP for
infections and infestations mirrors the advanced clinical condition of
the patients enrolled in this program. This SOC includes preferred terms
that are clearly markers of advanced HIV disease.

A total of 7 case reports have been received with at least 1 event
judged to be related to TPV/r treatment. On a case by case basis or
cumulatively, these cases do not change the present understanding of the
safety profile of TPV/r.

In the EUP, all fatal events were considered unrelated to TPV/r
treatment by the investigator. Consistent with the advanced nature of
the disease, baseline CD4+ cell count of the patients who died during
the treatment with a TPV/r-containing ARV regimen ranged from 0 to
190 cells/mm3 (median 8 cells/mm3). The baseline viral load ranged from
10,690 to 1,000,000 copies/mL.

**8.6.4 Safety in Women and Minorities**

In the RESIST trials, 15.6% (117 of 748) patients treated with TPV/r
were women. Overall, 92.3% of women reported adverse events as compared
to 88.3% of men. A higher percentage of female patients (\>5 %
difference) tended to experience nausea (28.2 vs. 17.6% among males),
vomiting (18.8 vs. 9.4%), headache (20.5 vs. 11.6%), and anxiety (7.7
vs. 1.4%). A higher percentage of males tended to experience fatigue
(12.8 vs 5.1% among females). Although rash was observed in women using
estrogen, the percentage of male and female TPV/r recipients in RESIST
who experienced rash were 6.5 and 8.5%, respectively. There was no
difference between genders in the percentage of TPV/r recipients in
RESIST who developed a Grade 3 or greater laboratory abnormality.

In the RESIST trials, 12.5% (94 of 748) patients were black, 76.4% (572
of 748) patients were white and the remaining patients primarily did not
have race reported due to local country regulations. Overall, 93.6% of
black patients reported adverse events as compared to 88.5% of white
patients. A higher percentage of black patients (\>5% difference)
reported adverse events in the infections and infestations and
respiratory disorders SOC.

Overall, the number of women and black patients in the RESIST trials is
small and no signals for differences in safety are detected.

**8.7 SAFETY CONCLUSIONS**

-   There have been 1,870 HIV-positive patients treated with the TPV/r
    500/200 mg dose for a total of 1,760 patient-years of exposure; 47%
    were treated for \>48 weeks with a maximum exposure of 5 years.

-   Although the overall rates and types of adverse events and SAEs,
    including fatal outcomes, reported in the RESIST trials were similar
    for TPV/r and CPI/r, TPV/r treated patients experienced more hepatic
    and lipid associated events. The adverse events seen with TPV/r are
    those expected with a ritonavir-boosted PI.

-   Grade 3/4 elevations in ALT/AST and hepatic adverse events were more
    common with TPV/r than CPI/r. These events were generally
    asymptomatic and most patients were successfully continued on
    treatment. Most patients can be managed with routine laboratory
    monitoring except for patients with chronic Hepatitis B or C
    co-infection or elevated baseline LFTs, where increased monitoring
    of LFTs is recommended.

-   Grade 3/4 elevations in cholesterol and triglycerides and
    lipodystrophy were more common with TPV/r. The lipid abnormalities
    were not associated with an increased risk of pancreatitis. It is
    not possible to draw definitive conclusions regarding the risk of
    potential long term sequelae of elevated plasma lipids, e.g.
    ischemic heart disease, given the limited number of patients exposed
    to TPV/r for more than one year.

-   Lipodystrophy was more common with TPV/r. Many of the patients in
    the RESIST trials had extensive ARV exposure and entered with
    lipodystrophy. The definitive assessment of lipodystrophy will occur
    in the metabolic substudy of the naïve patient trial BI 1182.33.

[]{#__RefHeading___Toc101398980 .anchor}9. OVERALL Conclusions

The emergence of a large and growing population of individuals infected
with broadly antiretroviral drug resistant HIV-1 is of continuing
concern. Tipranavir, a novel non-peptidic protease inhibitor, was the
first PI to be developed with the intent that it would have activity in
these patients and thus improve their clinical status. The interim data
reviewed in this application provides for an appropriate benefit/risk
profile of TPV/r for the treatment of PI‑experienced patients.

As of 30 September 2004, a total of 3,367 HIV-positive patients have
been treated with TPV/r, representing over 1,760 patient-years of drug
exposure. More than 900 patients have been treated for at least 48
weeks, and some patients have received TPV/r for over five years. 1,411
patients have been treated with the TPV/r 500/200 mg dose with 1,206
having received this to-be-marketed dose for at least 24 weeks.

Early in pre-clinical development, it was recognized that tipranavir had
significant antiviral activity against viral isolates with resistance to
other ARV drugs. Additional studies that tested TPV against clinical
isolates from the Phase II and III program confirmed that TPV maintains
significant *in vitro* antiviral activity (\<3-fold resistance) against
the majority of HIV-1 clinical isolates from PI-resistant treatment
experienced patients that have reduced susceptibility to the following
currently approved PIs: amprenavir, atazanavir, indinavir, lopinavir,
ritonavir, nelfinavir and saquinavir.

The tipranavir development program is the first PI to be primarily
studied for use in treatment experienced patients. The *in vitro*
resistance profile of tipranavir has shown that TPV retains antiviral
activity against many viral isolates that are resistant to existing PI
options.

The TPV development program has included 39 clinical studies, ranging
from small single-dose PK trials to large, multi-national, controlled
Phase III pivotal studies. The combined data from these broadly variable
trials demonstrates that TPV/r has potent antiviral activity in PI
treatment-experienced patients and has a safety profile that is
generally similar to that of other RTV-boosted PIs.

The primary focus of the development program has been to establish the
efficacy of TPV in patients with PI treatment experience without other
available treatment options. Based on the data from the Phase III RESIST
studies, the antiviral activity---as demonstrated by multiple efficacy
endpoints---is encouraging. Tipranavir has demonstrated statistical
superiority to optimized standard of care regimens in multiple drug
experienced patients.

The 24-week interim analysis of the RESIST program has succeeded in
demonstrating efficacy of TPV across multiple efficacy endpoints (Table
9: 1). In short, these data show that TPV/r has potent antiviral
activity in patients with PI-resistant virus who have previously been
exposed to 2 or more PI-containing antiretroviral regimens and these
data demonstrate that the difference between patients receiving TPV/r is
statistically significantly superior to patients receiving an optimized
standard of care regimen of currently marketed RTV-boosted PIs. In
addition, patients using TPV/r had a statistically superior immunologic
improvement and had fewer AIDS progression events than patients
receiving the optimized standard of care comparator PI. The antiviral
and immunologic benefits for patients receiving TPV/r were further
enhanced in the presence of other active background drugs, such as
enfuvirtide.

Table 9: 1 Overview of Week 24 efficacy endpoints - combined RESIST
trials

+------------------------------------------+-------------+-------------+
|                                          | TPV/r + OBR | CPI/r + OBR |
|                                          |             |             |
|                                          | N = 582     | N = 577     |
+------------------------------------------+-------------+-------------+
| Median baseline viral load (range)       | 4.83        | 4.82        |
|                                          | (2.34 -     | (2.01 -     |
|                                          | 6.52)       | 6.76)       |
+------------------------------------------+-------------+-------------+
| Median baseline CD4+ count (range)       | 155 (1 -    | 158 (1 -    |
|                                          | 1893)       | 1184)       |
+------------------------------------------+-------------+-------------+
| Treatment Response                       | 41 %        | 19 %        |
+------------------------------------------+-------------+-------------+
| Median HIV VL change from baseline       | -0.80       | -0.25       |
| (log~10~ copies/mL)                      |             |             |
+------------------------------------------+-------------+-------------+
| HIV VL \< 400 copies/mL                  | 34 %        | 15 %        |
+------------------------------------------+-------------+-------------+
| HIV VL \< 50 copies/mL                   | 24 %        | 9 %         |
+------------------------------------------+-------------+-------------+
| Median increase in CD4+ cell count       | 34          | 4           |
| (cells/mm^3^)                            |             |             |
+------------------------------------------+-------------+-------------+
| Reasons for treatment failure            | 59 %        | 81 %        |
+------------------------------------------+-------------+-------------+
| Death                                    | 1 %         | 1 %         |
+------------------------------------------+-------------+-------------+
| Discontinued or OBR change due to lack   | 6 %         | 37 %        |
| of efficacy                              |             |             |
+------------------------------------------+-------------+-------------+
| Virologic rebound                        | 15 %        | 11 %        |
+------------------------------------------+-------------+-------------+
| No confirmed virologic response          | 24 %        | 23 %        |
+------------------------------------------+-------------+-------------+
| Discontinued due to any adverse event    | 8 %         | 3 %         |
+------------------------------------------+-------------+-------------+
| Discontinued due to other reasons        | 4 %         | 5 %         |
+------------------------------------------+-------------+-------------+

The clinical efficacy results confirm what the *in vitro* resistance
testing results have shown and extend what was known about the TPV
resistance profile from the early pre-clinical development stage. Based
on resistance analyses from the Phase II and III program, it is now
known that: (1) It takes 3 key mutations and \> 4 TPV-associated
mutations to produce decreased TPV susceptibility
([\>]{.underline} 3-fold wild-type) *in vitro* or decreased antiviral
responses clinical isolates; (2) high level resistance (\> 10-fold wild
type) generally requires the presence of all 4 key mutations or \> 7
TPV-associated mutations that are uncommon in clinical HIV-1 isolates
from treatment-experienced patients; (3) many of the mutations that
produce reduced TPV susceptibility are different than the mutations that
produce drug resistance to currently available PIs (TPV mutation score
vs. IAS mutation count). These *in vitro* and clinical data confirm
earlier data demonstrating that there is a high genetic barrier to
resistance with TPV. For patients considering the use of TPV/r,
genotypic resistance testing may assist in the selection of drugs to
combine with TPV/r and in determination of which patients are most
likely to benefit from a TPV/r-based regimen.

Despite the demonstrated efficacy and resistance benefits of TPV, these
data must be balanced with the knowledge of the potential safety risks
for patients who may receive the drug.

Based on the interim analyses of the RESIST studies and available longer
term safety data from other trials, tipranavir is generally safe to
administer to treatment-experienced patients. The rate and type of AEs
reported by patients receiving TPV/r is similar to those reported in
other patients receiving RTV-boosted PIs.

As might be expected for any PI, the most commonly reported AEs for
patients receiving TPV/r involve the GI tract. These were generally mild
to moderate in severity and resolved spontaneously without treatment
interruption. Both SAEs and deaths reported in the TPV development
program appear to reflect the advanced nature of the patients studied,
and there were no commonly occurring events that suggest a pattern of
possible treatment-relatedness.

Most laboratory tests were unaffected by treatment with TPV/r. However,
both hepatic enzyme elevations and plasma lipid elevations were more
common in patients receiving TPV/r than in patients on the CPI/r arms of
the RESIST studies.

While most patients with hepatic enzyme elevations were asymptomatic and
were able to safely continue on treatment without permanent
discontinuation, the higher rate of ALT/AST elevations and the minority
of patients who were symptomatic suggests that clinicians should be
vigilant in monitoring their patients who begin treatment with TPV/r,
especially in patients with increased hepatic risk factors at baseline.
Specifically, the hepatic observations from the RESIST trials warrant
that patients treated with TPV/r be monitored appropriately. LFT tests
should be obtained prior to initiating therapy with TPV/r and during
treatment. Increased monitoring is necessary when TPV/r is administered
to patients with elevated baseline ALT or AST levels or chronic
hepatitis B or C. As with any potentially hepatotoxic agent, patients
with signs or symptoms of clinical hepatitis should discontinue TPV/r
treatment and seek medical evaluation.

Given the limited number of hepatitis B or C co-infected patients in the
TPV/r clinical development program, additional TPV/r studies,
epidemiologic and clinical trials, will be conducted to better quantify
the risks and benefits of TPV/r-containing antiretroviral regimens in
hepatitis B or C co-infected HIV-1 patients. TPV/r is contraindicated in
patients with severe liver diseases, i.e. Child-Pugh C cirrhosis. There
have been a limited number of cases of clinical hepatitis or death due
to hepatic failure in the TPV development program, primarily in patients
with advanced HIV disease taking multiple concomitant medications and a
causal relationship to TPV/r was not established.

Lipid elevations are challenging to fully understand because most
patients who received TPV/r in the Phase II/III program were
treatment-experienced and entered with variable levels of pre-existing
lipid abnormalities or even lipodystrophy. Nonetheless, the rate of
Grade 3 or 4 lipid elevations was higher in the TPV/r arms than in the
CPI/r arms, though this may have also resulted from the higher dose of
RTV given in the TPV arms. The ongoing study in treatment-naïve adult
patients (BI 1182.33) will better define the risk of blood lipid
abnormalities and lipodystrophy when those patients complete 48 weeks of
treatment.

From a pharmacokinetic standpoint, tipranavir is a unique protease
inhibitor with a potent inductive effect on the cytochrome P450 3A
isoenzyme. TPV 500 mg must be given simultaneously with ritonavir 200 mg
both given twice daily to obtain the desired therapeutic drug levels.
When TPV is combined with 200 mg of ritonavir there is a net inhibition
of CYP3A. Due to its metabolism through the CYP 3A4 pathway, clinicians
should be aware of the potential drug-drug interactions that could occur
when patients take TPV/r with other commonly co-administered drugs. In
general, the pharmacokinetic drug interactions for most concomitant
medications with TPV/r are consistent with other RTV-boosted PIs.

While reductions in plasma concentrations of abacavir and zidovudine
have been observed when they are combined with TPV/r, the clinical
relevance of these changes has not been established and no dose
adjustment can be recommended at this time. In addition, drug levels for
RTV-boosted lopinavir, saquinavir, and amprenavir were significantly
reduced when combined with TPV/r, therefore these combinations are not
recommended. PI levels for novel dual PI regimens containing TPV/r
cannot be predicted without formal drug interaction studies possibly due
to the mixed patterns of inhibition and induction of CYP pathways seen
with these drug combinations.

Additional information that will be forthcoming from the ongoing Phase
III clinical development program involves the use of TPV/r in
antiretroviral naïve adults and HIV-positive children (ages 2 to 18).
The naïve adult study (BI 1182.33) is designed to help discern (1)
whether a lower RTV dose (100 mg) to boost TPV provides sufficient
antiviral activity in treatment-naïve patients; (2) the safety and
tolerability profile of TPV/r, especially regarding elevations of
ALT/AST and lipids, and whether it is different for naïve versus
treatment-experienced individuals; (3) the resistance mutations that
emerge in naïve patients and the effect of those mutations on
susceptibility to the other available PIs. The ongoing pediatric study
(BI 1182.14) will determine the safety, tolerability, pharmacokinetics,
efficacy and optimal dose of tipranavir oral solution for children and
adolescents.

Based on these short-term analyses of efficacy, safety, and
pharmacokinetics, the benefit risk profile of tipranavir is clearly
favorable for treatment experienced patients. The use of TPV/r based
regimens in patients resistant to other treatment options meets a large
unmet clinical need in the community. In summary, the balance of the
benefits and risks of drug regimens containing TPV/r supports the
indication for use in PI treatment-experienced patients with HIV-1
infection.

[]{#__RefHeading___Toc101398981 .anchor}10. PLANS FOR COMPLETING
REQUIREMENTS FOR TRADITIONAL APPROVAL

BI will provide 48-week data from the RESIST studies once the final
analyses and clinical trial reports are completed; these 48-week data
are intended to support the application for Traditional Approval.

[]{#__RefHeading___Toc101398982 .anchor}APPENDIX 1 NONCLINICAL
PHARMACOLOGY AND TOXICOLOGY

[]{#__RefHeading___Toc101398983 .anchor}Appendix 1.1 Overview

General/safety pharmacology studies were performed following single
administration to assess TPV's potential effects on a number of organ
systems including: central nervous system, cardiovascular, pulmonary,
renal and gastrointestinal. The cardiovascular assessment included both
*in vitro* and *in vivo* evaluations of TPV for possible pro‑arrhythmic
risk potential. Owing to its targeted patient population, TPV was also
evaluated for effects on immune function.

A number of single and repeated dose pharmacokinetic studies were
conducted in several animal species (including CD-1 mouse, Sprague
Dawley rat, New Zealand White rabbit, beagle dog and rhesus monkey) to
derive pharmacokinetic parameters both with and without RTV
co-administration. A number of formulations were evaluated in dogs to
optimize systemic exposure. Studies using radiolabelled TPV were also
conducted to assess the absorption, distribution, and excretion of TPV
in mouse, rat, rabbit and dog. Metabolism studies in rat are also
included. *In vivo* metabolism studies in mouse and dog are ongoing.
Protein binding studies were performed with plasma of a number of
species as well as FBS contained in media that was used in studies to
determine *in vitro* potencies to inhibit viral proteases. Whole body
autoradiography studies in rat were conducted to select the appropriate
radiolabelled dose of TPV for the human ADME study. Studies in pregnant
rats were conducted to assess placental transfer and lacteal secretion.
*Ex vivo* analyses of induction in rats and dogs by TPV were performed.

*In vitro* metabolism studies were conducted using hepatic microsomes
from a number of species and rat and human hepatocytes. Since these
studies were conducted in the absence of RTV, the data is not expected
to reflect what occurs *in vivo*. Studies to assess permeability and
active transport of TPV were conducted *in vitro* using Caco 2 and MDCK
cells transfected with Pgp. The stereochemical stability of TPV in
plasma samples was confirmed by capillary electrophoresis. Most of these
studies were not conducted under GLP.

Since TPV is a chronically administered drug, the nonclinical safety
assessment strategy was designed to address repeated dose administration
over an extended period of time. A battery of nonclinical studies has
been performed with TPV to address toxicity in support of clinical
trials and final registration. Repeat-dose toxicity of TPV has been
addressed in both rats and beagle dogs by the oral route of
administration for durations of up to 26 weeks and 39 weeks,
respectively, and repeat-dose toxicity of TPV with RTV co-administration
has been performed in rats and beagle dogs in studies up to 26 weeks of
duration. Genotoxicity was evaluated in *in vitro* and *in vivo* assays.
Traditional two-year carcinogenicity studies with TPV and TPV/RTV are
on-going in mice and rats. The effects of TPV on reproduction,
teratogenicity, and pre- and post-natal development were assessed in
standard tests in rats and rabbits. Specific studies have been performed
to address toxicity of drug substance (DS) and drug product (DP)
impurities and degradation products. Finally, single- and repeat-dose
studies have been performed to evaluate the toxicity of the TPV bulk
fill solution formulation (i.e., for TPV capsules 250 mg). An assessment
of the safety of excipients in the TPV oral solution has been performed,
based on information available in the literature, but no toxicity
studies were performed to evaluate this formulation. Overall, the
nonclinical pharmacokinetic and toxicology studies supported the use of
tipranavir in Phase I, II, and III studies.

[]{#__RefHeading___Toc101398984 .anchor}Appendix 1.2 General and Safety
Pharmacology

TPV was investigated in a number of general/safety pharmacology tests, a
series of secondary pharmacodynamic immune function tests, and a
biochemical receptor assay screen. TPV was well tolerated in most *in
vivo* tests, with some effects seen in the renal and GI systems. TPV
demonstrated an inhibitory effect *in vitro* on the HERG-associated
potassium channel (Ikr). However, no effects were observed *in vitro* in
action potential duration studies. TPV demonstrated no effects on QT
prolongation in *in vivo* conscious dog ECG studies. Taken together,
these *in vitro* and *in vivo* proarrhythmic risk studies suggest that
TPV has little potential to prolong the QT interval; findings in the
clinical support this view as no evidence of QT prolongation in humans
has been shown. Finally, due to the targeted patient population, TPV was
evaluated for effects on immune function, and slight to modest effects
on T-cell activation in mice were observed.

In studies on renal function, TPV caused significant changes in sodium
and potassium excretion following single oral doses of 62.5, 200 and 500
mg/kg in female rats and 62.5, 200 and 625 mg/kg in male rats. No
relevant effects on water consumption, urine volume or chloride
excretion were demonstrated. In studies on GI function at the same
doses, TPV caused decreased gastric emptying and decreased GI propulsion
in both female and male rats. In addition, gastric fluid volume was
significantly increased in male rats at the high dose, and the acid
concentration of the gastric fluid was significantly decreased in both
female and male rats at the high dose levels studied. Acid output was
not significantly altered.

TPV's potential to prolong QT interval was assessed both *in vitro* and
*in vivo*. In HEK293 cells transfected with HERG cDNA to express the
HERG-associated potassium channel (Ikr), TPV demonstrated an IC50 of 2.9
M in a protein-free environment. Since TPV demonstrated no effects
related to QT interval prolongation *in vitro* on action potential
duration in the guinea pig papillary muscle assay at similar
concentrations, or *in vivo* in conscious dog ECG studies following
single administration, it is unlikely that the compound possesses a risk
for causing cardiac arrhythmias, a finding supported by multiple
clinical evaluations.

Due to the immunodeficient targeted patient population, TPV was
evaluated for effects on immune function. In studies designed to assess
effects on T-cell activation, TPV displayed some slight (25%) to modest
(39%) effects in mice at a dose of 300 mg/kg (41µM, four hours
post-administration). In other tests, TPV did not affect T‑cell
independent B-cell activation and did not exhibit immunogenic effects up
to the limit of solubility.

[]{#__RefHeading___Toc101398985 .anchor}Appendix 1.3 Absorption,
Distribution, Metabolism, and Excretion

The results of preclinical *in vitro* studies and *in vivo*
pharmacokinetic/toxicokinetic studies in animals are summarized below:

[Absorption]{.underline}

-   Oral bioavailability after a single oral or intravenous dose of TPV
    in rats, dogs, mice, and rabbits was generally low to moderate (6.5
    to 28%). Systemic exposure increased in a dose-dependent manner for
    all species administered repeated daily, oral doses of TPV. Levels
    in humans exceed levels achievable in animals.

-   RTV boosted levels of TPV in all non-clinical species tested to
    various extents based on species and repeat dose toxicity studies.

[Distribution]{.underline}

-   Plasma protein binding was high with animal and human plasma. In
    human plasma at a TPV concentration of 20 µM, the unbound fraction
    was 0.032%. At 2 and 20 µM, the unbound fraction in cell culture was
    0.12% and 3.7%, respectively.

-   Following oral dosing, drug-related radioactivity was primarily
    associated with the liver and with the tissues and contents of the
    GI tract. Radioactivity did not readily cross the blood brain
    barrier. The pharmacokinetic parameters for radioactivity were
    similar for pigmented and non-pigmented rats. There was no apparent
    melanin binding. Partitioning of radioactivity into red blood cells
    was very low. The distribution of TPV with RTV co‑administration was
    similar to that observed without RTV co-administration.

-   Drug-related radioactivity was secreted in milk of lactating rats
    orally dosed with TPV and RTV. Radioactivity also crossed the
    placenta of pregnant rats.

[Metabolism]{.underline}

-   Since the onset of the Phase IIB development program, TPV is always
    co-administered with RTV in humans. With RTV co-administration, TPV
    accounted for most of the drug-related radioactivity in plasma,
    feces, and urine in the species studies to date, rat and human, with
    excreted metabolites accounting for only about 6% or less of the
    administered \[14C\]TPV. The observation of significantly decreased
    levels of metabolites is consistent with the mechanism of inhibition
    of metabolism by RTV. In vitro studies conducted in the absence of
    RTV do not reflect in vivo and are of limited significance.

-   CYP3A is the predominant human isoform of CYP450 involved in TPV
    metabolism. TPV also appears to be a substrate for efflux
    transporter(s), in particular P-glycoprotein.

[Elimination]{.underline}

-   In mouse, rat, and dog, the main route of excretion of drug-related
    radioactivity following oral dosing of radiolabelled TPV (with RTV)
    was via feces (87%, 75 %, and 68%, respectively).

-   Enterohepatic recirculation of TPV-related material was observed in
    rats

[]{#__RefHeading___Toc101398986 .anchor}Appendix 1.4 Toxicology

[]{#__RefHeading___Toc101398987 .anchor}Appendix 1.4.1 Single dose
toxicity studies (acute toxicity)

In acute toxicity studies, the minimum lethal oral dose of TPV was
3000 mg/kg in mice, 1500 mg/kg in rats, and \>500 mg/kg in dogs. Common
findings among the species tested were gastrointestinal symptoms
including emesis, soft stools and/or diarrhea. In rats, slight
elevations of coagulation parameters were noted in females after single
administration of 1500 to 3000 mg/kg.

[Repeat dose toxicity studies]{.underline}

Primary target organs of TPV identified in mice, rats, dogs and/or
monkeys in repeat-dose toxicity studies include the liver and
gastrointestinal tract. Additional organs that were affected included
the thyroid gland, testes, and to a lesser extent, the adrenal gland,
kidneys, spleen, and heart. The changes in these organs are discussed
below. None of the effects noted in target organs preclude use of TPV in
humans.

[Short-term Studies]{.underline}

Repeat dose toxicity studies of 2 to 13 weeks duration were conducted
with TPV to identify target organs of toxicity in mice, rats, dogs, and
cynomologus monkeys. TPV was administered by oral gavage (BID, 8 hours
apart), 7 days per week. Selected studies were performed by TPV
administered orally by diet or dermally via skin application. Identified
target organs were the GI tract and liver in all species tested, and the
thyroid gland in rodents.

*[Mice]{.underline}* During 4 to 13 week oral gavage studies, TPV (80
mg/kg/day) reduced food consumption and body weight gains. Clinical
pathology assessments revealed that 360 mg/kg/day increased activated
partial thromboplastin time (aPTT), plasma fibrinogen concentrations and
ALT, while daily doses of 400 mg/kg caused increased thyroxine and
triiodothyronine (T4 and T3, respectively) concentrations with a trend
to increased thyroid stimulating hormone (TSH). Doses of 300 mg/kg/day
caused hepatocellular hypertrophy, vacuolation, and necrosis; and 800
mg/kg/day caused thyroid follicle cell hypertrophy.

Administration of TPV by dietary admixture for 13 weeks to mice at dose
levels escalated up to 3240 mg/kg/day resulted in findings similar to
those observed with oral gavage administration. Additional changes noted
included heart changes of myocarditis and minimal to mild myocardial
degeneration at ≥360 mg/kg/day and liver findings of cholangiohepatitis,
Kupffer cell hyperplasia, and interstitial fibrosis at the escalated
dose level. The heart was not noted as a target organ in any other
studies with TPV in mice, nor in any other species tested. Dermal
administration of TPV for 4 weeks in mice confirmed liver as a target
organ, with similar changes as noted with organ gavage.

*[Rats]{.underline}* During 2- and 4-weeks studies in rats, TPV (40 to
1,250 mg/kg/day) reduced food consumption and body weight gains and
increased prothrombin and activated partial thromboplastin times.
Thyroid effects included elevated plasma TSH and decreased plasma T3 and
T4 concentrations, increased thyroid weights, and thyroid follicle cell
hypertrophy. Liver weights were increased in a dose-related manner, and
microscopic examination revealed hepatocellular hypertrophy. During the
4-week study, TPV was associated with increased adrenal gland weights,
but histopathological correlates were not apparent.

*[Dogs]{.underline}* During an 8-day study, TPV (75 to 300 mg/kg/day)
caused emesis, soft stools, diarrhea, and increased alkaline phosphatase
(AP). The highest dose increased liver weights, but histopathologic
changes were absent. During a 4-week study with a 4‑week recovery
period, TPV (30 to 320 mg/kg/day) caused emesis, salivation, and soft
stools/diarrhea. Doses ≥75 mg/kg/day caused decreases in body weights
and decreased aPTT and increased AP both of which were reversible
effects. Increased liver weights were observed with ≥160 mg/kg/day
causing hepatocellular hypertrophy and 320 mg/kg/day causing
hepatocellular hypertrophy associated with proliferation of smooth
endoplasmic reticulum. Doses of ≥75 mg/kg/day increased adrenal weights,
but there were no histopathologic correlates.

*[Non-human primates]{.underline}* Male cynomologus monkeys had
TPV-related emesis, diarrhea, and/or soft stools at all dose levels but
most frequently at 320 mg/kg/day, the highest dose tested. At the
conclusion of the 2-week study, there were elevated plasma fibrinogen
concentrations in all dose groups. Histopathology data are not available
because the animals were not sacrificed at the study conclusion. Studies
in non‑human primates have not been pursued beyond 2 weeks duration
because of low systemic exposure to TPV in this species compared to that
in rats and dogs.

[]{#__RefHeading___Toc101398988 .anchor}Appendix 1.4.2 Chronic studies

Chronic studies in rats (26 weeks with 13 weeks of recovery) and dogs
(39 weeks with 9 weeks of recovery) revealed target organ effects
essentially identical to those observed during short-term studies. In
addition, the dog testes and gallbladder were identified as target
organs during the 39-week study, although further evaluation has
determined that the former finding was without merit, as described
below.

*[Rats]{.underline}* TPV (0, 20, 40, 125, and 400 mg/kg/day) was
administered for 26-weeks, and groups of Control and 400 mg/kg/day
animals were afforded a 13-week recovery period after cessation of
dosing. The no observable toxic effect levels in this study were judged
to be 40 and 20 mg/kg/day for males and females, respectively.
TPV-associated changes consistent with earlier studies included
dose-related increases in aPTT and PT (only in males), and hepatic and
thyroid changes. Findings unique to the chronic study included decreases
in red blood cell (RBC) parameters, increases in plasma total protein,
globulin and albumin, urinary protein, and kidney weights and increased
numbers of multinucleated hepatocytes, and increased incidences of
chronic progressive nephropathy. Chronic progressive nephropathy is an
age-related, rat-specific lesion; the increased incidence was considered
to be a stress-related exacerbation of a naturally occurring disease and
not a primary effect of TPV on the kidneys. Changes observed in 400
mg/kg/day rats afforded 13‑weeks for recovery included increased urinary
protein in females, increased liver weights in both sexes, slightly
increased kidney weights, increased incidences of chronic progressive
nephropathy and multinucleate hepatocytes in both sexes. The magnitude
of these changes after recovery was small relative to changes observed
at the time of cessation of dosing, suggesting reversibility of the
findings.

*[Dogs]{.underline}* TPV (0, 20, 75, and 320 mg/kg/day) was administered
to dogs for 39 weeks, and reversibility of induced changes was assessed
after a 9-week recovery period. The no observable toxic effect dose
level was judged to be 20 mg/kg/day in both sexes. Consistent with
short-term studies, TPV caused emesis, salivation and soft stools,
increases in alkaline phosphatase, hepatomegaly, and hepatocellular
hypertrophy during the chronic study. TPV‑associated changes unique to
the chronic study in dogs included 10-15% decreases in total plasma
protein, albumin, and albumin/globulin ratio, RBC parameters and
calcium. Microscopic changes, included hepatocellular hypertrophy,
splenic hematopoiesis, cystic hyperplasia of the gallbladder, testicular
degeneration/atrophy, and bile duct hyperplasia. Cystic hyperplasia of
the gallbladder was present but less prominent in high-dose dogs
afforded the 9-week recovery period. One of three recovery group males
also exhibited degeneration of the seminiferous tubules and abnormal
germ cells in the epididymis. Re-evaluation of testes changes by a group
of experts revealed that the microscopic findings in the testes were
within normal variation for beagle dogs. Consequently, testes were
judged not to be a target organ in this study.

[]{#__RefHeading___Toc101398989 .anchor}Appendix 1.4.3 TPV-ritonavir
co-administration studies

Co-administration of TPV and RTV for 4 weeks in mice and for up to 26
weeks in rats and dogs revealed no target organs other than those
already identified for each drug, nor did co‑administration exacerbate
the known toxicity of either drug. Toxicokinetic assessments revealed
that co-administration of the drugs increased systemic exposure to TPV
while decreasing exposure to RTV in both species.

*[Mice]{.underline}* In a 4-week study in mice (15/sex/group), TPV was
co-administered with RTV in a 3.75:1 ratio, the same dose ratio as the
clinical dose of 750/200 TPV/r BID. Dose levels included 0, 150/40,
300/80, and 600/160 mg/kg/day TPV/RTV, 600 mg/kg/day TPV, or
160 mg/kg/day RTV. The principal organ of toxicity was the liver, and
changes upon co‑administration were the same as with TPV alone.
Hypertrophy of the zona fasciculate of the adrenal was noted in males
only at 600/160 mg/kg/day TPV/RTV and to a lesser extent at
600 mg/kg/day TPV. Secondary changes consisting of spontaneous changes
in mice exacerbated by treatment included mixed cell infiltrates and
focal mineralization in the parenchyma of the liver, granulocytic
hyperplasia in the bone marrow, extramedullary hematopoesis in the
spleen, and lymphoid follicular hyperplasia in the spleen.

*[Rats]{.underline}* In a 2-week dose range-finding (5/sex/group) and a
26-week study in rats (20/sex/group), TPV and RTV were co‑administered
in a consistent TPV: RTV ratio of 3.75:1. In the 26-week study,
administered doses included 0, 120/32, 600/160, or 1200/320 mg/kg/day
TPV/r, 1200 mg/kg/day TPV, or 160 mg/kg/day RTV. In both studies,
co-administration of TPV and RTV resulted in toxicities common to the
individual compounds administered separately. Target organs resulting
from the gavage administration of TPV/r co‑administration to rats for 26
weeks comprised effects seen previously on the thyroid gland and liver
with TPV, with additional liver findings including an increased
incidence in karyomegaly, a documented finding in rat studies with RTV.
At high dose levels administered in this study, effects on aPTT and PT
were augmented, with resultant observations of excessive hemorrhage and
consequent increases in lethality, notably in males. Lymphoid depletion
of multiple tissues, thymic lymphocytolysis, and subcutaneous fat
depletion were observed at high dose levels. Bilateral testicular
degeneration was noted in males administered the high-dose of TPV/r.
When TPV was administered alone, target organs were similar to those of
TPV/r at the same TPV dose level, with the exception that no hepatic
karyomegaly was observed, and there were no testicular findings. Hepatic
karyomegaly and testicular degeneration are findings associated with RTV
administration, with the former finding observed in this study at the
RTV alone dose level, but the latter finding not evident. Testes changes
were re-evaluated by an expert panel. These testicular changes in rats,
seen in only three animals at a high dose level, were morphologically
and pathogenically unrelated and therefore not related to drug
treatment. Consequently, testes are not considered to be a target organ
of toxicity.

*[Dogs]{.underline}* Two-week (1 dog/sex/group) and 26-week (3
dogs/sex/group) toxicity studies were conducted with co-administered
dosage regimens of 15/4, 37.5/10, or 75/20 (escalated to 150/40)
mg/kg/day TPV/r. Additional groups of dogs received TPV or RTV alone.
Treatment-induced emesis was the dose-limiting factor during these
studies. Co-administration of the drugs did not influence toxicity,
although during the 26‑week study a single female (75-150/20-40 TPV/r)
exhibited mild, diffuse hypertrophy superficial transitional epithelium
of the urinary bladder. Similar to studies with TPV alone,
hepatocellular hypertrophy was observed in a dose-related fashion.
Conversely, microscopic changes in the bone marrow, gallbladder, and
spleen were seen in dogs dosed with TPV and RTV alone but not in animals
administered both drugs. A no toxic effect level was not determined, due
to the presence of hepatocellular hypertrophy at 15/4 mg/kg/day.

Repeated administration of TPV has been shown to increase activity of
hepatic drug metabolizing enzymes CYP2B and CYP3A in rats and, to a
lesser degree, in dogs. The toxicokinetics results of these drug-drug
interaction studies most likely reflect a preferential metabolism of RTV
by the induced CYP2A and CYP3A.

[Summary of Effect on Target Organs]{.underline}

*[Effects on the GI System]{.underline}* GI effects of TPV, observed in
all species tested, may reflect local actions, although correlative
macro- or microscopic changes have not been observed. Addition of RTV to
TPV dosage regimens was without effect on either the incidence or
severity of GI effects in rats and dogs.

*[Effects on the Liver]{.underline}* Hepatic effects of TPV were
dose-related, reversible, and likely reflective of hepatic enzyme
induction. Increases in liver weights in rats and dogs were correlated
with increased CYP3A and CYP2B content, and hepatocellular hypertrophy
was characterized by small mitochondria in rats and proliferation of
smooth endoplasmic reticulum in rats and dogs. At higher doses, rodents
showed evidence of hepatocellular degeneration (including vacuolation),
mineral deposition in mice, and multinucleated hepatocytes in rats.
Karyomegaly, a well-documented effect of RTV in rats, was observed at a
low incidence in rats administered TPV/r for 26 weeks. In mice, clinical
chemistry evaluation revealed the presence of enzyme leakage (e.g., ALT,
AST) at high dose levels, mirrored in the histopathologic evaluation as
hepatocellular necrosis. Changes in coagulation indices, observed only
in rodents, were judged secondary to hepatic enzyme induction and/or
effects on vitamin K recycling. In contrast, no adverse effects on
coagulation were noted in dogs receiving TPV alone up to 39 weeks or
TPV/r up to 26 weeks.

*[Effects on the Testes]{.underline}* Testicular effects consisting of
decreased weights and bilateral seminiferous tubule degeneration and/or
atrophy were observed in a 26-week TPV/r study in rats and a 39‑week TPV
study in dogs. Re-evaluation of these data by an expert panel indicated
that the findings in the beagle dog were within normal limits of
variation. The testicular changes in rats, seen in only three animals at
a high dose level, were morphologically and pathogenically unrelated and
therefore not related to drug treatment. Consequently, testes are not
considered to be a target organ of toxicity.

*[Effects on the Thyroid Gland in Rodents]{.underline}* Thyroid gland
changes in TPV-dosed rodents are considered to reflect a rodent-specific
increase in thyroid hormone metabolism secondary to induction of hepatic
drug metabolizing enzymes. The primary clearance of thyroid hormone in
rodents is via glucuronidation and biliary excretion, whereas humans
readily deiodinate T4 and T3, making conjugation a minor elimination
pathway.

*[Additional Effects]{.underline}* Chronic progressive nephropathy (CPN)
is a spontaneous, age- and stress-related change commonly observed in
rats. Increased urinary protein observed in TPV-dosed rats was
considered due to exacerbation of CPN by stress and therefore an action
without predictive validity for humans.

Increased extramedullary hematopoiesis was observed in the spleen in
mice, rats, and dogs. This finding was judged secondary to the mildly
reduced red blood cell parameters in rats and dogs, and hemorrhage
observed in the 26-week TPV/r rat study.

Adrenal gland effects consisted of increased adrenal weights without
correlative microscopic changes, with the exception of one 4-week study
in mice where hypertrophy of the zona fasciculata was observed at the
highest TPV and TPV/RTV dose levels. Based on the high dose levels that
caused these findings, the minimal to mild effects noted, and the lack
of biologically relevant changes in dogs, the effects on the adrenal
gland in rodents were attributed to stress, and not a direct effect of
TPV.

Minimal to mild myocardial degeneration was observed in one study in
mice when TPV was administered by diet over 13 weeks. No heart changes
were observed in any gavage administration study in mice up to 13-weeks,
nor have heart changes been seen in any study in rats or dogs, up to 26-
and 39-weeks, respectively. Consequently, the significance of this
finding in relation to humans is unclear. However, it is judged that
TPV, if it had any cardiotoxic liability, would have caused cardiac
changes in multiple species, or consistently in one species, rather than
showing evidence in only one study.

[]{#__RefHeading___Toc101398990 .anchor}Appendix 1.4.4 Genotoxicity
studies

TPV was neither mutagenic nor clastogenic in a battery of five *in
vitro* and *in vivo* assays widely employed for the assessment of
genotoxicity. *In vitro* tests included the Ames Assay, assessment of
unscheduled DNA synthesis in rat hepatocytes, induction of gene mutation
in Chinese hamster ovary cells, and a chromosome aberration assay in
human peripheral lymphocytes. The *in* *vivo* test was a micronucleus
assay in mice.

[]{#__RefHeading___Toc101398991 .anchor}Appendix 1.4.5 Reproduction
toxicology

[Fertility and Embryotoxicity]{.underline}

TPV administered at dose levels as high as 1000 mg/kg/day was without
effects on spermatogenesis, estrous cycles, copulation, conception,
fertility, implantation, or early embryonic development in rats. A dose
of 1000 mg/kg/day produced a Cmax of 258 µM in female rats.

[Teratogenicity]{.underline}

*[Rats]{.underline}* In both range-findings and definitive studies, TPV
at oral dose levels of 40 to 1000 mg/kg/day showed no evidence of
teratogenicity or embryolethality. However, maternal toxicity, as well
as decreased fetal body weight and sternebrae ossification, was observed
at dose levels of 400 mg/kg/day and above. Consequently, the no toxic
effect level for maternal and developmental toxicity was 40 mg/kg/day,
corresponding to a mean Cmax and AUC of 30.4 µM and 304 µM·h,
respectively.

*[Rabbits]{.underline}* TPV was without teratogenic effect when
administered to pregnant rabbits in daily (gestation Days 6 through 20)
doses up to 150 mg/kg, although that dose caused maternal toxicity
(abortion). During a dose range-finding study in pregnant rabbits, daily
administration of up to 750 mg/kg was embryotoxic and produced maternal
(e.g., deaths, abortions, decreased body weight) and developmental
toxicity (i.e., decreased fetal weights), but neither external
malformations nor variations. However, in a definitive study in rabbits,
375 mg/kg/day of TPV caused maternal toxicity similar to that previously
seen at 750 mg/kg/day in the range-finding study, as well as
developmental toxicity (i.e., decreased fetal weight, increased gross
malformations). Gross malformations included dome-shaped head (with
associated hydrocephaly), omphalocele, carpal flexure, bent femurs,
arthrogryposis, and wavy ribs. It is noteworthy that a single litter was
responsible for 75--80% of fetuses with gross and visceral malformations
and 50% with skeletal malformation. This suggests that anomalies may
have been due to a litter effect rather than a TPV-induced
teratogenesis. Consequently, the maternal no toxic effect level was
determined to be 75 mg/kg/day, while the fetal no toxic effect level was
150 mg/kg/day. These dose levels were associated with steady state Cmax
values of 4.9 and 8.4 µM and AUC0-24 values of 66 and 120 µM·h/mL,
respectively. Based on the lack of characteristics typical of known
developmental toxicants coupled with the marked maternal toxicity
observed, the results of these experiments in rabbits support a
conclusion that TPV is not a selective developmental toxicant.

[Pre-natal and Postnatal Studies]{.underline}

In a pre-natal and postnatal development study in rats, an oral dose of
40 mg/kg/day of TPV was considered a no toxic effect level in dams and
pups if administered from Day 6 of gestation to Day 21 postpartum.
Administration of 400 mg/kg/day and above caused dose-related maternal
toxicity and retarded pup growth, but no post-weaning functions were
affected nor was there any evidence of teratogenicity at any dose level.

[]{#__RefHeading___Toc101398992 .anchor}Appendix 1.4.6 Other toxicity

[Immunotoxicity]{.underline}

Daily exposure of female CD-1 mice (10/group) to TPV co-administered
with RTV, TPV alone, or RTV alone for a period of 28 days did not result
in alterations of the major organs of the immune system, the thymus or
the spleen, or on the humoral immune response as evaluated in the IgM
antibody-forming cell response to the T-dependent antigen, sheep red
blood cells. TPV was co-administered with RTV at dose levels of 30/8,
100/26.7, or 300/80 mg/kg/day TPV/RTV. In addition, a Sham Control
group, Vehicle Control group, Positive Control group, and TPV alone (300
mg/kg/day) and RTV alone (80 mg/kg/day) groups were included in this
study. In TPV/RTV, TPV, or RTV-treated groups, there was no
statistically significant effect on spleen cell number or IgM production
when evaluated as either specific activity or as total spleen activity.
The Positive Control (cyclophosphamide), behaved as expected, resulting
in decreases in mean thymus and spleen weights as well as a 99% decrease
in specific activity and 100% decrease in total spleen activity.
Therefore, under the conditions of this study, TPV administered with or
without RTV was considered to have no effect on the T-dependent immune
response of CD-1 female mice.

[Evaluation of Formulations]{.underline}

The toxicity of various TPV SEDDS formulations has been investigated in
a series of toxicity studies in rats and dogs. In rats, acute to 13-week
studies revealed no toxicities specific to the SEDDS formulation at up
to 2 mL/kg/day or \~30-fold the equivalent human exposure on a body
weight basis. The 26-week safety study in beagle dogs was designed to
particularly address the toxicity of one excipient of the bulk fill
solution, Cremophor EL (CrEL; polyoxyl castor oil 35). Dogs have been
shown to be a species sensitive to effects of CrEL. To this end, this
dog study employed a SEDDS formulation similar to the bulk fill solution
in that the levels of excipients were in the same ratios, but volume of
the SEDDS formulation administered was varied while the level of TPV/RTV
present was fixed in the treatment groups. In this study, Control and
High-dose dogs were exposed to approximately 30-fold the human exposure
of CrEL at a TPV/RTV dose of 500/200 mg BID, based on body weight
(mg/kg/day). Results of this study indicate leukocytosis with
neutrophilia, as well as an increase in liver AP isoenzymes, related to
exposure to the high-dose level of SEDDS vehicle. Mortality occurred in
one Control female exposed to 30-fold the human exposure of CrEL. No
changes in dogs were noted at 10-fold human exposure to SEDDS. Further,
no CrEL was detectable during analysis of plasma samples from over 100
patients receiving TPV in the SEDDS formulation. The formulation at the
proposed human dose of 500/200 mg BID TPV/RTV is considered safe for use
in humans. The exposure to other excipients present in the TPV SEDDS
formulation is considered within standards for pharmaceutical use of
these materials.

The components of the TPV oral solution formulation are different than
those of the TPV bulk fill solution used in TPV capsules 250 mg. This
formulation has not been evaluated in toxicity tests in animals.
However, an evaluation of its individual components has been performed,
based on literature review. In this review, the addition of excipients
contained in RTV oral solution have been taken into account, as this
formulation contains propylene glycol (PG) as well as 43% ethanol.

The levels of the following excipients are above WHO acceptable limits
when TPV and RTV oral solutions are co-administered: polyethylene glycol
400 (PEG 400), propylene glycol, and Vitamin E TPGS. All other
excipients are within acceptable limits. Key issues relating to these
excipients above WHO acceptable limits are discussed below. However, the
levels of all excipients present are considered appropriate with the
caveats described under the key issues.

The level of propylene glycol (PG), when TPV and RTV oral solutions are
co‑administered, is above WHO acceptable limits, but is considered safe,
as toxicity of PG is very low. Review of potential PG exposure revealed
that PG levels with RTV co administration are below that of currently
marketed formulations (e.g., Norvir® oral solution). Consequently, no
precautionary labeling is warranted. There are concerns regarding
metabolism of this excipient in infants and children less than 2 years
of age, due to the low levels of the PG-metabolizing enzyme alcohol
dehydrogenase expressed by young livers. Consequently, caution must be
exercised when administering this combination to infants or children
less than 2 year of age when administering TPV oral and RTV oral
solutions along with other prescription and/or non-prescription
medications containing propylene glycol and/or ethanol. Clinically, CNS
effects similar to those of ethanol intoxication should be monitored
for, e.g. stupor, ataxia.

PEG 400, at this dose level, may contribute somewhat to GI disturbances
such as soft stool and/or diarrhea, but these effects may not be
distinguishable from the GI side-effects of TPV itself. There are no
systemic toxicity concerns regarding the level of PEG 400 in the TPV
oral solution formulation, based on literature assessment.

Due to the presence of Vitamin E TPGS at 300 mg/mL in the TPV oral
solution, it is recommended that the labeling state that Vitamin E
supplementation should not be taken along with this medication since the
Vitamin E content of this product exceeds the Reference Daily Intake (30
IU/day for adults and children over 4, 10 IU/day for children under 4,
and 5 IU/day for infants). At the therapeutic dose level of 500/200 mg
TPV/RTV BID, an individual would consume 1160 IU Vitamin E/day when
taking the oral solution. Literature indicates a tendency for high doses
of Vitamin E to cause an anticoagulant effect. A number of studies in
rats with oral administration of high dose levels of tocopherols showed
increases in prothrombin and partial thromboplastin times along with
hemorrhages in the epididymis and other organs. The biochemical
mechanism(s) of the reduction of blood coagulation factors II, VII, IX,
and X by Vitamin E has not been studied, but are considered linked to
Vitamin K cycling. Evidence from several large clinical trials in which
human adults received 300‑800 IU of Vitamin E daily for 1.4-4.5 years
showed no increased risk of stroke, but at least one study (ATBC Cancer
Prevention study) reported an increased mortality from hemorrhagic
stroke in male smokers receiving 50 IU of Vitamin E daily. An increase
in hemorrhagic stroke was not detected in a 2 year study in Alzheimer's
patients receiving 2100 IU of Vitamin E daily. Oral Vitamin E, up to a
daily intake of 600 IU for up to 3 years in healthy individuals, did not
adversely affect blood coagulation. However, the possibility that the
relatively high dosages of Vitamin E could exacerbate coagulation
defects in individuals who are deficient in Vitamin K or are receiving
anticoagulant therapy, suggests that caution is warranted.

[]{#__RefHeading___Toc101398993 .anchor}APPENDIX 2 TPV Clinical Trial
Program

[]{#__RefHeading___Toc101398994 .anchor}Appendix 2.1 Biopharmaceutic
Studies

Table 1 Listing of Biopharmaceutic Studies

<table>
<colgroup>
<col style="width: 6%" />
<col style="width: 10%" />
<col style="width: 8%" />
<col style="width: 13%" />
<col style="width: 10%" />
<col style="width: 16%" />
<col style="width: 6%" />
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 8%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>Type of<br />
Study</strong></td>
<td><strong>Study No. and BI Report No. (P&amp;U Protocol Number,<br />
if applicable)<br />
</strong></td>
<td><strong>Countries Study Conducted</strong></td>
<td><strong>Objective(s)<br />
of<br />
the Study</strong></td>
<td><strong>Study<br />
Design and<br />
Type of<br />
Control</strong></td>
<td><strong>Test<br />
Product(s) and<br />
Dosage<br />
Regimen</strong></td>
<td><strong>Number of<br />
Human Subjects<br />
Entered</strong></td>
<td><strong>Healthy<br />
Subjects or<br />
Diagnosis of<br />
Patients</strong></td>
<td><strong>Planned Duration of<br />
Treatment</strong></td>
<td><strong>Study<br />
Status;<br />
Type of<br />
Report</strong></td>
</tr>
<tr class="even">
<td colspan="10"><strong>Reports of Biopharmaceutic
Studies</strong></td>
</tr>
<tr class="odd">
<td><p>PK/Safety</p>
<p>Phase I</p></td>
<td><p>No BI study number</p>
<p>U00-3208</p></td>
<td><blockquote>
<p>United States</p>
</blockquote></td>
<td><p>To assess the effect of RTV on the PK of TPV;</p>
<p>To assess the effect of TPV on the PK of RTV;</p>
<p>To assess PK of TPV given q 12 h;</p>
<p>To assess the short term safety and tolerance of TPV + RTV</p></td>
<td>Open-label, multiple-dose, single‑treatment</td>
<td><p>TPV: 1350-mg dose BID:</p>
<p>150-mg HFC x 9</p>
<p>RTV: escalating doses:</p>
<p>100-mg capsules x 2, 3, 4, 5 – all BID, except as noted</p>
<p>Day 1-7: TPV 1350 mg BID (AM dose only Day 7)</p>
<p>Day 8-9: RTV 200 mg</p>
<p>Day 10-11: RTV 300 mg</p>
<p>Day 12-15: RTV 400 mg</p>
<p>Day 16-31: RTV 500 mg (AM dose only on Day 31)</p>
<p>Day 22-31: TPV 1350 mg BID (AM dose only on Day 31)</p></td>
<td><blockquote>
<p>n = 14</p>
</blockquote></td>
<td><blockquote>
<p>HIV-1 negative, healthy male and female volunteers</p>
</blockquote></td>
<td><blockquote>
<p>31-day study period</p>
</blockquote></td>
<td>Complete; Final report</td>
</tr>
</tbody>
</table>

NOTE: Footnotes and translations of abbreviations for this table follow
below.

Table 1 (continued) Listing of Biopharmaceutic Studies (Page 2 of 3)

<table>
<colgroup>
<col style="width: 7%" />
<col style="width: 10%" />
<col style="width: 8%" />
<col style="width: 13%" />
<col style="width: 9%" />
<col style="width: 16%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 8%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>Type of<br />
Study</strong></td>
<td><strong>Study No. and BI Report No. (P&amp;U Protocol Number,<br />
if applicable)<br />
</strong></td>
<td><strong>Countries Study Conducted</strong></td>
<td><strong>Objective(s)<br />
of<br />
the Study</strong></td>
<td><strong>Study<br />
Design and<br />
Type of<br />
Control</strong></td>
<td><strong>Test<br />
Product(s) and<br />
Dosage<br />
Regimen</strong></td>
<td><strong>Number of Human Subjects Entered</strong></td>
<td><strong>Healthy<br />
Subjects or<br />
Diagnosis of<br />
Patients</strong></td>
<td><strong>Planned Duration of<br />
Treatment</strong></td>
<td><strong>Study<br />
Status;<br />
Type of<br />
Report</strong></td>
</tr>
<tr class="even">
<td colspan="10"><strong>Reports of Biopharmaceutic Studies
(continued)</strong></td>
</tr>
<tr class="odd">
<td><p>PK/Safety</p>
<p>Phase I</p></td>
<td><p>1182.5</p>
<p>U01-3295</p></td>
<td><blockquote>
<p>United States</p>
</blockquote></td>
<td><ul>
<li><p>Determine the effects of TPV/r on the cytochrome P‑450
activity;</p></li>
<li><p>Establish the dependency of the TPV M1 metabolite on RTV
co‑administration;</p></li>
<li><p>Evaluate the short term safety and tolerance of TPV/r.</p></li>
</ul></td>
<td>Open label, parallel group</td>
<td><p>TPV 250 mg/RTV 200 mg BID;</p>
<p>TPV 500 mg/RTV 100 mg BID;</p>
<p>TPV 500 mg/RTV 200 mg BID;</p>
<p>TPV 750 mg/RTV 100 mg BID;</p>
<p>TPV 750 mg/RTV 200 mg BID;</p>
<p>TPV 1000 mg/RTV 100 mg BID;</p>
<p>TPV 1000 mg/RTV 200 mg BID;</p>
<p>TPV 1250 mg/RTV 100 mg BID</p></td>
<td><blockquote>
<p>n = 13</p>
<p>n = 13</p>
<p>n = 13</p>
<p>n = 12</p>
<p>n = 14</p>
<p>n = 14</p>
<p>n = 13</p>
<p>n = 21</p>
<p>Total = 113</p>
</blockquote></td>
<td><p>Healthy</p>
<p>HIV negative volunteers</p></td>
<td>10 days TPV monotherapy, then 21 days of TPV/r therapy: 31 days
total</td>
<td>Complete; Final report</td>
</tr>
<tr class="even">
<td><p>PK</p>
<p>Phase I</p></td>
<td><p>1182.45</p>
<p>U04-1751</p></td>
<td>Germany</td>
<td><ul>
<li><p>Evaluate the bioavailability of TPV/r solution vs. TPV/r
capsules</p></li>
<li><p>Evaluate the bioavailability of TPV/r solution with food vs.
without food.</p></li>
</ul></td>
<td>Open label, single-dose, three-way crossover trial</td>
<td><blockquote>
<p>Liquid and SEDDS</p>
<p>TPV formulations</p>
</blockquote></td>
<td><blockquote>
<p>n = 30</p>
</blockquote></td>
<td><blockquote>
<p>Healthy</p>
<p>HIV negative volunteers</p>
</blockquote></td>
<td><blockquote>
<p>1 day (single dose) for each treatment, total 3 days</p>
</blockquote></td>
<td>Complete; Final report</td>
</tr>
</tbody>
</table>

NOTE: Footnotes and translations of abbreviations for this table follow
below.

Table 1 (continued) Listing of Biopharmaceutic Studies (Page 3 of 3)

<table>
<colgroup>
<col style="width: 6%" />
<col style="width: 10%" />
<col style="width: 8%" />
<col style="width: 13%" />
<col style="width: 10%" />
<col style="width: 16%" />
<col style="width: 7%" />
<col style="width: 9%" />
<col style="width: 7%" />
<col style="width: 8%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>Type of<br />
Study</strong></td>
<td><strong>Study No. and BI Report No. (P&amp;U Protocol Number,<br />
if applicable)<br />
</strong></td>
<td><strong>Countries Study Conducted</strong></td>
<td><strong>Objective(s)<br />
of<br />
the Study</strong></td>
<td><strong>Study<br />
Design and<br />
Type of<br />
Control</strong></td>
<td><strong>Test<br />
Product(s) and<br />
Dosage<br />
Regimen</strong></td>
<td><strong>Number of Human Subjects Entered</strong></td>
<td><strong>Healthy<br />
Subjects or<br />
Diagnosis of<br />
Patients</strong></td>
<td><strong>Planned Duration of<br />
Treatment</strong></td>
<td><strong>Study<br />
Status;<br />
Type of<br />
Report</strong></td>
</tr>
<tr class="even">
<td colspan="10"><strong>Reports of Biopharmaceutic Studies
(continued)</strong></td>
</tr>
<tr class="odd">
<td><p>PK/Safety</p>
<p>Phase I</p></td>
<td><p>No BI study number</p>
<p>U00-3267</p></td>
<td><blockquote>
<p>United States</p>
</blockquote></td>
<td><p>To assess the bioavailability of three SEDDS TPV formulations
relative to a 300‑mg TPV HFC formulation</p>
<p>To assess the effect of a high-fat meal on the bioavailability of TPV
SEDDS and HFC formulations</p>
<p>To assess short-term safety</p></td>
<td>Randomized, open-label, four-way crossover + fifth treatment period
to assess food effect</td>
<td><blockquote>
<p>TPV: single 1200-mg dose</p>
</blockquote>
<ol type="A">
<li><p>4 x 300-mg HFC capsules</p></li>
<li><p>4 x 300-mg SEC (SEDDS no-base)</p></li>
<li><p>4 x 300-mg SEC (SEDDS, Tris with GDO/GMO)</p></li>
<li><p>5 x 240 mg HFC (SEDDS, Tris with Capmul MCM)</p></li>
</ol>
<blockquote>
<p>Fifth period: Treatments A, B, C, D with high-fat meal</p>
</blockquote></td>
<td><blockquote>
<p>n = 16</p>
</blockquote></td>
<td><blockquote>
<p>HIV-1 negative, healthy male and female volunteers</p>
</blockquote></td>
<td><blockquote>
<p>31-day study period</p>
</blockquote></td>
<td><blockquote>
<p>Complete;</p>
<p>Final report</p>
</blockquote></td>
</tr>
<tr class="even">
<td><p>PK/Safety</p>
<p>Phase I</p></td>
<td><p>No BI study number</p>
<p>U01-3056</p></td>
<td><blockquote>
<p>United States</p>
</blockquote></td>
<td><p>To assess the bioavailability of two 300-mg SEDDS TPV
formulations relative to a 300‑mg TPV HFC formulation</p>
<p>To assess safety and tolerability</p></td>
<td><blockquote>
<p>Randomized, open-label, parallel‑group</p>
</blockquote></td>
<td><blockquote>
<p>TPV: 1200 mg BID:</p>
<p>300-mg SEDDS x 4 and</p>
<p>2400 mg BID: 300 mg HFC x 8</p>
</blockquote>
<ul>
<li><p>8 x 300-mg HFC</p></li>
<li><p>4 x 300-mg SEC (SEDDS no‑base)</p></li>
<li><p>4 x 300-mg SEC (SEDDS, Tris with GDO/GMO)</p></li>
</ul></td>
<td><blockquote>
<p>n = 18</p>
</blockquote></td>
<td><blockquote>
<p>HIV-1 negative, healthy male and female volunteers</p>
</blockquote></td>
<td><blockquote>
<p>10-day study period</p>
</blockquote></td>
<td><blockquote>
<p>Complete;</p>
<p>Final report</p>
</blockquote></td>
</tr>
</tbody>
</table>

NOTE: Footnotes and translations of abbreviations for this table follow
below.

[]{#__RefHeading___Toc101398995 .anchor}Appendix 2.2 Human
Pharmacokinetic Studies

Table 2 Listing of Human Pharmacokinetic Studies

<table>
<colgroup>
<col style="width: 7%" />
<col style="width: 11%" />
<col style="width: 8%" />
<col style="width: 13%" />
<col style="width: 10%" />
<col style="width: 15%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>Type of<br />
Study</strong></td>
<td><strong>Study No. and BI Report No. (P&amp;U Protocol Number,<br />
if applicable)<br />
</strong></td>
<td><strong>Countries Study Conducted</strong></td>
<td><strong>Objective(s)<br />
of<br />
the Study</strong></td>
<td><strong>Study<br />
Design and<br />
Type of<br />
Control</strong></td>
<td><strong>Test<br />
Product(s) and<br />
Dosage<br />
Regimen</strong></td>
<td><strong>Number of Human Subjects Entered</strong></td>
<td><strong>Healthy<br />
Subjects or<br />
Diagnosis of<br />
Patients</strong></td>
<td><strong>Planned Duration of<br />
Treatment</strong></td>
<td><strong>Study<br />
Status;<br />
Type of<br />
Report</strong></td>
</tr>
<tr class="even">
<td colspan="10"><strong>Reports of Human Pharmacokinetic
Studies</strong></td>
</tr>
<tr class="odd">
<td><blockquote>
<p>PK</p>
<p>Phase I</p>
</blockquote></td>
<td><blockquote>
<p>No BI study number</p>
<p>U00-3265</p>
</blockquote></td>
<td><blockquote>
<p>United States</p>
</blockquote></td>
<td>Evaluate the safety and PK of multiple doses of TPV after an oral
administration to normal healthy volunteers</td>
<td>Single-center, randomized, double-blind PBO-controlled escalating
dose</td>
<td><p>PBO capsules</p>
<p>TPV hand filled</p>
<p>Capsules (free acid equivalent capsules): 100 mg and 300 mg</p>
<p>Doses given:</p>
<p>300 mg</p>
<p>600 mg</p>
<p>900 mg</p>
<p>1200 mg</p>
<p>1600 mg</p>
<p>2000 mg</p></td>
<td><p>n = 12</p>
<p>n = 36</p>
<p>n = 6</p>
<p>n = 6</p>
<p>n = 6</p>
<p>n = 6</p>
<p>n = 6</p>
<p>n = 6</p>
<p>Total = 48</p></td>
<td>HIV-1 negative, healthy male and female volunteers</td>
<td>Single dose, followed by 2 days of no drug and then 9.3 days of
multiple doses</td>
<td>Complete; Final report</td>
</tr>
</tbody>
</table>

Table 2 (continued) Listing of Human Pharmacokinetic Studies (Page 2 of
8)

<table style="width:100%;">
<colgroup>
<col style="width: 8%" />
<col style="width: 10%" />
<col style="width: 0%" />
<col style="width: 7%" />
<col style="width: 13%" />
<col style="width: 11%" />
<col style="width: 0%" />
<col style="width: 15%" />
<col style="width: 8%" />
<col style="width: 0%" />
<col style="width: 8%" />
<col style="width: 0%" />
<col style="width: 8%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>Type of<br />
Study</strong></td>
<td><strong>Study No. and BI Report No. (P&amp;U Protocol Number,<br />
if applicable)<br />
</strong></td>
<td colspan="2"><strong>Countries Study Conducted</strong></td>
<td><strong>Objective(s)<br />
of<br />
the Study</strong></td>
<td><strong>Study<br />
Design and<br />
Type of<br />
Control</strong></td>
<td colspan="2"><strong>Test<br />
Product(s) and<br />
Dosage<br />
Regimen</strong></td>
<td colspan="2"><strong>Number of Human Subjects Entered</strong></td>
<td><strong>Healthy<br />
Subjects or<br />
Diagnosis of<br />
Patients</strong></td>
<td colspan="2"><strong>Planned Duration of<br />
Treatment</strong></td>
<td><strong>Study<br />
Status;<br />
Type of<br />
Report</strong></td>
</tr>
<tr class="even">
<td colspan="14"><strong>Reports of Human Pharmacokinetic Studies
(continued)</strong></td>
</tr>
<tr class="odd">
<td><p>Safety, Efficacy and PK</p>
<p>Phase II</p></td>
<td colspan="2"><blockquote>
<p>1182.1</p>
<p>U01-3010</p>
<p>U02-3090</p>
</blockquote></td>
<td><blockquote>
<p>United States</p>
</blockquote></td>
<td><p>- Determine the safety, tolerance, maximum tolerated dose, and PK
of TPV with two NRTIs in patients who have received the same two NRTIs
for a minimum of 2 months and who have not previously been treated with
PIs.</p>
<p>- Determine the efficacy of TPV when administered in combination with
two NRTIs to PI-naïve patients.</p></td>
<td colspan="2">Open label, non randomized</td>
<td><p>PI naive:</p>
<p>TPV 900 mg TID;</p>
<p>TPV 1200 mg TID;</p>
<p>TPV 1500 mg TID</p>
<p>PI experienced (Exp):</p>
<p>TPV 1500 mg TID</p>
<p>Hard filled capsules (HFC)</p>
<p>Optional Extension</p>
<p>TPV 1200 mg TID</p>
<p>TPV 1500 mg TID</p>
<p>(up to 184 weeks) HFC then SEDDS</p></td>
<td><p>n = 8</p>
<p>n = 8</p>
<p>n = 8</p>
<p>naïve = 24</p>
<p>Exp = 16</p>
<p>Trial total = 40</p>
<p>n = 1</p>
<p>n = 1</p>
<p>Total = 2</p></td>
<td colspan="3">HIV positive patients; PI‑naïve and PI‑ experienced</td>
<td>PI-naïve: 24 weeks with optional extension; PI- experienced: 4 weeks
with optional extension</td>
<td><p>Complete;</p>
<p>Final report</p></td>
</tr>
<tr class="even">
<td><p>PK (ADME mass balance)</p>
<p>Phase I</p></td>
<td><blockquote>
<p>1182.24</p>
<p>U03-3605-01</p>
</blockquote></td>
<td colspan="2">United States</td>
<td>- To characterize the excretion balance and metabolite profile of
14C‑radiolabelled TPV in healthy male subjects.</td>
<td>Open label, single dose 14C TPV 500 mg labelled with RTV 200 mg</td>
<td colspan="2">TPV 500 mg/RTV 200 mg BID for 7 days followed by a
single dose <sup>14</sup>C TPV 500 mg /RTV 200 mg , followed by TPV
500 mg/RTV 200 mg BID for 7-14 additional days as specified</td>
<td colspan="2">n = 12</td>
<td><p>Healthy</p>
<p>HIV negative male volunteers</p></td>
<td colspan="2"><blockquote>
<p>Up to 3 weeks</p>
</blockquote></td>
<td><p>Complete;</p>
<blockquote>
<p>Final report</p>
</blockquote></td>
</tr>
</tbody>
</table>

Table 2 (continued) Listing of Human Pharmacokinetic Studies (Page 3 of
8)

<table>
<colgroup>
<col style="width: 8%" />
<col style="width: 10%" />
<col style="width: 7%" />
<col style="width: 13%" />
<col style="width: 11%" />
<col style="width: 15%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>Type of<br />
Study</strong></td>
<td><strong>Study No. and BI Report No. (P&amp;U Protocol Number,<br />
if applicable)<br />
</strong></td>
<td><strong>Countries Study Conducted</strong></td>
<td><strong>Objective(s)<br />
of<br />
the Study</strong></td>
<td><strong>Study<br />
Design and<br />
Type of<br />
Control</strong></td>
<td><strong>Test<br />
Product(s) and<br />
Dosage<br />
Regimen</strong></td>
<td><strong>Number of Human Subjects Entered</strong></td>
<td><strong>Healthy<br />
Subjects or<br />
Diagnosis of<br />
Patients</strong></td>
<td><strong>Planned Duration of<br />
Treatment</strong></td>
<td><strong>Study<br />
Status;<br />
Type of<br />
Report</strong></td>
</tr>
<tr class="even">
<td colspan="10"><strong>Reports of Human Pharmacokinetic Studies
(continued)</strong></td>
</tr>
<tr class="odd">
<td><p>PK (hepatic insufficiency)</p>
<p>Phase I</p></td>
<td><blockquote>
<p>1182.32</p>
<p>U04-3373</p>
</blockquote></td>
<td><blockquote>
<p>Canada</p>
</blockquote></td>
<td><blockquote>
<p>- To provide dosage recommendations in patients with different
severities of hepatic impairment.</p>
</blockquote></td>
<td><blockquote>
<p>Open label</p>
</blockquote></td>
<td><blockquote>
<p>TPV 500 mg/RTV 200 mg</p>
<p>single dose</p>
<p>oral</p>
</blockquote></td>
<td><blockquote>
<p>n = 20 in SCS<br />
n = 24 in final report 9 mild/ 9 controls;<br />
3 moderate /3 controls</p>
</blockquote></td>
<td>Hepatic impaired, HIV negative patients with matching controls</td>
<td><blockquote>
<p>1 week for mild hepatic insufficiency; single-dose for moderate
hepatic insufficiency</p>
</blockquote></td>
<td><blockquote>
<p>Complete;</p>
<p>Final Report</p>
</blockquote></td>
</tr>
</tbody>
</table>

NOTE: Footnotes and translations of abbreviations for this table follow
below.

Table 2 (continued) Listing of Human Pharmacokinetic Studies (Page 4 of
8)

<table style="width:100%;">
<colgroup>
<col style="width: 7%" />
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 13%" />
<col style="width: 9%" />
<col style="width: 16%" />
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>Type of<br />
Study</strong></td>
<td><strong>Study No. and BI Report No. (P&amp;U Protocol Number,<br />
if applicable)<br />
</strong></td>
<td><strong>Countries Study Conducted</strong></td>
<td><strong>Objective(s)<br />
of<br />
the Study</strong></td>
<td><strong>Study<br />
Design and<br />
Type of<br />
Control</strong></td>
<td><strong>Test<br />
Product(s) and<br />
Dosage<br />
Regimen</strong></td>
<td><strong>Number of Human Subjects Entered</strong></td>
<td><strong>Healthy<br />
Subjects or<br />
Diagnosis of<br />
Patients</strong></td>
<td><strong>Planned Duration of<br />
Treatment</strong></td>
<td><strong>Study<br />
Status;<br />
Type of<br />
Report</strong></td>
</tr>
<tr class="even">
<td colspan="10"><strong>Reports of Human Pharmacokinetic Studies
(continued)</strong></td>
</tr>
<tr class="odd">
<td><blockquote>
<p>PK</p>
<p>Phase I‑IIa</p>
</blockquote></td>
<td><blockquote>
<p>1182.6</p>
<p>U03-3131-01</p>
</blockquote></td>
<td><blockquote>
<p>Belgium, Germany, Denmark, Spain, France, United States</p>
</blockquote></td>
<td><blockquote>
<p>- Determine the effects of three dose combinations of TPV/r on the
steady state of zidovudine, lamivudine, stavudine, abacavir, didanosine,
nevirapine and efavirenz.</p>
</blockquote></td>
<td><blockquote>
<p>Open label, sequential PK</p>
</blockquote></td>
<td><blockquote>
<p>TPV 250 mg/RTV 200 mg BID;</p>
<p>TPV 750 mg/RTV 100 mg BID;</p>
<p>TPV 1250 mg/RTV 100 mg BID</p>
<p>with zidovudine, lamivudine, stavudine, abacavir, didanosine,
nevirapine and efavirenz.</p>
</blockquote></td>
<td><blockquote>
<p>n = 87</p>
<p>n = 63</p>
<p>n = 58</p>
<p>Total = 208</p>
</blockquote></td>
<td><blockquote>
<p>HIV positive patients</p>
</blockquote></td>
<td><blockquote>
<p>PK exposure 22 days, with optional safety extension of 20 weeks</p>
</blockquote></td>
<td><blockquote>
<p>Complete;</p>
<p>Final report</p>
</blockquote></td>
</tr>
<tr class="even">
<td><blockquote>
<p>PK</p>
<p>Phase I</p>
</blockquote></td>
<td><blockquote>
<p>1182.37</p>
<p>U03-3120-01</p>
</blockquote></td>
<td><blockquote>
<p>United States</p>
</blockquote></td>
<td><blockquote>
<p>- Characterize the effects of two dose combinations of TPV/r
administered BID on the PK of zidovudine (ZDV) and ZDV‑glucuronide and
the effects of ZDV on the PK of TPV and RTV.</p>
</blockquote></td>
<td><blockquote>
<p>Randomized, open label, parallel group</p>
</blockquote></td>
<td><blockquote>
<p>TPV 500 mg/RTV 100 mg BID;</p>
<p>TPV 750 mg/RTV 200 mg BID and ZDV 300 mg on<br />
Days 1 and 13</p>
</blockquote></td>
<td><blockquote>
<p>n = 30</p>
<p>n = 30</p>
<p>Total = 60</p>
</blockquote></td>
<td><blockquote>
<p>Healthy</p>
<p>HIV negative volunteers</p>
</blockquote></td>
<td><blockquote>
<p>13 days</p>
<p>(12 days TPV/r)</p>
</blockquote></td>
<td><blockquote>
<p>Complete; Final report</p>
</blockquote></td>
</tr>
</tbody>
</table>

NOTE: Footnotes and translations of abbreviations for this table follow
below.

Table 2 (continued) Listing of Human Pharmacokinetic Studies (Page 5 of
8)

<table>
<colgroup>
<col style="width: 7%" />
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 13%" />
<col style="width: 9%" />
<col style="width: 15%" />
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 9%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>Type of<br />
Study</strong></td>
<td><strong>Study No. and BI Report No. (P&amp;U Protocol Number,<br />
if applicable)<br />
</strong></td>
<td><strong>Countries Study Conducted</strong></td>
<td><strong>Objective(s)<br />
of<br />
the Study</strong></td>
<td><strong>Study<br />
Design and<br />
Type of<br />
Control</strong></td>
<td><strong>Test<br />
Product(s) and<br />
Dosage<br />
Regimen</strong></td>
<td><strong>Number of Human Subjects Entered</strong></td>
<td><strong>Healthy<br />
Subjects or<br />
Diagnosis of<br />
Patients</strong></td>
<td><strong>Planned Duration of<br />
Treatment</strong></td>
<td><strong>Study<br />
Status;<br />
Type of<br />
Report</strong></td>
</tr>
<tr class="even">
<td colspan="10"><strong>Reports of Human Pharmacokinetic Studies
(continued)</strong></td>
</tr>
<tr class="odd">
<td><blockquote>
<p>PK</p>
<p>Phase I</p>
</blockquote></td>
<td><blockquote>
<p>1182.42</p>
<p>U03-1070</p>
</blockquote></td>
<td><blockquote>
<p>Germany</p>
</blockquote></td>
<td><blockquote>
<p>- Evaluate the PK interaction between two doses of TPV/r administered
BID at steady state with single-dose didanosine.</p>
</blockquote></td>
<td><blockquote>
<p>Randomized, open label, parallel group</p>
</blockquote></td>
<td><blockquote>
<p>TPV 500 mg/RTV 100 mg BID;</p>
<p>TPV 750 mg/RTV 200 mg BID</p>
<p>and</p>
<p>ddI 400 mg on Days 1 and 15.</p>
</blockquote></td>
<td><blockquote>
<p>n = 11</p>
<p>n = 12</p>
<p>Total = 23</p>
</blockquote></td>
<td><blockquote>
<p>Healthy</p>
<p>HIV negative volunteers</p>
</blockquote></td>
<td><blockquote>
<p>15 days</p>
<p>(14 days TPV/r)</p>
</blockquote></td>
<td><blockquote>
<p>Discontinued;</p>
<p>Final report</p>
</blockquote></td>
</tr>
<tr class="even">
<td><blockquote>
<p>PK</p>
<p>Phase I</p>
</blockquote></td>
<td><blockquote>
<p>1182.46</p>
<p>U04-1249-01</p>
</blockquote></td>
<td><blockquote>
<p>United Kingdom</p>
</blockquote></td>
<td><blockquote>
<p>- Evaluate the PK interaction between two doses of TPV/r administered
BID with single-dose tenofovir capsules</p>
</blockquote></td>
<td><blockquote>
<p>Randomized, open label, parallel group</p>
</blockquote></td>
<td><blockquote>
<p>TPV 500 mg/RTV 100 mg BID;</p>
<p>TPV 750 mg/RTV 200 mg BID</p>
<p>And tenofovir 300 mg on Days 1 and 13</p>
</blockquote></td>
<td><blockquote>
<p>n = 24</p>
<p>n = 25</p>
<p>Total = 49</p>
</blockquote></td>
<td><blockquote>
<p>Healthy</p>
<p>HIV negative volunteers</p>
</blockquote></td>
<td><blockquote>
<p>13 days</p>
<p>(12 days TPV/r)</p>
</blockquote></td>
<td><blockquote>
<p>Complete; Final report</p>
</blockquote></td>
</tr>
<tr class="odd">
<td><blockquote>
<p>PK</p>
<p>Phase I</p>
</blockquote></td>
<td><blockquote>
<p>1182.41</p>
<p>U03-3217-01</p>
</blockquote></td>
<td><blockquote>
<p>United States</p>
</blockquote></td>
<td><blockquote>
<p>- Characterize the PK interaction between two doses of TPV/r
administered BID with efavirenz2.</p>
</blockquote></td>
<td><blockquote>
<p>Randomized, open label, parallel group</p>
</blockquote></td>
<td><blockquote>
<p>TPV 500 mg/RTV 100 mg BID;</p>
<p>TPV 750 mg/RTV 200 mg BID</p>
<p>and</p>
<p>EFV 600 mg</p>
</blockquote></td>
<td><blockquote>
<p>n = 34</p>
<p>n = 34 (32 TPV treated)</p>
<p>Total = 68 (66 TPV treated)</p>
</blockquote></td>
<td><blockquote>
<p>Healthy</p>
<p>HIV negative volunteers</p>
</blockquote></td>
<td><blockquote>
<p>19 days</p>
<p>(10 days TPV/r)</p>
</blockquote></td>
<td><blockquote>
<p>Complete;</p>
<p>Final report</p>
</blockquote></td>
</tr>
</tbody>
</table>

NOTE: Footnotes and translations of abbreviations for this table follow
below.

Table 2 (continued) Listing of Human Pharmacokinetic Studies (Page 6 of
8)

<table>
<colgroup>
<col style="width: 7%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 13%" />
<col style="width: 11%" />
<col style="width: 12%" />
<col style="width: 12%" />
<col style="width: 8%" />
<col style="width: 7%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>Type of<br />
Study</strong></td>
<td><strong>Study No. and BI Report No. (P&amp;U Protocol Number,<br />
if applicable)<br />
</strong></td>
<td><strong>Countries Study Conducted</strong></td>
<td><strong>Objective(s)<br />
of<br />
the Study</strong></td>
<td><strong>Study<br />
Design and<br />
Type of<br />
Control</strong></td>
<td><strong>Test<br />
Product(s) and<br />
Dosage<br />
Regimen</strong></td>
<td><strong>Number of Human Subjects Entered</strong></td>
<td><strong>Healthy<br />
Subjects or<br />
Diagnosis of<br />
Patients</strong></td>
<td><strong>Planned Duration of<br />
Treatment</strong></td>
<td><strong>Study<br />
Status;<br />
Type of<br />
Report</strong></td>
</tr>
<tr class="even">
<td colspan="10"><strong>Reports of Human Pharmacokinetic Studies
(continued)</strong></td>
</tr>
<tr class="odd">
<td><p>PK</p>
<p>Phase IIb</p></td>
<td><p>1182.51</p>
<p>U04-1726</p></td>
<td>Australia, Belgium, Canada, Germany, Denmark, France, Greece, Italy,
Netherlands, Switzerland, United Kingdom, United States</td>
<td>- To evaluate the PK of TPV/r alone or with SQV, APV or LPV plus an
OBR</td>
<td><blockquote>
<p>Randomized, open label, parallel group</p>
</blockquote></td>
<td>TPV 500 mg/RTV 200 mg BID alone or with SQV, APV or LPV plus an
OBR</td>
<td><p>Total = 315</p>
<p>TPV treated = 308</p>
<p>CPI only = 7</p></td>
<td><blockquote>
<p>HIV positive patients</p>
</blockquote></td>
<td>24 weeks</td>
<td><p>Complete;</p>
<p>Final report</p></td>
</tr>
<tr class="even">
<td><p>PK</p>
<p>Phase I</p></td>
<td><p>1182.10</p>
<p>U04-3100</p></td>
<td>Canada</td>
<td>- Drug interaction potential of fluconazole and TPV/r</td>
<td><blockquote>
<p>Open label,</p>
<p>(A) fluconazole;</p>
<p>(B) TPV/r A + B</p>
</blockquote></td>
<td><p>Fluconazole 200 mg</p>
<p>TPV 500 mg/RTV 200 mg</p>
<p>single oral doses</p></td>
<td>n = 20</td>
<td><blockquote>
<p>Healthy</p>
<p>HIV negative volunteers</p>
</blockquote></td>
<td><p>13 days</p>
<p>(7 days TPV/r)</p></td>
<td><p>Complete;</p>
<p>Final report</p></td>
</tr>
<tr class="odd">
<td><p>PK</p>
<p>Phase I</p></td>
<td><p>1182.44</p>
<p>U04-3198</p></td>
<td>Canada</td>
<td>- To characterize the drug interaction potential of rifabutin and
TPV/r (including metabolites)</td>
<td><blockquote>
<p>Open label</p>
<p>(A) rifabutin;</p>
<p>(B) TPV/r</p>
<p>A + B</p>
</blockquote></td>
<td><p>TPV 500 mg/RTV 200 mg</p>
<p>Rifabutin 300 mg on Days 1 and 15</p></td>
<td>n = 24</td>
<td><blockquote>
<p>Healthy</p>
<p>HIV negative volunteers</p>
</blockquote></td>
<td>14 days (13 days TPV/r)</td>
<td><p>Complete;</p>
<p>Final report</p></td>
</tr>
</tbody>
</table>

NOTE: Footnotes and translations of abbreviations for this table follow
below.

Table 2 (continued) Listing of Human Pharmacokinetic Studies (Page 7 of
8)

<table>
<colgroup>
<col style="width: 7%" />
<col style="width: 11%" />
<col style="width: 8%" />
<col style="width: 13%" />
<col style="width: 10%" />
<col style="width: 15%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 7%" />
<col style="width: 9%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>Type of<br />
Study</strong></td>
<td><strong>Study No. and BI Report No. (P&amp;U Protocol Number,<br />
if applicable)<br />
</strong></td>
<td><strong>Countries Study Conducted</strong></td>
<td><strong>Objective(s)<br />
of<br />
the Study</strong></td>
<td><strong>Study<br />
Design and<br />
Type of<br />
Control</strong></td>
<td><strong>Test<br />
Product(s) and<br />
Dosage<br />
Regimen</strong></td>
<td><strong>Number of Human Subjects Entered</strong></td>
<td><strong>Healthy<br />
Subjects or<br />
Diagnosis of<br />
Patients</strong></td>
<td><strong>Planned Duration of<br />
Treatment</strong></td>
<td><strong>Study<br />
Status;<br />
Type of<br />
Report</strong></td>
</tr>
<tr class="even">
<td colspan="10"><strong>Reports of Human Pharmacokinetic Studies
(continued)</strong></td>
</tr>
<tr class="odd">
<td><p>PK</p>
<p>Phase I</p></td>
<td><p>1182.11</p>
<p>U04-1257</p></td>
<td>Canada</td>
<td>- To characterize the drug interaction potential of clarithromycin
and TPV/r (including metabolites)</td>
<td><blockquote>
<p>Open label</p>
<p>(A) clarithromycin;</p>
<p>(B) TPV/r A + B</p>
</blockquote></td>
<td><p>Clarithromycin 500 mg</p>
<p>TPV 500 mg/RTV 200 mg single oral doses</p></td>
<td><blockquote>
<p>n = 24</p>
</blockquote></td>
<td><p>Healthy</p>
<p>HIV negative volunteers</p></td>
<td>13 days (8 days TPV/r)</td>
<td>Complete; Final report</td>
</tr>
<tr class="even">
<td><p>PK</p>
<p>Phase I</p></td>
<td><p>1182.21</p>
<p>U04-3216</p></td>
<td>Canada</td>
<td>- To characterize the drug interaction potential of atorvastatin and
TPV/r (including metabolites)</td>
<td><blockquote>
<p>Open label,</p>
<p>(A) atorvastatin;</p>
<p>(B) TPV/r A + B</p>
</blockquote></td>
<td><p>Atorvastatin 20 mg</p>
<p>TPV 500 mg/RTV 200 mg single oral doses</p></td>
<td><blockquote>
<p>n = 23</p>
</blockquote></td>
<td><p>Healthy</p>
<p>HIV negative volunteers</p></td>
<td><p>11 days</p>
<p>(10 days TPV/r)</p></td>
<td>Complete; Final report</td>
</tr>
<tr class="odd">
<td><p>PK</p>
<p>Phase I</p></td>
<td><p>1182.22</p>
<p>U03-3408</p></td>
<td>Canada</td>
<td>- Characterize the PK interaction between two doses of TPV/r
administered BID on the PK characteristics of norethindrone-ethinyl
estradiol (NET/EE Ortho® 1/35).</td>
<td><blockquote>
<p>Open label, Randomized, parallel group</p>
</blockquote></td>
<td><p>TPV 500 mg/RTV 100 mg BID;</p>
<p>TPV 750mg/RTV 200 mg BID</p>
<p>TPV/r on Days</p>
<p>4–16 and NET/EE Ortho® 1/35 on Days 1 and 15</p></td>
<td><blockquote>
<p>n = 26</p>
<p>n = 26</p>
<p>Total = 52</p>
</blockquote></td>
<td><p>Healthy</p>
<p>HIV negative, female volunteers</p></td>
<td><p>16 days</p>
<p>(13 days TPV/r)</p></td>
<td>Discontinued; Final report</td>
</tr>
</tbody>
</table>

NOTE: Footnotes and translations of abbreviations for this table follow
below.

Table 2 (continued) Listing of Human Pharmacokinetic Studies (Page 8 of
8)

<table>
<colgroup>
<col style="width: 7%" />
<col style="width: 10%" />
<col style="width: 8%" />
<col style="width: 12%" />
<col style="width: 9%" />
<col style="width: 15%" />
<col style="width: 7%" />
<col style="width: 8%" />
<col style="width: 11%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>Type of<br />
Study</strong></td>
<td><strong>Study No. and BI Report No. (P&amp;U Protocol Number,<br />
if applicable)<br />
</strong></td>
<td><strong>Countries Study Conducted</strong></td>
<td><strong>Objective(s)<br />
of<br />
the Study</strong></td>
<td><strong>Study<br />
Design and<br />
Type of<br />
Control</strong></td>
<td><strong>Test<br />
Product(s) and<br />
Dosage<br />
Regimen</strong></td>
<td><strong>Number of Human Subjects Entered</strong></td>
<td><strong>Healthy<br />
Subjects or<br />
Diagnosis of<br />
Patients</strong></td>
<td><strong>Planned Duration of<br />
Treatment</strong></td>
<td><strong>Study<br />
Status;<br />
Type of<br />
Report</strong></td>
</tr>
<tr class="even">
<td colspan="10"><strong>Reports of Human Pharmacokinetic Studies
(continued)</strong></td>
</tr>
<tr class="odd">
<td><p>PK/PD drug interaction</p>
<p>Phase I</p></td>
<td><p>1182.55</p>
<p>U04-3125</p></td>
<td>United States</td>
<td><blockquote>
<p>-To determine if the co-administration of loperamide with TPV or RTV
or with the combination of TPV/r causes a clinically significant change
in respiratory response to carbon dioxide.</p>
</blockquote></td>
<td>Open label, randomized, parallel group</td>
<td><p>TPV 750 mg/RTV 200 mg BID</p>
<p>TPV 500 mg/RTV 200 mg BID</p>
<p>and loperamide 16 mg on Days 1, 9 and 22</p>
<p>TPV 750 mg or RTV 200 mg and loperamide 16 mg on specified study
days, then TPV 750 mg/RTV 200 mg BID</p>
<p>and loperamide 16 mg daily on specified study days3</p></td>
<td><p>n = 12</p>
<p>n = 12</p>
<p>n = 24</p>
<p>Total = 24</p></td>
<td>Healthy<br />
HIV negative volunteers</td>
<td>TPV or RTV for 5.5 consecutive days. Subsequent to this, all
subjects received TPV/ r for 10.5 consecutive days. All subjects
received loperamide on Days 1, 9, and 22.</td>
<td><blockquote>
<p>Complete; Final report</p>
</blockquote></td>
</tr>
</tbody>
</table>

NOTE: Footnotes and translations of abbreviations for this table follow
below.

[]{#__RefHeading___Toc101398996 .anchor}Appendix 2.3 Human
Pharmacodynamic Studies

Table 3 Listing of Human Pharmacodynamic Studies

<table>
<colgroup>
<col style="width: 6%" />
<col style="width: 12%" />
<col style="width: 8%" />
<col style="width: 11%" />
<col style="width: 9%" />
<col style="width: 15%" />
<col style="width: 7%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 10%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>Type of<br />
Study</strong></td>
<td><strong>Study No. and BI Report No. (P&amp;U Protocol Number,<br />
if applicable)<br />
</strong></td>
<td><strong>Countries Study Conducted</strong></td>
<td><strong>Objective(s)<br />
of<br />
the Study</strong></td>
<td><strong>Study<br />
Design and<br />
Type of<br />
Control</strong></td>
<td><strong>Test<br />
Product(s) and<br />
Dosage<br />
Regimen</strong></td>
<td><strong>Number of<br />
Human Subjects<br />
Entered</strong></td>
<td><strong>Healthy<br />
Subjects or<br />
Diagnosis of<br />
Patients</strong></td>
<td><strong>Planned Duration of<br />
Treatment</strong></td>
<td><strong>Study<br />
Status;<br />
Type of<br />
Report</strong></td>
</tr>
<tr class="even">
<td colspan="10"><strong>Reports of Human Pharmacodynamic Studies
(continued)</strong></td>
</tr>
<tr class="odd">
<td><p>Safety, Efficacy and PK</p>
<p>Phase II</p></td>
<td><p>1182.3</p>
<p>U01-3009<br />
U01‑3352</p></td>
<td>Puerto Rico, United States, South Africa</td>
<td>- To evaluate the effectiveness and the safety and tolerability of
TPV alone and two TPV/r dose combinations.</td>
<td>Open label, Randomized, parallel group</td>
<td><p>TPV 1200 mg BID;</p>
<p>TPV 300 mg/RTV 200 mg BID;</p>
<p>TPV 1200 mg/RTV 200 mg BID</p>
<p>(all SEDDS)</p></td>
<td><p>n = 10</p>
<p>n = 10</p>
<p>n = 11</p>
<p>Total = 31</p></td>
<td><p>HIV positive patients;</p>
<p>ARV naïve</p></td>
<td>14 days with TPV alone or in combination with RTV; Optional
extension with DLV, ZDV, and 3TC for additional 46 weeks with no
TPV</td>
<td><p>Complete;</p>
<p>Final report on 14-day portion; Safety Summary of 18 patients on 46
week optional extension (no TPV).</p></td>
</tr>
</tbody>
</table>

NOTE: Footnotes and translations of abbreviations for this table follow
below.

Table 3 (continued) Listing of Human Pharmacodynamic Studies (Page 2 of
2)

<table>
<colgroup>
<col style="width: 7%" />
<col style="width: 11%" />
<col style="width: 8%" />
<col style="width: 10%" />
<col style="width: 9%" />
<col style="width: 15%" />
<col style="width: 8%" />
<col style="width: 10%" />
<col style="width: 10%" />
<col style="width: 8%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>Type of<br />
Study</strong></td>
<td><strong>Study No. and BI Report No. (P&amp;U Protocol Number,<br />
if applicable)<br />
</strong></td>
<td><strong>Countries Study Conducted</strong></td>
<td><strong>Objective(s)<br />
of<br />
the Study</strong></td>
<td><strong>Study<br />
Design and<br />
Type of<br />
Control</strong></td>
<td><strong>Test<br />
Product(s) and<br />
Dosage<br />
Regimen</strong></td>
<td><strong>Number of<br />
Human Subjects<br />
Entered</strong></td>
<td><strong>Healthy<br />
Subjects or<br />
Diagnosis of<br />
Patients</strong></td>
<td><strong>Planned Duration of<br />
Treatment</strong></td>
<td><strong>Study<br />
Status;<br />
Type of<br />
Report</strong></td>
</tr>
<tr class="even">
<td colspan="10"><strong>Reports of Human Pharmacodynamic Studies
(continued)</strong></td>
</tr>
<tr class="odd">
<td><p>PK and Safety Pediatrics</p>
<p>Phase</p>
<p>I/IIA</p></td>
<td><p>1182.14</p>
<p>U04-3384</p>
<p><mark></mark></p></td>
<td>Argentina, Brazil, Canada, France, Germany, Italy, Spain, Mexico,
United States</td>
<td>- To obtain information concerning the safety, tolerability, and PK
of TPV together with low-dose RTV in subjects 2‑18 years old that will
provide a systemic exposure similar to adults.</td>
<td>Open label, randomized, dose finding</td>
<td><p>TPV 290 mg/m2 BID /RTV 115 mg/m2 BID + OBR or</p>
<p>TPV 375 mg/m2 BID /RTV 150 mg/m2 BID + OBR</p>
<p>Liquid TPV formulation = 100 mg per mL</p>
<p>Liquid RTV formulation = 80 mg per mL</p>
<p>All subjects take TPV liquid formulation for the initial 4 weeks.
After that adolescents will be offered the option to cross over to an
equivalent TPV dose using the SEDDS 500 mg BID</p></td>
<td>57 randomized and treated with at least one dose of study drug;
however, only 37 patients had CRFs entered in the database at the time
of data cut-off.</td>
<td>HIV positive patients: PI experienced and naïve children between
2‑18 years of age</td>
<td>48 weeks with optimal safety extension</td>
<td>Ongoing; Summary Report , up to 4-week data</td>
</tr>
</tbody>
</table>

NOTE: Footnotes and translations of abbreviations for this table follow
below.

[]{#__RefHeading___Toc101398997 .anchor}Appendix 2.4 Clinical Efficacy
and Safety Studies

Table 4 Listing of Phase II and III Efficacy and Safety Studies (Page 1
of 8)

<table>
<colgroup>
<col style="width: 6%" />
<col style="width: 11%" />
<col style="width: 8%" />
<col style="width: 11%" />
<col style="width: 9%" />
<col style="width: 16%" />
<col style="width: 8%" />
<col style="width: 11%" />
<col style="width: 8%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>Type of<br />
Study</strong></td>
<td><strong>Study No. and BI Report No. (P&amp;U Protocol Number,<br />
if applicable)<br />
</strong></td>
<td><strong>Countries Study Conducted</strong></td>
<td><strong>Objective(s)<br />
of<br />
the Study</strong></td>
<td><strong>Study<br />
Design and<br />
Type of<br />
Control</strong></td>
<td><strong>Test<br />
Product(s) and<br />
Dosage<br />
Regimen</strong></td>
<td><strong>Number of<br />
Human Subjects<br />
Entered</strong></td>
<td><strong>Healthy<br />
Subjects or<br />
Diagnosis of<br />
Patients</strong></td>
<td><strong>Planned Duration of<br />
Treatment</strong></td>
<td><strong>Study<br />
Status;<br />
Type of<br />
Report</strong></td>
</tr>
<tr class="even">
<td colspan="10"><strong>Reports of Efficacy and Safety
Studies</strong></td>
</tr>
<tr class="odd">
<td><p>Safety and Efficacy</p>
<p>Phase II</p></td>
<td><p>1182.2</p>
<p>U03-3006</p></td>
<td>United States</td>
<td>- To evaluate the antiviral activity and safety of two regimens of
TPV/r given with one new NRTI + one new NNRTI (efavirenz) in multiple
PI-experienced HIV positive patients.</td>
<td>Open label, randomized, parallel group</td>
<td><p>TPV 1200 mg HFC (hard filled capsules)/ RTV 100 mg BID,
subsequently:</p>
<p>TPV 500 mg (SEDDS)/RTV 100 mg BID</p>
<p>TPV 2400 mg HFC/RTV 200 mg BID, subsequently: TPV 1000 mg (SEDDS)/RTV
100 mg BID EFV 600 mg QD</p></td>
<td><p>n = 19</p>
<p>n = 22</p>
<p>Total = 41</p></td>
<td>HIV positive patients: multiple PI‑experienced with clinical
virological failure; NNRTI naïve</td>
<td><p>24 weeks with an optional extension period</p>
<p>up to 112 weeks</p></td>
<td><p>Complete;</p>
<p>Final report</p></td>
</tr>
</tbody>
</table>

NOTE: Footnotes and translations of abbreviations for this table follow
below.

Table 4 (continued) Listing of Phase II and III Efficacy and Safety
Studies (Page 2 of 8)

<table>
<colgroup>
<col style="width: 6%" />
<col style="width: 0%" />
<col style="width: 11%" />
<col style="width: 8%" />
<col style="width: 11%" />
<col style="width: 9%" />
<col style="width: 16%" />
<col style="width: 7%" />
<col style="width: 0%" />
<col style="width: 8%" />
<col style="width: 2%" />
<col style="width: 7%" />
<col style="width: 0%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="2"><strong>Type of<br />
Study</strong></td>
<td><strong>Study No. and BI Report No. (P&amp;U Protocol Number,<br />
if applicable)<br />
</strong></td>
<td><strong>Countries Study Conducted</strong></td>
<td><strong>Objective(s)<br />
of<br />
the Study</strong></td>
<td><strong>Study<br />
Design and<br />
Type of<br />
Control</strong></td>
<td><strong>Test<br />
Product(s) and<br />
Dosage<br />
Regimen</strong></td>
<td><strong>Number of<br />
Human Subjects<br />
Entered</strong></td>
<td colspan="2"><strong>Healthy<br />
Subjects or<br />
Diagnosis of<br />
Patients</strong></td>
<td colspan="2"><strong>Planned Duration of<br />
Treatment</strong></td>
<td colspan="2"><strong>Study<br />
Status;<br />
Type of<br />
Report</strong></td>
</tr>
<tr class="even">
<td colspan="14"><strong>Reports of Efficacy and Safety
Studies</strong></td>
</tr>
<tr class="odd">
<td><p>Safety and Efficacy</p>
<p>Phase II</p></td>
<td colspan="2"><p>1182.4</p>
<p>U03-3207-01</p></td>
<td><p>France, Italy,</p>
<p>United States</p></td>
<td>- To evaluate the safety and efficacy of two TPV/r doses compared
with that of a standard dual PI combination and to evaluate the dose
response of the two TPV/r doses.</td>
<td>Open label, randomized, active control</td>
<td><p>TPV 500 mg /RTV100 mg BID;</p>
<p>TPV 1250 mg /RTV 100 mg BID;</p>
<p>Saquinavir 400 mg / RTV 400 mg BID</p></td>
<td colspan="2"><p>n = 25</p>
<p>n =25</p>
<p>n = 29</p>
<p>Total = 79</p>
<p>2 additional patients entered but were not treated.</p></td>
<td colspan="2">HIV positive patients: single PI-experienced with
clinical virological failure; NNRTI experienced</td>
<td colspan="2">24 weeks with an optional extension period up to 96
weeks</td>
<td><p>Complete;</p>
<p>Final report</p></td>
</tr>
<tr class="even">
<td colspan="2"><p>Safety, Efficacy and PK</p>
<p>Phase IIb</p></td>
<td><blockquote>
<p>1182.52</p>
<p>U03-3236-03</p>
</blockquote></td>
<td>Australia, Canada, Germany, Spain, France, Italy, Netherlands,
United Kingdom, United States</td>
<td>- To demonstrate the most tolerable and effective dose of TPV/r for
use in Phase III studies.</td>
<td>Randomized, double-blind, dose optimization</td>
<td><p>TPV 500 mg/RTV 100 mg BID;</p>
<p>TPV 500 mg/RTV 200 mg BID;</p>
<p>TPV 750 mg/RTV 200 mg BID</p></td>
<td><p>n = 73</p>
<p>n = 72</p>
<p>n = 71</p>
<p>Total = 216</p></td>
<td colspan="2">HIV positive patients; multiple PI-experienced with
primary PI resistance mutations on TRUGENE testing; NNRTI
experienced.</td>
<td colspan="2">2 weeks functional monotherapy (TPV/r + current ARV
therapy); then 10-30 weeks TPV/r + optimized ARV; up to 32 weeks
total</td>
<td colspan="2">Complete; Final report</td>
</tr>
</tbody>
</table>

NOTE: Footnotes and translations of abbreviations for this table follow
below.

Table 4 (continued) Listing of Phase II and III Efficacy and Safety
Studies (Page 3 of 8)

<table>
<colgroup>
<col style="width: 6%" />
<col style="width: 0%" />
<col style="width: 10%" />
<col style="width: 0%" />
<col style="width: 8%" />
<col style="width: 11%" />
<col style="width: 9%" />
<col style="width: 16%" />
<col style="width: 7%" />
<col style="width: 0%" />
<col style="width: 8%" />
<col style="width: 1%" />
<col style="width: 8%" />
<col style="width: 8%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>Type of<br />
Study</strong></td>
<td colspan="2"><strong>Study No. and BI Report No. (P&amp;U Protocol
Number,<br />
if applicable)<br />
</strong></td>
<td colspan="2"><strong>Countries Study Conducted</strong></td>
<td><strong>Objective(s)<br />
of<br />
the Study</strong></td>
<td><strong>Study<br />
Design and<br />
Type of<br />
Control</strong></td>
<td><strong>Test<br />
Product(s) and<br />
Dosage<br />
Regimen</strong></td>
<td colspan="2"><strong>Number of<br />
Human Subjects<br />
Entered</strong></td>
<td colspan="2"><strong>Healthy<br />
Subjects or<br />
Diagnosis of<br />
Patients</strong></td>
<td><strong>Planned Duration of<br />
Treatment</strong></td>
<td><strong>Study<br />
Status;<br />
Type of<br />
Report</strong></td>
</tr>
<tr class="even">
<td colspan="14"><strong>Reports of Efficacy and Safety Studies
(continued)</strong></td>
</tr>
<tr class="odd">
<td colspan="2"><p>Safety, Efficacy and PK</p>
<p>Phase III</p></td>
<td colspan="2"><blockquote>
<p>1182.12</p>
<p>U04-3339</p>
</blockquote></td>
<td>Australia, Canada, United States</td>
<td>- Determine the safety and efficacy of TPV/r versus an active
control arm in highly treatment experienced HIV positive patients.</td>
<td>Open label, randomized, active control</td>
<td><p>TPV 500 mg/RTV 200 mg BID</p>
<p>or</p>
<p>CPI/RTV, stratified according to pre‑selected PI.</p></td>
<td><p>n = 313 entered, 311 treated</p>
<p>n = 317</p>
<p>entered, 309 treated</p>
<p>Total = 630 entered, 620 treated</p></td>
<td colspan="2">HIV positive patients</td>
<td colspan="2">96 weeks</td>
<td>Ongoing; Interim report, up to 24‑week data</td>
</tr>
</tbody>
</table>

NOTE: Footnotes and translations of abbreviations for this table follow
below.

Table 4 (continued) Listing of Phase II and III Efficacy and Safety
Studies (Page 4 of 8)

<table>
<colgroup>
<col style="width: 6%" />
<col style="width: 10%" />
<col style="width: 9%" />
<col style="width: 11%" />
<col style="width: 9%" />
<col style="width: 13%" />
<col style="width: 3%" />
<col style="width: 8%" />
<col style="width: 10%" />
<col style="width: 8%" />
<col style="width: 0%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>Type of<br />
Study</strong></td>
<td><strong>Study No. and BI Report No. (P&amp;U Protocol Number,<br />
if applicable)<br />
</strong></td>
<td><strong>Countries Study Conducted</strong></td>
<td><strong>Objective(s)<br />
of<br />
the Study</strong></td>
<td><strong>Study<br />
Design and<br />
Type of<br />
Control</strong></td>
<td><strong>Test<br />
Product(s) and<br />
Dosage<br />
Regimen</strong></td>
<td colspan="2"><strong>Number of<br />
Human Subjects<br />
Entered</strong></td>
<td><strong>Healthy<br />
Subjects or<br />
Diagnosis of<br />
Patients</strong></td>
<td colspan="2"><strong>Planned Duration of<br />
Treatment</strong></td>
<td><strong>Study<br />
Status;<br />
Type of<br />
Report</strong></td>
</tr>
<tr class="even">
<td colspan="12"><strong>Reports of Efficacy and Safety Studies
(continued)</strong></td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Safety, Efficacy and PK</p>
<p>Phase III</p>
</blockquote></td>
<td><blockquote>
<p>1182.48</p>
<p>U04-1526</p>
</blockquote></td>
<td>Argentina, Austria, Belgium, Brazil, Germany, Denmark, Spain,
France, Greece, Ireland, Italy, Luxembourg, Mexico, Netherlands,
Portugal, Sweden, Switzerland, United Kingdom</td>
<td>- Determine the safety and efficacy of TPV/r versus an active
control group in highly treatment‑ experienced HIV positive
patients.</td>
<td>Open label, randomized, active control</td>
<td colspan="2"><p>TPV 500 mg/RTV 200 mg BID</p>
<p>or</p>
<p>CPI/RTV, stratified according to pre‑selected PI.</p></td>
<td><p>n = 442 entered, 435 treated</p>
<p>n = 437 entered, 428 treated</p>
<p>Total = 879 entered, 863 treated</p></td>
<td>HIV positive patients</td>
<td>96 weeks</td>
<td colspan="2">Ongoing; Interim report, up to 24‑week data</td>
</tr>
</tbody>
</table>

NOTE: Footnotes and translations of abbreviations for this table follow
below.

Table 4 (continued) Listing of Phase II and III Efficacy and Safety
Studies (Page 5 of 8)

<table>
<colgroup>
<col style="width: 6%" />
<col style="width: 10%" />
<col style="width: 9%" />
<col style="width: 11%" />
<col style="width: 9%" />
<col style="width: 13%" />
<col style="width: 11%" />
<col style="width: 10%" />
<col style="width: 9%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>Type of<br />
Study</strong></td>
<td><strong>Study No. and BI Report No. (P&amp;U Protocol Number,<br />
if applicable)<br />
</strong></td>
<td><strong>Countries Study Conducted</strong></td>
<td><strong>Objective(s)<br />
of<br />
the Study</strong></td>
<td><strong>Study<br />
Design and<br />
Type of<br />
Control</strong></td>
<td><strong>Test<br />
Product(s) and<br />
Dosage<br />
Regimen</strong></td>
<td><strong>Number of<br />
Human Subjects<br />
Entered</strong></td>
<td><strong>Healthy<br />
Subjects or<br />
Diagnosis of<br />
Patients</strong></td>
<td><strong>Planned Duration of<br />
Treatment</strong></td>
<td><strong>Study<br />
Status;<br />
Type of<br />
Report</strong></td>
</tr>
<tr class="even">
<td colspan="10"><strong>Reports of Efficacy and Safety Studies
(continued)</strong></td>
</tr>
<tr class="odd">
<td><p>Safety</p>
<p>Phase IV</p></td>
<td><p>1182.58</p>
<p>U04-0094</p></td>
<td>Australia, Austria, Belgium, Canada, Denmark, France, Germany,
Greece, Italy, Netherlands, Portugal, Spain, Sweden, Switzerland, United
Kingdom, United States</td>
<td>- To evaluate the safety of TPV/r when used in combination with
other agents for the treatment of HIV positive patients.</td>
<td>Open-label</td>
<td>TPV 500 mg/RTV 200 mg BID</td>
<td>n = 451 (as per report cut-off date); 450 of the 451 were treated;
448 of the 450 are newly exposed patients to TPV</td>
<td>HIV positive patients</td>
<td>24 months</td>
<td><p>Ongoing;</p>
<p>Summary Report</p></td>
</tr>
</tbody>
</table>

NOTE: Footnotes and translations of abbreviations for this table follow
below.

Table 4 (continued) Listing of Phase II and III Efficacy and Safety
Studies (Page 6 of 8)

<table style="width:100%;">
<colgroup>
<col style="width: 6%" />
<col style="width: 10%" />
<col style="width: 9%" />
<col style="width: 11%" />
<col style="width: 9%" />
<col style="width: 13%" />
<col style="width: 10%" />
<col style="width: 10%" />
<col style="width: 0%" />
<col style="width: 8%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>Type of<br />
Study</strong></td>
<td><strong>Study No. and BI Report No. (P&amp;U Protocol Number,<br />
if applicable)<br />
</strong></td>
<td><strong>Countries Study Conducted</strong></td>
<td><strong>Objective(s)<br />
of<br />
the Study</strong></td>
<td><strong>Study<br />
Design and<br />
Type of<br />
Control</strong></td>
<td><strong>Test<br />
Product(s) and<br />
Dosage<br />
Regimen</strong></td>
<td><strong>Number of<br />
Human Subjects<br />
Entered</strong></td>
<td colspan="2"><strong>Healthy<br />
Subjects or<br />
Diagnosis of<br />
Patients</strong></td>
<td><strong>Planned Duration of<br />
Treatment</strong></td>
<td><strong>Study<br />
Status;<br />
Type of<br />
Report</strong></td>
</tr>
<tr class="even">
<td><p>Safety</p>
<p>Phase II</p></td>
<td><p>1182.17</p>
<p>U04-3360</p></td>
<td>All countries of RESIST-1 and 2</td>
<td>- To determine the long term safety and tolerance of multiple oral
doses of TPV and RTV alone or in combination with one or more marketed
anti-retroviral therapies.4</td>
<td>Open-label long‑term, rollover trial-subjects from trials:
M3342/0004 (1182.1), 1182.2, 1182.4, 1182.6, 1182.12, 1182.48, 1182.51,
1182.52</td>
<td>Early patients were on various TPV or TPV/r doses; as of March 2003,
nearly all patients have been switched to the TPV/r 500 mg/ 200 mg BID
dose</td>
<td>n = 748 (as per report cut-off); with 286 CPI/r virologic failures
from 1182.12 or 1182.48 included in the report</td>
<td>HIV positive patients who have successfully completed participation
in combination TPV/r studies or failed the comparator PI in Trials
1182.12 or 1182.48.</td>
<td colspan="2"><blockquote>
<p>Until TPV is licensed</p>
</blockquote></td>
<td><blockquote>
<p>Ongoing; Interim report</p>
</blockquote></td>
</tr>
</tbody>
</table>

Table 4 (continued) Listing of Phase II and III Efficacy and Safety
Studies (Page 7 of 8)

<table style="width:100%;">
<colgroup>
<col style="width: 6%" />
<col style="width: 10%" />
<col style="width: 9%" />
<col style="width: 11%" />
<col style="width: 9%" />
<col style="width: 13%" />
<col style="width: 10%" />
<col style="width: 10%" />
<col style="width: 8%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>Type of<br />
Study</strong></td>
<td><strong>Study No. and BI Report No. (P&amp;U Protocol Number,<br />
if applicable)<br />
</strong></td>
<td><strong>Countries Study Conducted</strong></td>
<td><strong>Objective(s)<br />
of<br />
the Study</strong></td>
<td><strong>Study<br />
Design and<br />
Type of<br />
Control</strong></td>
<td><strong>Test<br />
Product(s) and<br />
Dosage<br />
Regimen</strong></td>
<td><strong>Number of<br />
Human Subjects<br />
Entered</strong></td>
<td><strong>Healthy<br />
Subjects or<br />
Diagnosis of<br />
Patients</strong></td>
<td><strong>Planned Duration of<br />
Treatment</strong></td>
<td><strong>Study<br />
Status;<br />
Type of<br />
Report</strong></td>
</tr>
<tr class="even">
<td><p>Safety and Efficacy</p>
<p>Phase IIb</p></td>
<td><p>1182.33</p>
<p>U04-1642</p></td>
<td>Argentina, Australia, Brazil, Caribbean Canada, Columbia, France,
Germany, Mexico, Poland, Romania, Russia, Spain, UK, Thailand,
Uganda</td>
<td>- Determine the safety and efficacy of TPV/RTV in naïve HIV positive
patients</td>
<td>Open label (Data are currently blinded to the sponsor)</td>
<td>TPV 500 mg plus 100 mg or 200 mg RTV in combination with TDF + 3TC
versus Kaletra in combination with TDF + 3 TC</td>
<td>n = 16 ( as per report cut-off date); 15 treated with either TPV/r
or LPV/r</td>
<td>Naïve HIV positive patients</td>
<td><blockquote>
<p>48 weeks (with extension up to 156 weeks)</p>
</blockquote></td>
<td><blockquote>
<p>Ongoing; Summary report</p>
</blockquote></td>
</tr>
</tbody>
</table>

NOTE: Footnotes and translations of abbreviations for this table follow
below.

Table 4 (continued) Listing of Phase II and III Efficacy and Safety
Studies (Page 8 of 8)

Footnotes to Table 2.4: 1:

1 All doses were administered orally. All doses were administered BID,
with the exception of Trial 1182.1, a Phase I trial in 24 HIV-positive
patients, in which TPV monotherapy was administered by using the Hard
Filled Capsule (HFC) formulation of tipranavir at doses of 900 mg, 1200
mg and 1500 mg, all TID.

> Prior to acquisition of TPV by BI in 2000, P&U conducted 14 trials
> with several different formulations. For the BI trials, all
> subjects/patients received the Self-Emulsifying Drug Delivery System
> (SEDDS) formulation of tipranavir with the exception of those in the
> 1182.1 trial and patients in the 1182.2 trial, who received the HFC
> formulation initially and then were switched to the SEDDS formulation.
> Pediatric patients in Trial 1182.14 received a liquid formulation of
> tipranavir. Bioequivalence/bioavailability Trial 1182.45 used both the
> SEDDS and liquid formulations.
>
> 147 of all treated subjects/patients received TPV monotherapy: 113 in
> Trial 1182.5 (TPV 250 mg, 500 mg, 750 mg, 1000 mg, or 1250 mg BID),
> for the first 10 days of the study, 24 in Trial 1182.1 monotherapy
> (TPV 900 mg, 1200 mg or 1500 mg TID), and 10 in Trial 1182.3 (TPV 1200
> mg BID).

2 In Trial 1182.41, subjects were scheduled to take TPV/r for 10 days (3
days as a single dose - trial Days 3, 5, and 14), and 7 days BID (Trial
Days 15-21). Subjects were scheduled to take EFV as a single daily dose
on 17 days (Trial Days 1, 5, and 7-21).

3 In Trial 1182.55, loperamide (16 mg) was administered on Days 1, 9 and
22. On Days 4-9 (5.5 days), subjects received either TPV 750 mg BID or
RTV 200 mg BID. From Days 12-22 (10.5 days), subjects received TPV 750
mg and RTV 200 mg BID. No drugs were administered on Days 2 and 3 and
Days 10 and 11.

4 Nearly all patients in Trial 1182.17 were transitioned to the standard
TPV/r dose of 500 mg/200 mg BID as of January 20, 2003

[]{#__RefHeading___Toc101398998 .anchor}Appendix 3 DRUG INTERACTIONS

Table 1 Drug Interactions: Pharmacokinetic Parameters for Tipranavir in
the Presence of Co-administered Drugs

+--------+---------+---------+----+---+---------+---------+---------+
| **Coad | **Co    | **      | *  | * | **Ratio |         |         |
| minist | adminis | TPV/r** | *n | * | (90%    |         |         |
| ered** | tered** |         | ** | P | Con     |         |         |
|        |         | **Drug  |    | K | fidence |         |         |
| **     | **Drug  | Dose**  |    | * | In      |         |         |
| Drug** | Dose**  |         |    | * | terval) |         |         |
|        |         | **(Sche |    |   | of      |         |         |
|        | **(Sche | dule)** |    |   | Tip     |         |         |
|        | dule)** |         |    |   | ranavir |         |         |
|        |         |         |    |   | P       |         |         |
|        |         |         |    |   | harmaco |         |         |
|        |         |         |    |   | kinetic |         |         |
|        |         |         |    |   | Par     |         |         |
|        |         |         |    |   | ameters |         |         |
|        |         |         |    |   | with/   |         |         |
|        |         |         |    |   | without |         |         |
|        |         |         |    |   | Coadmin |         |         |
|        |         |         |    |   | istered |         |         |
|        |         |         |    |   | Drug;** |         |         |
|        |         |         |    |   |         |         |         |
|        |         |         |    |   | **No    |         |         |
|        |         |         |    |   | Effect  |         |         |
|        |         |         |    |   | =       |         |         |
|        |         |         |    |   | 1.00**  |         |         |
+--------+---------+---------+----+---+---------+---------+---------+
|        |         |         |    |   | *       | **AUC** | *       |
|        |         |         |    |   | *Cmax** |         | *Cmin** |
+--------+---------+---------+----+---+---------+---------+---------+
| Atorva | 10 mg   | 500/200 | 22 |   | 0.96    | 1.08    | 1.04    |
| statin |         | mg bid  |    |   | (0.86,  | (1.00,  | (0.89,  |
|        | (1      |         |    |   | 1.07)   | 1.15)   | 1.22)   |
|        | dose)   | (14     |    |   |         |         |         |
|        |         | doses)  |    |   |         |         |         |
+--------+---------+---------+----+---+---------+---------+---------+
| Cl     | 500 mg  | 500/200 | 2  |   | 1.40    | 1.66    | 2.00    |
| arithr | BID     | BID\*   | 4/ |   | (1.24   | (1.43   | (1.58   |
| omycin |         |         | 68 |   | --      | --      | --      |
|        | (25     |         |    |   | 1.47)   | 1.73)   | 2.47)   |
|        | doses)  |         |    |   |         |         |         |
+--------+---------+---------+----+---+---------+---------+---------+
| Dida   | 400 mg  | 500/100 | 5  |   | 1.32    | 1.08    | 0.66    |
| nosine |         | mg bid  |    |   | (1.09,  | (0.82,  | (0.31,  |
|        | (1      |         |    |   | 1.60)   | 1.42)   | 1.43)   |
|        | dose)   | (27     |    |   |         |         |         |
|        |         | doses)  |    |   |         |         |         |
+--------+---------+---------+----+---+---------+---------+---------+
| Efa    | 600 mg  | 500/100 | 24 |   | 0.93    | 0.92    | 0.90    |
| virenz |         | mg      |    |   | (0.82,  | (0.81,  | (0.78,  |
|        | (1      |         | 26 |   | 1.06)   | 1.04)   | 1.04)   |
|        | dose)   | 750/200 |    |   |         |         |         |
|        |         | mg      |    |   | 0.91    | 0.93    | 0.88    |
|        |         |         |    |   | (0.81,  | (0.79,  | (0.69,  |
|        |         | (1      |    |   | 1.03)   | 1.10)   | 1.11)   |
|        |         | dose)   |    |   |         |         |         |
+--------+---------+---------+----+---+---------+---------+---------+
|        | 600 mg  | 500/100 | 21 |   | 0.61    | 0.43    | 0.23    |
|        | qd      | mg      |    |   | (0.51,  | (0.35,  | (0.16,  |
|        |         |         | 25 |   | 0.72)   | 0.52)   | 0.33)   |
|        | (8      | 750/200 |    |   |         |         |         |
|        | doses)  | mg      | 2  |   | 0.69    | 0.66    | 0.64    |
|        |         |         | 1/ |   | (0.58,  | (0.56,  | (0.52,  |
|        |         | (1      | 89 |   | 0.83)   | 0.79)   | 0.79)   |
|        |         | dose)   |    |   |         |         |         |
|        |         |         | 25 |   | 0.79    | 0.69    | 0.58    |
|        |         | 500/100 | /1 |   | (0.69   | (0.57   | (0.36   |
|        |         | mg\*    | 00 |   | --      | --      | --      |
|        |         |         |    |   | 0.89)   | 0.83)   | 0.86)   |
|        |         | 750/200 |    |   |         |         |         |
|        |         | mg\*    |    |   | 0.97    | 1.01    | 0.97    |
|        |         |         |    |   | (0.85   | (0.85   | (0.69   |
|        |         |         |    |   | --      | --      | --      |
|        |         |         |    |   | 1.09)   | 1.18)   | 1.28)   |
+--------+---------+---------+----+---+---------+---------+---------+
| E      | 0.      | 500/100 | 21 |   | 1.10    | 0.98    | 0.73    |
| thinyl | 035/1.0 | mg bid  |    |   | (0.98,  | (0.88,  | (0.59,  |
| est    | mg      |         |    |   | 1.24)   | 1.11)   | 0.90)   |
| radiol |         | (21     |    |   |         |         |         |
| /      | (1      | doses)  |    |   |         |         |         |
|        | dose)   |         |    |   |         |         |         |
| N      |         |         |    |   |         |         |         |
| orethi |         |         |    |   |         |         |         |
| ndrone |         |         |    |   |         |         |         |
+--------+---------+---------+----+---+---------+---------+---------+
|        |         | 750/200 | 13 |   | 1.01    | 0.98    | 0.91    |
|        |         | mg bid  |    |   | (0.96,  | (0.90,  | (0.69,  |
|        |         |         |    |   | 1.06)   | 1.07)   | 1.20)   |
|        |         | (21     |    |   |         |         |         |
|        |         | doses)  |    |   |         |         |         |
+--------+---------+---------+----+---+---------+---------+---------+
| Fluco  | 100 mg  | 500/200 | 2  |   | 1.32    | 1.50    | 1.69    |
| nazole | QD\     | BID\*   | 0/ |   | (1.18   | (1.29   | (1.33   |
|        | (12     |         | 68 |   | --      | --      | --      |
|        | dose)   |         |    |   | 1.47)   | 1.73)   | 2.09)   |
+--------+---------+---------+----+---+---------+---------+---------+
| Lope   | 16 mg   | 750/200 | 24 |   | 1.03    | 0.98    | 0.74    |
| ramide |         | mg bid  |    |   | (0.92,  | (0.86,  | (0.62,  |
|        | (1      |         |    |   | 1.17)   | 1.12)   | 0.88)   |
|        | dose)   | (21     |    |   |         |         |         |
|        |         | doses)  |    |   |         |         |         |
+--------+---------+---------+----+---+---------+---------+---------+
| Rif    | 150 mg  | 500/200 | 21 |   | 0.99    | 1.00    | 1.16    |
| abutin |         | mg bid  |    |   | (0.93,  | (0.96,  | (1.07,  |
|        | (1      |         |    |   | 1.07)   | 1.04)   | 1.27)   |
|        | dose)   | (15     |    |   |         |         |         |
|        |         | doses)  |    |   |         |         |         |
+--------+---------+---------+----+---+---------+---------+---------+
| Ten    | 300 mg  | 500/100 | 22 |   | 0.83    | 0.82    | 0.79    |
| ofovir |         | mg bid  |    |   | (0.74,  | (0.75,  | (0.70,  |
|        | (1      |         | 20 |   | 0.94)   | 0.91)   | 0.90)   |
|        | dose)   | 750/200 |    |   |         |         |         |
|        |         | mg bid  |    |   | 0.89    | 0.91    | 0.88    |
|        |         |         |    |   | (0.84,  | (0.85,  | (0.78,  |
|        |         | (23     |    |   | 0.96)   | 0.97)   | 1.00)   |
|        |         | doses)  |    |   |         |         |         |
+--------+---------+---------+----+---+---------+---------+---------+
| Zido   | 300 mg  | 500/100 | 29 |   | 0.87    | 0.82    | 0.77    |
| vudine |         | mg bid  |    |   | (0.80,  | (0.76,  | (0.68,  |
|        | (1      |         | 25 |   | 0.94)   | 0.89)   | 0.87)   |
|        | dose)   | 750/200 |    |   |         |         |         |
|        |         | mg bid  |    |   | 1.02    | 1.02    | 1.07    |
|        |         |         |    |   | (0.94,  | (0.92,  | (0.86,  |
|        |         | (23     |    |   | 1.10)   | 1.13)   | 1.34)   |
|        |         | doses)  |    |   |         |         |         |
+--------+---------+---------+----+---+---------+---------+---------+

\*steady state comparison to historical data

+----------+----------+---------+---+---+---+---------+---------+----------+
| Table 2  |          |         |   |   |   |         |         |          |
| Drug     |          |         |   |   |   |         |         |          |
| Inter    |          |         |   |   |   |         |         |          |
| actions: |          |         |   |   |   |         |         |          |
| Pharmac  |          |         |   |   |   |         |         |          |
| okinetic |          |         |   |   |   |         |         |          |
| Pa       |          |         |   |   |   |         |         |          |
| rameters |          |         |   |   |   |         |         |          |
| for      |          |         |   |   |   |         |         |          |
| Co-admi  |          |         |   |   |   |         |         |          |
| nistered |          |         |   |   |   |         |         |          |
| Drug in  |          |         |   |   |   |         |         |          |
| the      |          |         |   |   |   |         |         |          |
| Presence |          |         |   |   |   |         |         |          |
| of       |          |         |   |   |   |         |         |          |
| Tipr     |          |         |   |   |   |         |         |          |
| anavir/R |          |         |   |   |   |         |         |          |
| itonavir |          |         |   |   |   |         |         |          |
+----------+----------+---------+---+---+---+---------+---------+----------+
| **       | **       | **      |   | * | * | **Ratio |         |          |
| Coadmini | Coadmini | TPV/r** |   | * | * | (90%    |         |          |
| stered** | stered** |         |   | n | P | Con     |         |          |
|          |          | **Drug  |   | * | K | fidence |         |          |
| **Drug** | **Drug   | Dose**  |   | * | * | In      |         |          |
|          | Dose**   |         |   |   | * | terval) |         |          |
|          |          | **(Sche |   |   |   | of      |         |          |
|          | **(Sch   | dule)** |   |   |   | Coadmin |         |          |
|          | edule)** |         |   |   |   | istered |         |          |
|          |          |         |   |   |   | Drug    |         |          |
|          |          |         |   |   |   | P       |         |          |
|          |          |         |   |   |   | harmaco |         |          |
|          |          |         |   |   |   | kinetic |         |          |
|          |          |         |   |   |   | Par     |         |          |
|          |          |         |   |   |   | ameters |         |          |
|          |          |         |   |   |   | with/   |         |          |
|          |          |         |   |   |   | without |         |          |
|          |          |         |   |   |   | T       |         |          |
|          |          |         |   |   |   | PV/r;** |         |          |
|          |          |         |   |   |   |         |         |          |
|          |          |         |   |   |   | **No    |         |          |
|          |          |         |   |   |   | Effect  |         |          |
|          |          |         |   |   |   | =       |         |          |
|          |          |         |   |   |   | 1.00**  |         |          |
+----------+----------+---------+---+---+---+---------+---------+----------+
|          |          |         |   |   |   | *       | **AUC** | **Cmin** |
|          |          |         |   |   |   | *Cmax** |         |          |
+----------+----------+---------+---+---+---+---------+---------+----------+
| Amprena  | 600/100  | 500/200 | 1 |   |   | 0.61    | 0.56    | 0.45     |
| vir/RTV† | mg bid   | mg bid  | 6 |   |   | (0.51,  | (0.49,  | (0.38,   |
|          |          |         |   |   |   | 0.73)\* | 0.64)\* | 0.53)\*  |
|          | (27      | (28     | 7 |   |   |         |         |          |
|          | doses)   | doses)  | 4 |   |   | \-      | \-      | 0.44     |
|          |          |         |   |   |   |         |         | (0.39,   |
|          |          |         |   |   |   |         |         | 0        |
|          |          |         |   |   |   |         |         | .49)\*\* |
+----------+----------+---------+---+---+---+---------+---------+----------+
| A        | 300 mg   | 250/200 | 2 |   |   | 0.56    | 0.56    | \-       |
| bacavir† | bid      | mg bid  | 8 |   |   | (0.48,  | (0.49,  |          |
|          |          |         |   |   |   | 0.66)   | 0.63)   | \-       |
|          | (43      | 750/100 | 1 |   |   |         |         |          |
|          | doses)   | mg bid  | 4 |   |   | 0.54    | 0.64    | \-       |
|          |          |         |   |   |   | (0.47,  | (0.55,  |          |
|          |          | 1       | 1 |   |   | 0.63)   | 0.74)   |          |
|          |          | 250/100 | 1 |   |   |         |         |          |
|          |          | mg bid  |   |   |   | 0.48    | 0.65    |          |
|          |          |         |   |   |   | (0.42,  | (0.55,  |          |
|          |          |         |   |   |   | 0.53)   | 0.76)   |          |
+----------+----------+---------+---+---+---+---------+---------+----------+
| Ator     | 10 mg    | 500/200 | 2 |   |   | 8.61    | 9.36    | 5.19     |
| vastatin |          | mg bid  | 2 |   |   | (7.25,  | (8.02,  | (4.21,   |
|          | (1 dose) |         |   |   |   | 10.21)  | 10.94)  | 6.40)    |
|          |          | (17     |   |   |   |         |         |          |
|          |          | doses)  |   |   |   |         |         |          |
+----------+----------+---------+---+---+---+---------+---------+----------+
| O        |          |         | 2 |   |   | 0.02    | 0.11    | 0.07     |
| rthohydr |          |         | 1 |   |   | (0.02,  | (0.08,  | (0.06,   |
| oxy-ator |          |         | , |   |   | 0.03)   | 0.17)   | 0.08)    |
| vastatin |          |         | 1 |   |   |         |         |          |
|          |          |         | 2 |   |   |         |         |          |
|          |          |         | , |   |   |         |         |          |
|          |          |         | 1 |   |   |         |         |          |
|          |          |         | 7 |   |   |         |         |          |
+----------+----------+---------+---+---+---+---------+---------+----------+
| Parahydr |          |         | 1 |   |   | 1.04    | 0.18    | 0.33     |
| oxy-ator |          |         | 3 |   |   | (0.87,  | (0.14,  | (NA)     |
| vastatin |          |         | , |   |   | 1.25)   | 0.24)   |          |
|          |          |         | 2 |   |   |         |         |          |
|          |          |         | 2 |   |   |         |         |          |
|          |          |         | , |   |   |         |         |          |
|          |          |         | 1 |   |   |         |         |          |
+----------+----------+---------+---+---+---+---------+---------+----------+
| Clarit   | 500 mg   | 500/200 | 2 |   |   | 0.88    | 1.00    | 1.50     |
| hromycin | bid      | mg      | 4 |   |   | (0.78,  | (0.91,  | (1.31,   |
|          |          |         |   |   |   | 1.00)   | 1.11)   | 1.71)    |
|          | (11      | (1      |   |   |   |         |         |          |
|          | doses)   | dose)   |   |   |   |         |         |          |
+----------+----------+---------+---+---+---+---------+---------+----------+
| 14-O     |          |         | 2 |   |   | 0.75    | 0.54    | 0.39     |
| H-clarit |          |         | 4 |   |   | (0.68,  | (0.48,  | (0.35,   |
| hromycin |          |         |   |   |   | 0.83)   | 0.59)   | 0.44)    |
+----------+----------+---------+---+---+---+---------+---------+----------+
| Clarit   | 500 mg   | 500/200 | 2 |   |   | 0.95    | 1.19    | 1.68     |
| hromycin | bid      | mg bid  | 1 |   |   | (0.83,  | (1.04,  | (1.42,   |
|          |          |         |   |   |   | 1.09)   | 1.37)   | 1.98)    |
|          | (25      | (15     |   |   |   |         |         |          |
|          | doses)   | doses)  |   |   |   |         |         |          |
+----------+----------+---------+---+---+---+---------+---------+----------+
| 14-O     |          |         | 2 |   |   | 0.03    | 0.03    | 0.05     |
| H-clarit |          |         | 1 |   |   | (0.02,  | (0.02,  | (0.04,   |
| hromycin |          |         |   |   |   | 0.04)   | 0.04)   | 0.07)    |
+----------+----------+---------+---+---+---+---------+---------+----------+
| Dida     | 200 mg   | 250/200 |   | 1 |   | 0.57    | 0.67    | \-       |
| nosine†† | bid,     | mg bid  |   | 0 |   | (0.42,  | (0.51,  |          |
|          | [\       |         |   |   |   | 0.79)   | 0.88)   | \-       |
|          | >]{.unde | 750/100 |   | 8 |   |         |         |          |
|          | rline}60 | mg bid  |   |   |   | 0.76    | 0.97    | \-       |
|          | Kg       |         |   | 9 |   | (0.49,  | (0.64,  |          |
|          |          | 1       |   |   |   | 1.17)   | 1.47)   |          |
|          | 125 mg   | 250/100 |   |   |   |         |         |          |
|          | bid,     | mg bid  |   |   |   | 0.77    | 0.87    |          |
|          | \<60 Kg  |         |   |   |   | (0.4    | (0.47,  |          |
|          |          | (42     |   |   |   | 7,1.26) | 1.65)   |          |
|          | (43      | doses)  |   |   |   |         |         |          |
|          | doses)   |         |   |   |   |         |         |          |
+----------+----------+---------+---+---+---+---------+---------+----------+
|          | 400 mg   | 500/100 |   | 5 |   | 0.80    | 0.90    | 1.17     |
|          |          | mg bid  |   |   |   | (0.63,  | (0.72,  | (0.62,   |
|          | (1 dose) |         |   |   |   | 1.02)   | 1.11)   | 2.20)    |
|          |          | (27     |   |   |   |         |         |          |
|          |          | doses)  |   |   |   |         |         |          |
+----------+----------+---------+---+---+---+---------+---------+----------+
| Efa      | 600 mg   | 250/200 | 2 |   |   | 1.13    | 1.12    | 1.01     |
| virenz†† | qd       | mg bid  | 3 |   |   | (0.99,  | (1.02,  | (0.84,   |
|          |          |         |   |   |   | 1.28)   | 1.24)   | 1.20)    |
|          | (22      | 750/100 | 1 |   |   |         |         |          |
|          | doses)   | mg bid  | 9 |   |   | 0.95    | 0.91    | 0.92     |
|          |          |         |   |   |   | (0.83,  | (0.80,  | (0.80,   |
|          |          | 1       | 1 |   |   | 1.08)   | 1.03)   | 1.07)    |
|          |          | 250/100 | 5 |   |   |         |         |          |
|          |          | mg bid  |   |   |   | 0.95    | 0.92    | 1.02     |
|          |          |         |   |   |   | (0.81,  | (0.75,  | (0.79,   |
|          |          | (42     |   |   |   | 1.12)   | 1.12)   | 1.31)    |
|          |          | doses)  |   |   |   |         |         |          |
+----------+----------+---------+---+---+---+---------+---------+----------+
|          | 600 mg   | 500/100 |   | 3 |   | 1.37    | 1.04    | 1.01     |
|          |          | mg      |   | 0 |   | (1.24,  | (0.91,  | (0.90,   |
|          | (1 dose) |         |   |   |   | 1.50)   | 1.18)   | 1.12)    |
|          |          | 750/200 |   | 2 |   |         |         |          |
|          |          | mg      |   | 6 |   | 1.19    | 0.92    | 0.95     |
|          |          |         |   |   |   | (1.08,  | (0.81,  | (0.84,   |
|          |          | (1      |   |   |   | 1.32)   | 1.05)   | 1.07)    |
|          |          | dose)   |   |   |   |         |         |          |
+----------+----------+---------+---+---+---+---------+---------+----------+
|          | 600 mg   | 500/100 |   | 2 |   | 1.18    | 1.11    | 1.04     |
|          | qd       | mg      |   | 8 |   | (1.12,  | (1.08,  | (1.00,   |
|          |          |         |   |   |   | 1.25)   | 1.15)   | 1.08)    |
|          | (8       | 750/200 |   | 2 |   |         |         |          |
|          | doses)   | mg      |   | 8 |   | 1.22    | 1.15    | 1.07     |
|          |          |         |   |   |   | (1.15,  | (1.11,  | (0.99,   |
|          |          | (1      |   |   |   | 1.29)   | 1.20)   | 1.14)    |
|          |          | dose)   |   |   |   |         |         |          |
+----------+----------+---------+---+---+---+---------+---------+----------+
|          | 600 mg   | 500/100 |   | 2 |   | 1.09    | 1.04    | 1.02     |
|          | qd       | mg bid  |   | 4 |   | (0.99,  | (0.97,  | (0.92,   |
|          |          |         |   |   |   | 1.19)   | 1.12)   | 1.12)    |
|          | (15      | 750/200 |   | 2 |   |         |         |          |
|          | doses)   | mg bid  |   | 2 |   | 1.12    | 1.00    | 0.94     |
|          |          |         |   |   |   | (0.98,  | (0.93,  | (0.84,   |
|          |          | (15     |   |   |   | 1.28)   | 1.09)   | 1.04)    |
|          |          | doses)  |   |   |   |         |         |          |
+----------+----------+---------+---+---+---+---------+---------+----------+
| Ethinyl  | 0.035 mg | 500/100 | 2 |   |   | 0.52    | 0.52    | \-       |
| e        |          | mg bid  | 1 |   |   | (0.47,  | (0.48,  |          |
| stradiol | (1 dose) |         |   |   |   | 0.57)   | 0.56)   | \-       |
|          |          | 750/200 | 1 |   |   |         |         |          |
|          |          | mg bid  | 3 |   |   | 0.48    | 0.57    |          |
|          |          |         |   |   |   | (0.42,  | (0.54,  |          |
|          |          | (21     |   |   |   | 0.57)   | 0.60)   |          |
|          |          | doses)  |   |   |   |         |         |          |
+----------+----------+---------+---+---+---+---------+---------+----------+
| Flu      | 200 mg   | 500/200 | 1 |   |   | 0.97    | 0.99    | 0.98     |
| conazole | (Day 1)  | mg bid  | 9 |   |   | (0.94,  | (0.97,  | (0.94,   |
|          | then     |         |   |   |   | 1.01)   | 1.02)   | 1.02)    |
|          |          | (2 or   | 1 |   |   |         |         |          |
|          | 100 mg   | 14      | 9 |   |   | 0.94    | 0.92    | 0.89     |
|          | qd       | doses)  |   |   |   | (0.91,  | (0.88,  | (0.85,   |
|          |          |         |   |   |   | 0.98)   | 0.95)   | 0.92)    |
|          | (6 or 12 |         |   |   |   |         |         |          |
|          | doses)   |         |   |   |   |         |         |          |
+----------+----------+---------+---+---+---+---------+---------+----------+
| Lopina   | 400/100  | 500/200 | 2 |   |   | 0.53    | 0.45    | 0.30     |
| vir/RTV† | mg bid   | mg bid  | 1 |   |   | (0.40,  | (0.32,  | (0.17,   |
|          |          |         |   |   |   | 0.69)\* | 0.63)\* | 0.51)\*  |
|          | (27      | (28     | 6 |   |   |         |         |          |
|          | doses)   | doses)  | 9 |   |   | \-      | \-      | 0.48     |
|          |          |         |   |   |   |         |         | (0.40,   |
|          |          |         |   |   |   |         |         | 0        |
|          |          |         |   |   |   |         |         | .58)\*\* |
+----------+----------+---------+---+---+---+---------+---------+----------+
| Lo       | 16 mg    | 750/200 | 2 |   |   | 0.39    | 0.49    | \-       |
| peramide |          | mg bid  | 4 |   |   | (0.31,  | (0.40,  |          |
|          | (1 dose) |         |   |   |   | 0.48)   | 0.61)   |          |
|          |          | (21     |   |   |   |         |         |          |
|          |          | doses)  |   |   |   |         |         |          |
+----------+----------+---------+---+---+---+---------+---------+----------+
| N-Dem    |          |         | 2 |   |   | 0.21    | 0.23    |          |
| ethyl-Lo |          |         | 4 |   |   | (0.17,  | (0.19,  |          |
| peramide |          |         |   |   |   | 0.25)   | 0.27)   |          |
+----------+----------+---------+---+---+---+---------+---------+----------+

†HIV+ patients; ††HIV+ patients (TPV/r 250 mg/200 mg, 750mg/200 mg and
1250 mg/100 mg) and healthy volunteers (TPV/r 500 mg/100 mg and 750
mg/200 mg)

^a^Normalized sum of parent drug (rifabutin) and active metabolite
(25-O-desacetyl-rifabutin)

\*Intensive PK analysis

\*\*Therapeutic Drug Monitoring 8-16 hrs post-dose

Table 2 (continued) Drug Interactions: Pharmacokinetic Parameters for
Co-administered Drug in the Presence of Tipranavir/Ritonavir (Page 2 of
2)

+---------+----------+--------+---+---+----------+---+---------+---------+
| **Co    | **       | **T    | * | * | **Ratio  |   |         |         |
| adminis | Coadmini | PV/r** | * | * | (90%     |   |         |         |
| tered** | stered** |        | n | P | Co       |   |         |         |
|         |          | **Drug | * | K | nfidence |   |         |         |
| *       | **Drug   | Dose** | * | * | I        |   |         |         |
| *Drug** | Dose**   |        |   | * | nterval) |   |         |         |
|         |          | **     |   |   | of       |   |         |         |
|         | **(Sch   | (Sched |   |   | Coadmi   |   |         |         |
|         | edule)** | ule)** |   |   | nistered |   |         |         |
|         |          |        |   |   | Drug     |   |         |         |
|         |          |        |   |   | Pharmac  |   |         |         |
|         |          |        |   |   | okinetic |   |         |         |
|         |          |        |   |   | Pa       |   |         |         |
|         |          |        |   |   | rameters |   |         |         |
|         |          |        |   |   | with     |   |         |         |
|         |          |        |   |   | /without |   |         |         |
|         |          |        |   |   | TPV/r;** |   |         |         |
|         |          |        |   |   |          |   |         |         |
|         |          |        |   |   | **No     |   |         |         |
|         |          |        |   |   | Effect = |   |         |         |
|         |          |        |   |   | 1.00**   |   |         |         |
+---------+----------+--------+---+---+----------+---+---------+---------+
|         |          |        |   |   | **Cmax** | * |         | *       |
|         |          |        |   |   |          | * |         | *Cmin** |
|         |          |        |   |   |          | A |         |         |
|         |          |        |   |   |          | U |         |         |
|         |          |        |   |   |          | C |         |         |
|         |          |        |   |   |          | * |         |         |
|         |          |        |   |   |          | * |         |         |
+---------+----------+--------+---+---+----------+---+---------+---------+
| Lami    | 150 mg   | 2      | 6 |   | 0.96     |   | 0.95    | \-      |
| vudine† | bid      | 50/200 | 4 |   | (0.89,   |   | (0.89,  |         |
|         |          | mg bid |   |   | 1.03)    |   | 1.02)   | \-      |
|         | (43      |        | 4 |   |          |   |         |         |
|         | doses)   | 7      | 6 |   | 0.86     |   | 0.96    | \-      |
|         |          | 50/100 |   |   | (0.78,   |   | (0.90,  |         |
|         |          | mg bid | 3 |   | 0.94)    |   | 1.03)   |         |
|         |          |        | 5 |   |          |   |         |         |
|         |          | 12     |   |   | 0.71     |   | 0.82    |         |
|         |          | 50/100 |   |   | (0.62,   |   | (0.66,  |         |
|         |          | mg bid |   |   | 0.81)    |   | 1.00)   |         |
|         |          |        |   |   |          |   |         |         |
|         |          | (42    |   |   |          |   |         |         |
|         |          | doses) |   |   |          |   |         |         |
+---------+----------+--------+---+---+----------+---+---------+---------+
| Nevi    | 200 mg   | 2      | 2 |   | 0.97     |   | 0.97    | 0.96    |
| rapine† | bid      | 50/200 | 6 |   | (0.90,   |   | (0.91,  | (0.87,  |
|         |          | mg bid |   |   | 1.04)    |   | 1.04)   | 1.05)   |
|         | (43      |        | 2 |   |          |   |         |         |
|         | doses)   | 7      | 2 |   | 0.86     |   | 0.89    | 0.93    |
|         |          | 50/100 |   |   | (0.76,   |   | (0.78,  | (0.80,  |
|         |          | mg bid | 1 |   | 0.97)    |   | 1.01)   | 1.08)   |
|         |          |        | 7 |   |          |   |         |         |
|         |          | 12     |   |   | 0.71     |   | 0.76    | 0.77    |
|         |          | 50/100 |   |   | (0.62,   |   | (0.63,  | (0.64,  |
|         |          | mg bid |   |   | 0.82)    |   | 0.91)   | 0.92)   |
|         |          |        |   |   |          |   |         |         |
|         |          | (42    |   |   |          |   |         |         |
|         |          | doses) |   |   |          |   |         |         |
+---------+----------+--------+---+---+----------+---+---------+---------+
| Noreth  | 1.0 mg   | 5      | 2 |   | 1.03     |   | 1.14    | \-      |
| indrone |          | 00/100 | 1 |   | (0.94,   |   | (1.0    |         |
|         | (1 dose) | mg bid |   |   | 1.13)    |   | 6,1.22) | \-      |
|         |          |        | 1 |   |          |   |         |         |
|         |          | 7      | 3 |   | 1.08     |   | 1.27    |         |
|         |          | 50/200 |   |   | (0.97,   |   | (1.1    |         |
|         |          | mg bid |   |   | 1.20)    |   | 3,1.43) |         |
|         |          |        |   |   |          |   |         |         |
|         |          | (21    |   |   |          |   |         |         |
|         |          | doses) |   |   |          |   |         |         |
+---------+----------+--------+---+---+----------+---+---------+---------+
| Ri      | 150 mg   | 5      | 2 |   | 1.70     |   | 2.90    | 2.14    |
| fabutin |          | 00/200 | 0 |   | (1.49,   |   | (2.59,  | (1.90,  |
|         | (1 dose) | mg bid |   |   | 1.94)    |   | 3.26)   | 2.41)   |
|         |          |        |   |   |          |   |         |         |
|         |          | (15    |   |   |          |   |         |         |
|         |          | doses) |   |   |          |   |         |         |
+---------+----------+--------+---+---+----------+---+---------+---------+
| 25-     |          |        | 2 |   | 3.20     |   | 20.71   | 7.83    |
| 0-desac |          |        | 0 |   | (2.78,   |   | (17.66, | (6.70,  |
| etyl-ri |          |        |   |   | 3.68)    |   | 24.28)  | 9.14)   |
| fabutin |          |        |   |   |          |   |         |         |
+---------+----------+--------+---+---+----------+---+---------+---------+
| Rifa    |          |        | 2 |   | 1.86     |   | 4.33    | 2.76    |
| butin + |          |        | 0 |   | (1.63,   |   | (3.86,  | (2.44,  |
| 25-O-d  |          |        |   |   | 2.12)    |   | 4.86)   | 3.12)   |
| esacety |          |        |   |   |          |   |         |         |
| -lrifab |          |        |   |   |          |   |         |         |
| utin^a^ |          |        |   |   |          |   |         |         |
+---------+----------+--------+---+---+----------+---+---------+---------+
| S       | 600/100  | 5      | 2 |   | 0.30     |   | 0.24    | 0.1     |
| aquinav | mg bid   | 00/200 | 0 |   | (0.23,   |   | (0.19,  | 8(0.13, |
| ir/RTV† |          | mg bid |   |   | 0.40)\*  |   | 0.32)\* | 0.26)\* |
|         | (27      |        | 6 |   |          |   |         |         |
|         | doses)   | (28    | 8 |   | \-       |   | \-      | 0.20(   |
|         |          | doses) |   |   |          |   |         | 0.16,0. |
|         |          |        |   |   |          |   |         | 25)\*\* |
+---------+----------+--------+---+---+----------+---+---------+---------+
| Sta     | 40 mg    | 2      | 2 |   | 0.90     |   | 1.00    | \-      |
| vudine† | bid,     | 50/200 | 6 |   | (0.81,   |   | (0.91,  |         |
|         | [\       | mg bid |   |   | 1.02)    |   | 1.11)   | \-      |
|         | >]{.unde |        | 2 |   |          |   |         |         |
|         | rline}60 | 7      | 2 |   | 0.76     |   | 0.84    | \-      |
|         | Kg       | 50/100 |   |   | (0.66,   |   | (0.74,  |         |
|         |          | mg bid | 1 |   | 0.89)    |   | 0.96)   |         |
|         | 30 mg    |        | 9 |   |          |   |         |         |
|         | bid,     | 12     |   |   | 0.74     |   | 0.93    |         |
|         | \<60 Kg  | 50/100 |   |   | (0.69,   |   | (0.83,  |         |
|         |          | mg bid |   |   | 0.80)    |   | 1.05)   |         |
|         | (43      |        |   |   |          |   |         |         |
|         | doses)   | (42    |   |   |          |   |         |         |
|         |          | doses) |   |   |          |   |         |         |
+---------+----------+--------+---+---+----------+---+---------+---------+
| Te      | 300 mg   | 5      | 2 |   | 0.77     |   | 0.98    | 1.07    |
| nofovir |          | 00/100 | 2 |   | (0.68,   |   | (0.91,  | (0.98,  |
|         | (1 dose) | mg bid |   |   | 0.87)    |   | 1.05)   | 1.17)   |
|         |          |        | 2 |   |          |   |         |         |
|         |          | 7      | 0 |   | 0.62     |   | 1.02    | 1.14    |
|         |          | 50/200 |   |   | (0.54,   |   | (0.94,  | (1.01,  |
|         |          | mg bid |   |   | 0.71)    |   | 1.10)   | 1.27)   |
|         |          |        |   |   |          |   |         |         |
|         |          | (23    |   |   |          |   |         |         |
|         |          | doses) |   |   |          |   |         |         |
+---------+----------+--------+---+---+----------+---+---------+---------+
| Zidov   | 300 mg   | 2      | 4 |   | 0.54     |   | 0.58    | \-      |
| udine†† | bid      | 50/200 | 8 |   | (0.47,   |   | (0.51,  |         |
|         |          | mg bid |   |   | 0.62)    |   | 0.66)   | \-      |
|         | 300 mg   |        | 3 |   |          |   |         |         |
|         | bid      | 7      | 1 |   | 0.51     |   | 0.64    | \-      |
|         |          | 50/100 |   |   | (0.44,   |   | (0.55,  |         |
|         | 300 mg   | mg bid | 2 |   | 0.60)    |   | 0.75)   |         |
|         | bid      |        | 3 |   |          |   |         |         |
|         |          | 12     |   |   | 0.49     |   | 0.69    |         |
|         | (43      | 50/100 |   |   | (0.40,   |   | (0.49,  |         |
|         | doses)   | mg bid |   |   | 0.59)    |   | 0.97)   |         |
|         |          |        |   |   |          |   |         |         |
|         |          | (42    |   |   |          |   |         |         |
|         |          | doses) |   |   |          |   |         |         |
+---------+----------+--------+---+---+----------+---+---------+---------+
|         | 300 mg   | 5      | 2 | , | 0.39     | 0 |         | 0.89    |
|         |          | 00/100 | 9 |   | (0.33,   | . |         | (0.81,  |
|         | (1 dose) | mg bid |   |   | 0.45)    | 5 |         | 0.99)   |
|         |          |        | 2 |   |          | 7 |         |         |
|         |          | 7      | 5 |   | 0.44     | ( |         | 1.25    |
|         |          | 50/200 |   |   | (0.36,   | 0 |         | (1.08,  |
|         |          | mg bid |   |   | 0.54)    | . |         | 1.44)   |
|         |          |        |   |   |          | 5 |         |         |
|         |          | (23    |   |   |          | 2 |         |         |
|         |          | doses) |   |   |          | , |         |         |
|         |          |        |   |   |          | 0 |         |         |
|         |          |        |   |   |          | . |         |         |
|         |          |        |   |   |          | 6 |         |         |
|         |          |        |   |   |          | 3 |         |         |
|         |          |        |   |   |          | ) |         |         |
|         |          |        |   |   |          |   |         |         |
|         |          |        |   |   |          | 0 |         |         |
|         |          |        |   |   |          | . |         |         |
|         |          |        |   |   |          | 6 |         |         |
|         |          |        |   |   |          | 7 |         |         |
|         |          |        |   |   |          | ( |         |         |
|         |          |        |   |   |          | 0 |         |         |
|         |          |        |   |   |          | . |         |         |
|         |          |        |   |   |          | 6 |         |         |
|         |          |        |   |   |          | 2 |         |         |
|         |          |        |   |   |          | , |         |         |
|         |          |        |   |   |          | 0 |         |         |
|         |          |        |   |   |          | . |         |         |
|         |          |        |   |   |          | 7 |         |         |
|         |          |        |   |   |          | 3 |         |         |
|         |          |        |   |   |          | ) |         |         |
+---------+----------+--------+---+---+----------+---+---------+---------+
| Zid     |          | 5      | 2 |   | 0.82     |   | 1.02    | 1.52    |
| ovudine |          | 00/100 | 9 |   | (0.74,   |   | (0.97,  | (1.34,  |
| gluc    |          | mg bid |   |   | 0.90)    |   | 1.06)   | 1.71)   |
| uronide |          |        | 2 |   |          |   |         |         |
|         |          | 7      | 5 |   | 0.82     |   | 1.09    | 1.94    |
|         |          | 50/200 |   |   | (0.73,   |   | (1.05,  | (1.62,  |
|         |          | mg bid |   |   | 0.92)    |   | 1.14)   | 2.31)   |
|         |          |        |   |   |          |   |         |         |
|         |          | (23    |   |   |          |   |         |         |
|         |          | doses) |   |   |          |   |         |         |
+---------+----------+--------+---+---+----------+---+---------+---------+
| †HIV+   |          |        |   |   |          |   |         |         |
| p       |          |        |   |   |          |   |         |         |
| atients |          |        |   |   |          |   |         |         |
|         |          |        |   |   |          |   |         |         |
| ††HIV+  |          |        |   |   |          |   |         |         |
| p       |          |        |   |   |          |   |         |         |
| atients |          |        |   |   |          |   |         |         |
| (TPV/r  |          |        |   |   |          |   |         |         |
| 250     |          |        |   |   |          |   |         |         |
| mg/200  |          |        |   |   |          |   |         |         |
| mg,     |          |        |   |   |          |   |         |         |
| 75      |          |        |   |   |          |   |         |         |
| 0mg/200 |          |        |   |   |          |   |         |         |
| mg and  |          |        |   |   |          |   |         |         |
| 1250    |          |        |   |   |          |   |         |         |
| mg/100  |          |        |   |   |          |   |         |         |
| mg) and |          |        |   |   |          |   |         |         |
| healthy |          |        |   |   |          |   |         |         |
| vol     |          |        |   |   |          |   |         |         |
| unteers |          |        |   |   |          |   |         |         |
| (TPV/r  |          |        |   |   |          |   |         |         |
| 500     |          |        |   |   |          |   |         |         |
| mg/100  |          |        |   |   |          |   |         |         |
| mg and  |          |        |   |   |          |   |         |         |
| 750     |          |        |   |   |          |   |         |         |
| mg/200  |          |        |   |   |          |   |         |         |
| mg)     |          |        |   |   |          |   |         |         |
|         |          |        |   |   |          |   |         |         |
| ^a^Nor  |          |        |   |   |          |   |         |         |
| malized |          |        |   |   |          |   |         |         |
| sum of  |          |        |   |   |          |   |         |         |
| parent  |          |        |   |   |          |   |         |         |
| drug    |          |        |   |   |          |   |         |         |
| (rif    |          |        |   |   |          |   |         |         |
| abutin) |          |        |   |   |          |   |         |         |
| and     |          |        |   |   |          |   |         |         |
| active  |          |        |   |   |          |   |         |         |
| met     |          |        |   |   |          |   |         |         |
| abolite |          |        |   |   |          |   |         |         |
| (25-O   |          |        |   |   |          |   |         |         |
| -desace |          |        |   |   |          |   |         |         |
| ty-lrif |          |        |   |   |          |   |         |         |
| abutin) |          |        |   |   |          |   |         |         |
|         |          |        |   |   |          |   |         |         |
| \*In    |          |        |   |   |          |   |         |         |
| tensive |          |        |   |   |          |   |         |         |
| PK      |          |        |   |   |          |   |         |         |
| a       |          |        |   |   |          |   |         |         |
| nalysis |          |        |   |   |          |   |         |         |
|         |          |        |   |   |          |   |         |         |
| \       |          |        |   |   |          |   |         |         |
| *\*Ther |          |        |   |   |          |   |         |         |
| apeutic |          |        |   |   |          |   |         |         |
| Drug    |          |        |   |   |          |   |         |         |
| Mon     |          |        |   |   |          |   |         |         |
| itoring |          |        |   |   |          |   |         |         |
| 8-16    |          |        |   |   |          |   |         |         |
| hrs     |          |        |   |   |          |   |         |         |
| po      |          |        |   |   |          |   |         |         |
| st-dose |          |        |   |   |          |   |         |         |
+---------+----------+--------+---+---+----------+---+---------+---------+

[]{#__RefHeading___Toc101398999 .anchor}Appendix 4 FATAL EVENTS IN
RESIST TRIALS

Table 1 Summaries of Fatal Outcomes from RESIST trials including CPI/r
rollover patients to 1182.17

  -----------------------------------------------------------------------------------------------------------------------------------------------------
  **Pt Case         **Trial**   **Pt**   **Age**   **Bsl   **Bsl   **Treatment**   **Medical history**   **Intercurrent /  **Cause of death** **Death
  Number**                                         VL**    CD4**                                         Concurrent                           Week**
                                                                                                         Illnesses**                          
  ----------------- ----------- -------- --------- ------- ------- --------------- --------------------- ----------------- ------------------ ---------
  2003-BP-10111BP   12          1029     43 M      5.8     27      TPV/r           Renal failure, PCP,   Persistent PCP,   End stage AIDS     31.0
                                                                                   COPD                  bacterial                            
                                                                                                         pneumonia                            

  2003-BP-09677BP   12          1341     46 M      5.0     2       TPV/r           Wasting, CMV          HIV/AIDS,         AIDS related       22.0
                                                                                   retinitis, MAC,       cellulitis,       complex            
                                                                                   adrenal               anemia,                              
                                                                                   insufficiency, DM,    progressive CMV                      
                                                                                   seizure disorder,     infection,                           
                                                                                   depression, transient progressive                          
                                                                                   ischemic attacks      wasting,                             
                                                                                                         progressive IDDM,                    
                                                                                                         progressive                          
                                                                                                         electrolyte                          
                                                                                                         imbalance                            

  2003-BP-05935BP   12          1568     47 M      5.6     13      TPV/r           No significant or     Shingles,         Acquired           23.3
                                                                                   relevant past medical diarrhea, mental  immunodeficiency   
                                                                                   history               status changes,   syndrome           
                                                                                                         MRI of the head                      
                                                                                                         which showed                         
                                                                                                         increased atrophy                    

  2004-BP-06918BP   12          2272     36 M      5.3     4       TPV/r           MAC, PCP, chronic     Liver failure     Acquired           52.1
                                                                                   hepatitis,            (total bilirubin  immunodeficiency   
                                                                                   hyperbilirubinemia,   4.2), renal       syndrome           
                                                                                   CHF, CNS bacterial    failure                              
                                                                                   abscess, DM,                                               
                                                                                   pneumothorax, COPD,                                        
                                                                                   acute renal failure,                                       
                                                                                   hypokalemia                                                

  2003-BP-09673BP   12          2374     47 M      4.9     1       TPV/r           Disseminated          Left upper        Asthenia           8.3
                                                                                   cryptococcal          extremity                            
                                                                                   infection, wasting,   weakness,                            
                                                                                   diarrhea, pancreatic  pseudomonas                          
                                                                                   enzyme insufficiency  sinusitis, acute                     
                                                                                                         demyelinating                        
                                                                                                         sensorimotor                         
                                                                                                         polyneuropathy,                      
                                                                                                         necrotizing                          
                                                                                                         stomatitis,                          
  -----------------------------------------------------------------------------------------------------------------------------------------------------

Table 1 (continued) Summaries of Fatal Outcomes from RESIST trials
including CPI/r rollover patients to 1182.17 (Pg 2 of 9)

  ----------------- ----------- -------- --------- ------- ------- --------------- ----------------- ---------------- ------------------ ---------
  **Pt Case         **Trial**   **Pt**   **Age**   **Bsl   **Bsl   **Treatment**   **Medical         **Intercurrent / **Cause of death** **Death
  Number**                                         VL**    CD4**                   history**         Concurrent                          Week**
                                                                                                     Illnesses**                         

  2003-DE-03576GB   48          5061     44 M      4.7     96      TPV/r           HIV               Cachexia         Cachexia           3.0
                                                                                   encephalopathy,                                       
                                                                                   HIV cachexia,                                         
                                                                                   dehydration of                                        
                                                                                   unknown duration,                                     
                                                                                   esophageal                                            
                                                                                   candidiasis,                                          
                                                                                   mycobacterium                                         
                                                                                   tuberculosis,                                         
                                                                                   anemia                                                

  2004-BP-00953BR   48          9137     43 F      5.2     18      TPV/r           Hemiparesis,      Urinary tract    Acquired           18.4
                                                                                   toxoplasmosis,    infection,       immunodeficiency   
                                                                                   aspiration        pruritus,        syndrome           
                                                                                   pneumonia,        hypertension                        
                                                                                   dyspnea, chronic                                      
                                                                                   bronchitis,                                           
                                                                                   convulsive                                            
                                                                                   disorder                                              

  2003-BP-04975BP   12          2060     34 M      5.1     3       TPV/r           PCP,              CNS lymphoma,    Sepsis             1.3
                                                                                   pancytopenia,     PML,                                
                                                                                   IDDM,             cryptococcal                        
                                                                                   pancreatitis      meningitis,                         
                                                                                                     ARDS, sepsis                        

  2004-BP-07328BP   12          1884     61 M      3.7     152     TPV/r           PCP,              Malignant        Disseminated       58.9
                                                                                   hypothyroidism,   lymphoma,        lymphoma           
                                                                                   non Hodgkin\'s    dehydration,                        
                                                                                   lymphoma, oral    hypotension,                        
                                                                                   candidiasis       chronic                             
                                                                                                     hypothyroidism                      

  2003-BP-04600BP   12          1917     49 M      5.3     4       TPV/r           Anemia,           Febrile          Central nervous    1.4
                                                                                   neutropenia, PCP, neutropenia, CNS system lymphoma    
                                                                                   MAC, mental       lymphoma,                           
                                                                                   retardation, HIV  profound                            
                                                                                   encephalopathy,   weakness, mental                    
                                                                                   Kaposi\'s         status                              
                                                                                   sarcoma, wasting, deficiency,                         
                                                                                   depression,       brain herniation                    
                                                                                   hypothyroidism,                                       
                                                                                   pancreatitis                                          
  ----------------- ----------- -------- --------- ------- ------- --------------- ----------------- ---------------- ------------------ ---------

Table 1 (continued) Summaries of Fatal Outcomes from RESIST trials
including CPI/r rollover patients to 1182.17 (Pg 3 of 9)

  ----------------- ----------- -------- --------- ------- ------- --------------- ------------------ ------------------ ------------ ---------
  **Pt Case         **Trial**   **Pt**   **Age**   **Bsl   **Bsl   **Treatment**   **Medical          **Intercurrent /   **Cause of   **Death
  Number**                                         VL**    CD4**                   history**          Concurrent         death**      Week**
                                                                                                      Illnesses**                     

  2003-BP-08944BP   12          2280     43 M      4.7     31      TPV/r           Intermittent FUO,  Splenectomy,       Hodgkin\'s   10.9
                                                                                   splenomegaly,      pancreatitis,      disease      
                                                                                   periportal         iliac vein                      
                                                                                   lymphadenopathy,   thrombosis,                     
                                                                                   candida            hyperglycemia,                  
                                                                                   esophagitis, CMV   urinary tract                   
                                                                                   retinitis, PCP,    infection, anemia,              
                                                                                   MAC, toxoplasmosis candidiasis,                    
                                                                                   of the brain,      catheter-related                
                                                                                   wasting,           infection,                      
                                                                                   depression, renal  abnormal hepatic                
                                                                                   insufficiency      function,                       
                                                                                                      Hodgkin\'s                      
                                                                                                      lymphoma,                       
                                                                                                      post-surgical                   
                                                                                                      pancreatitis,                   
                                                                                                      peritonitis status              
                                                                                                      post laparotomy,                
                                                                                                      PICC line had a                 
                                                                                                      positive culture                
                                                                                                      for acinetobacter               

  2003-DE-03351DE   48          4168     63 M      5.3     15      TPV/r           Squamous cell      Depression,        B-cell       13.1
                                                                                   carcinoma, hepatic diarrhea,          lymphoma     
                                                                                   failure,           hypertension,                   
                                                                                   intra-abdominal    neutropenia,                    
                                                                                   hemorrhage,        multiple pulmonary              
                                                                                   esophageal         lesions,                        
                                                                                   candidiasis, PCP,  suspicious liver                
                                                                                   wasting            lesions, squamous               
                                                                                                      cell carcinoma,                 
                                                                                                      FUO, hepatic                    
                                                                                                      biopsy                          
                                                                                                      demonstrating                   
                                                                                                      B-cell lymphoma,                
                                                                                                      hepatic failure                 

  2004-BP-03860BP   12          1050     52 M      4.7     15      TPV/r           Melanoma of chest  Squamous cell      Metastatic   58.4
                                                                                   wall, squamous     neoplasm of the    malignant    
                                                                                   cell carcinoma of  oral cavity,       melanoma     
                                                                                   the eye lid        radiation therapy,              
                                                                                                      metastatic                      
                                                                                                      malignant                       
                                                                                                      melanoma,                       
                                                                                                      chemotherapy                    

  2003-BP-10241BP   12          1308     73 M      4.8     103     TPV/r           No significant     Anemia, oral       Rectal       49.7
                                                                                   past medical       thrush, metastatic cancer       
                                                                                   history            rectal cancer      metastatic   

  2003-FF-00518FF   48          3305     45 M      4.9     14      TPV/r           Kaposi\'s sarcoma, Diarrhea,          Kaposi\'s    14.3
                                                                                   alcoholism,        epilepsy, anal     sarcoma      
                                                                                   myocardial         abscess, pulmonary              
                                                                                   infarction,        Kaposi sarcoma,                 
                                                                                   dyspnea, angioma   sepsis                          
  ----------------- ----------- -------- --------- ------- ------- --------------- ------------------ ------------------ ------------ ---------

Table 1 (continued) Summaries of Fatal Outcomes from RESIST trials
including CPI/r rollover patients to 1182.17 (Pg 4 of 9)

  ----------------- ----------- -------- --------- ------- ------- --------------- ------------------ ----------------------- ------------- ---------
  **Pt Case         **Trial**   **Pt**   **Age**   **Bsl   **Bsl   **Treatment**   **Medical          **Intercurrent /        **Cause of    **Death
  Number**                                         VL**    CD4**                   history**          Concurrent Illnesses**  death**       Week**

  2004-BP-02646BP   58          181      41 M      2.3     86      TPV/r           Liver lymphoma     Hypertriglyceridemia,   Sepsis        10.3
                                                                                                      DM, CNS lymphoma,                     
                                                                                                      sepsis due to lymphoma                
                                                                                                      chemotherapy                          

  2004-BP-04366BP   12          1441     43 M      5.4     3       TPV/r           PCP                PCP, atrial             Respiratory   47.9
                                                                                                      fibrillation, intubated distress      
                                                                                                      for respiratory                       
                                                                                                      distress,                             
                                                                                                      pneumomediastinum,                    
                                                                                                      progressive respiratory               
                                                                                                      failure                               

  2004-BP-01447BP   12          1550     55 M      3.8     318     TPV/r           Emphysema,         COPD                    Chronic       18.4
                                                                                   cholinergic                                obstructive   
                                                                                   urticaria                                  airways       
                                                                                   secondary to agent                         disease       
                                                                                   orange, right                                            
                                                                                   bundle branch                                            
                                                                                   block, atrial                                            
                                                                                   dilatation                                               

  2003-BP-06839BP   12          1647     42 M      5.5     18      TPV/r           Aspergillosis,     Kaposi's sarcoma,       Respiratory   15.6
                                                                                   anemia, HTN,       bilateral pneumonia,    failure       
                                                                                   cardiomyopathy,    renal failure, severe                 
                                                                                   CHF, CMV           respiratory                           
                                                                                   retinitis, wasting insufficiency                         

  2003-BP-08880BP   12          1878     44 M      5.7     5       TPV/r           Anemia, history of CVA, UTI, sepsis, neck  Myocardial    11.7
                                                                                   seizures, cardiac  mass, spinal cord       infarction    
                                                                                   arrhythmias, HTN,  compression, lymphoma,                
                                                                                   PCP, wasting       MI                                    

  2004-BP-06332BP   12          1886     42 M      4.8     58      TPV/r           Lactic acidosis,   Wasting, elevated       Cardiac death 51.3
                                                                                   nephrolithiasis,   creatinine, hematuria,                
                                                                                   wasting            HIV nephropathy,                      
                                                                                                      hyperbilirubinemia,                   
                                                                                                      weakness, difficulty                  
                                                                                                      walking, HTN ASHD,                    
                                                                                                      cardiomegaly,                         
                                                                                                      atherosclerosis,                      
                                                                                                      cortical infract of                   
                                                                                                      kidney                                
  ----------------- ----------- -------- --------- ------- ------- --------------- ------------------ ----------------------- ------------- ---------

Table 1 (continued) Summaries of Fatal Outcomes from RESIST trials
including CPI/r rollover patients to 1182.17 (Pg 5 of 9)

  ----------------- ----------- -------- --------- ------- ------- --------------- --------------- -------------------- --------------------- ---------
  **Pt Case         **Trial**   **Pt**   **Age**   **Bsl   **Bsl   **Treatment**   **Medical       **Intercurrent /     **Cause of death**    **Death
  Number**                                         VL**    CD4**                   history**       Concurrent                                 Week**
                                                                                                   Illnesses**                                

  2004-BP-03640BP   12          2052     43 M      4.9     34      TPV/r           Pancreatitis,   Renal insufficiency, Hepatorenal syndrome  38.4
                                                                                   hepatitis B,    hepatosplenomegaly                         
                                                                                   esophageal                                                 
                                                                                   candidiasis,                                               
                                                                                   anemia,                                                    
                                                                                   neuropathy,                                                
                                                                                   wasting                                                    

  2004-CN-00310CN   12          3083     39 M      4.8     254     TPV/r           Asthma,         Urosepsis treated    Urosepsis             62.6
                                                                                   pulmonary       with piperacillin                          
                                                                                   congestion      and tobramycin,                            
                                                                                                   Hodgkin\'s lymphoma                        

  2004-BP-07236BR   48          9030     42 M      5.5     28      TPV/r           PCP             Disorientation,      Respiratory failure   49.0
                                                                                                   renal insufficiency,                       
                                                                                                   lactic acidosis,                           
                                                                                                   respiratory                                
                                                                                                   infection                                  

  2004-BP-04500RA   48          1097     46 M      5.1     5       TPV/r           Toxoplasmosis   Patient found dead   Not reported          39.3
                                                                                                   at home                                    

  2004-BP-07623BP   12          2048     37 M      5.2     7       TPV/r           PCP             Parasite infection,  Not reported          52.6
                                                                                                   GERD, dehydration,                         
                                                                                                   hypotension, HIV                           
                                                                                                   encephalopathy,                            
                                                                                                   pneumonia,                                 
                                                                                                   progressive                                
                                                                                                   weakness, difficulty                       
                                                                                                   swallowing, slow                           
                                                                                                   slurred speech,                            
                                                                                                   worsening confusion,                       
                                                                                                   presumptive MAC,                           
                                                                                                   presumptive TB                             

  2003-FF-00378FF   48          3150     37 M      5.1     27      CPI/r           Injection drug  Anorexia, esophageal Progressive           8.7
                                                                                   user, anorexia, candidiasis, walking multifocal            
                                                                                   esophageal      disorders, upper     leukoencephalopathy   
                                                                                   candidiasis,    limbs tremor,                              
                                                                                   PCP             asthenia, insomnia,                        
                                                                                                   cerebellous                                
                                                                                                   syndrome, PML, HIV                         
                                                                                                   encephalopathy                             
  ----------------- ----------- -------- --------- ------- ------- --------------- --------------- -------------------- --------------------- ---------

Table 1 (continued) Summaries of Fatal Outcomes from RESIST trials
including CPI/r rollover patients to 1182.17 (Pg 6 of 9)

  ----------------- ----------- -------- --------- ------- ------- --------------- ----------------------- --------------------- --------------------- ---------
  **Pt Case         **Trial**   **Pt**   **Age**   **Bsl   **Bsl   **Treatment**   **Medical history**     **Intercurrent /      **Cause of death**    **Death
  Number**                                         VL**    CD4**                                           Concurrent                                  Week**
                                                                                                           Illnesses**                                 

  2004-FF-00058FF   48          3270     50 M      4.8     18      CPI/r           Hypertriglyceridemia,   Upper limb weakness,  Progressive           28.4
                                                                                   renal artery stenosis   speech disorders,     multifocal            
                                                                                   with renal              progressive           leukoencephalopathy   
                                                                                   insufficiency,          multifocal                                  
                                                                                   hypertension, non       Leukoencephalopathy                         
                                                                                   insulin dependent       (PML), left                                 
                                                                                   diabetes                hemiplegia,                                 
                                                                                                           consciousness                               
                                                                                                           disorders, neurologic                       
                                                                                                           disorders were                              
                                                                                                           related to                                  
                                                                                                           aggravation of PML                          

  2003-BP-02218AU   12          4073     44 M      5.1     150     CPI/r           CMV retinitis, MAI,     PML, severe ataxia,   Acquired              8.9
                                                                                   AIDS dementia,          end stage AIDS        immunodeficiency      
                                                                                   lipodystrophy,                                syndrome              
                                                                                   peripheral neuropathy                                               

  2004-BP-00677BP   12          2091     43 M      5.5     6       CPI/r           Candida esophagitis,    Anemia, pancytopenia, Pneumonia             24.7
                                                                                   CMV retinitis, PCP,     diarrhea, nausea and  cytomegaloviral       
                                                                                   wasting                 gastritis, rectal                           
                                                                                                           hemorrhage, CMV                             
                                                                                                           pneumonia                                   

  2003-BP-02067BP   12          1199     50 M      5.2     55      CPI/r           MAC                     Non-Hodgkin\'s        Lymphoma              6.6
                                                                                                           lymphoma,                                   
                                                                                                           radiculopathy,                              
                                                                                                           decreased level of                          
                                                                                                           consciousness and                           
                                                                                                           intelligible speech,                        
                                                                                                           multiple sites of                           
                                                                                                           presumed lymphoma,                          
                                                                                                           bone marrow lymphoma,                       
                                                                                                           anemia                                      

  2003-BP-07278BP   12          1219     42 F      5.5     26      CPI/r           No conditions which may Imbalance, headaches, Central nervous       20.9
                                                                                   be considered relevant  CNS lymphoma          system lymphoma       
                                                                                   to the fatal event.                                                 

  2003-BP-10433BP   12          2087     43 M      3.0     545     CPI/r           No past medical history Progressive central   Central nervous       24.6
                                                                                   has been reported       neurologic symptoms,  system lymphoma       
                                                                                                           brain lymphoma                              
  ----------------- ----------- -------- --------- ------- ------- --------------- ----------------------- --------------------- --------------------- ---------

Table 1 (continued) Summaries of Fatal Outcomes from RESIST trials
including CPI/r rollover patients to 1182.17 (Pg 7 of 9)

  ----------------- ----------- -------- --------- ------- ------- --------------- ---------------------- -------------------- -------------------- ---------
  **Pt Case         **Trial**   **Pt**   **Age**   **Bsl   **Bsl   **Treatment**   **Medical history**    **Intercurrent /     **Cause of death**   **Death
  Number**                                         VL**    CD4**                                          Concurrent                                Week**
                                                                                                          Illnesses**                               

  2003-DE-03239PO   48          2211     33 M      4.8     658     CPI/r           No relevant past       Burkitt\'s Lymphoma, Burkitt\'s lymphoma  6.6
                                                                                   medical history noted  renal insufficiency                       
                                                                                                          and edema to be                           
                                                                                                          caused by                                 
                                                                                                          chemotherapy                              

  2003-BP-10341AU   12          4006     57 M      3.2     725     CPI/r           Cryptosporidiosis      Bone marrow          Acute myeloid        62.3
                                                                                                          infiltration with    leukaemia            
                                                                                                          acute myeloblastic                        
                                                                                                          leukemia                                  

  2003-ES-00310ES   48.58       7135     52 M      3.7     234     CPI/r           No significant or      Neutropenic fever,   Acute lymphocytic    27.9
                                                                                   relevant past medical  acute lymphoblastic  leukaemia            
                                                                                   history reported       leukaemia                                 

  2003-FF-00246FF   48          3033     51 M      6.6     13      CPI/r           Kaposi\'s syndrome,    Fever, dry cough,    Cardio-respiratory   5.0
                                                                                   diffuse digestive      severe dyspnea and   arrest               
                                                                                   candidiasis, MAC       severe anemia,                            
                                                                                   pulmonary infection    diarrhea, suspected                       
                                                                                                          mycobacterium avium                       
                                                                                                          or tuberculosis,                          
                                                                                                          loss of                                   
                                                                                                          consciousness and                         
                                                                                                          hypercapnia,                              
                                                                                                          cardio-respiratory                        
                                                                                                          arrest for which                          
                                                                                                          cardiac massage was                       
                                                                                                          performed                                 
                                                                                                          unsuccessfully                            

  2003-UK-00670UK   48          8032     46 M      5.7     17      CPI/r           No significant         Suspected PCP, multi Ventricular          11.7
                                                                                   relevant past medical  organ failure        fibrillation         
                                                                                   history reported                                                 

  2004-BP-03614BR   48          9328     44 M      4.8     51      CPI/r           Diabetes, candidiasis, Lymphoma             Multi-organ failure  25.7
                                                                                   herpes,                                                          
                                                                                   hypertriglyceridemia                                             

  2003-BP-10569BP   12          2090     44 M      4.8     165     CPI/r           Candidiasis, COPD      Found dead at home   Death                15.6

  2004-BP-00736BP   17          121783   40 M      5.2     3       C to TPV/r      MAC infection, renal   Renal failure,       Disease progression  16.4
                                                                                   failure                anemia, hospice                           
                                                                                   amikacin-related                                                 
  ----------------- ----------- -------- --------- ------- ------- --------------- ---------------------- -------------------- -------------------- ---------

Table 1 (continued) Summaries of Fatal Outcomes from RESIST trials
including CPI/r rollover patients to 1182.17 (Pg 8 of 9)

  ----------------- ----------- -------- --------- ------- ------- --------------- ------------------- ------------------- ----------------- ---------
  **Pt Case         **Trial**   **Pt**   **Age**   **Bsl   **Bsl   **Treatment**   **Medical history** **Intercurrent /    **Cause of        **Death
  Number**                                         VL**    CD4**                                       Concurrent          death**           Week**
                                                                                                       Illnesses**                           

  2004-BP-01767BP   17          121888   48 M      5.1     4       C to TPV/r      No relevant past    Cryptosporidium     Failure to thrive 13.6
                                                                                   medical history     infection, hospice,                   
                                                                                   noted               chronic wasting                       
                                                                                                       syndrome                              

  2003-BP-10274BP   17          122062   59 M      5.1     74      C to TPV/r      Cardiomyopathy,     MI, congestive      Immune            8.3
                                                                                   atrial fibrillation heart failure,      reconstitution    
                                                                                                       pulmonary edema,    syndrome          
                                                                                                       hypersensitive                        
                                                                                                       autoimmune reaction                   
                                                                                                       to HIV medications                    

  2003-BP-06681BP   17          121093   46 M      5.2     12      C to TPV/r      No relevant past    Septic shock,       Septic shock      9.3
                                                                                   medical history     pneumococcal                          
                                                                                   noted               bacteremia                            

  2004-BP-02871BP   17          121262   58 M      6.0     3       C to TPV/r      No relevant past    Aspergillus         Aspergillosis     46.3
                                                                                   medical history     infection,                            
                                                                                   noted               dehydration, lung                     
                                                                                                       abscess, anemia                       

  2004-BP-05859BP   17          121476   43 M      6.3     1       C to TPV/r      No relevant past    HIV encephalopathy, Pneumonia         31.9
                                                                                   medical history     dementia, hospice                     
                                                                                   noted                                                     

  2004-BP-07134BP   17          121479   48 M      5.2     7       C to TPV/r      No relevant past    Candida             Febrile           44.4
                                                                                   medical history     esophagitis, CMV    neutropenia       
                                                                                   noted               retinitis,                            
                                                                                                       neutropenia,                          
                                                                                                       thrombocytopenia,                     
                                                                                                       severe febrile                        
                                                                                                       illness,                              
                                                                                                       splenomegaly,                         
                                                                                                       pulmonary                             
                                                                                                       infiltrates, AIDS                     

  2004-DE-00489GB   17          485007   40 M      2.0     8       C to TPV/r      No relevant past    Esophagitis,        Encephalitis      27.0
                                                                                   medical history     cachexia, herpes    herpes            
                                                                                   noted               encephalitis,                         
                                                                                                       wasting,                              

  2003-DE-03806DE   58          None     57 M                      C to TPV/r      Intestinal          Diarrhea, vomiting, Gastroenteritis   
                                                                                   cryptosporidiosis   non-specified drug  cryptosporidial   
                                                                                                       allergy                               

  2004-BP-00114BP   17          121025   39 M      4.7     69      C to TPV/r      AIDS, wasting,      Herpes zoster,      Hepatic failure   20.7
                                                                                   Cryptococcus,       cachexia, abdominal                   
                                                                                   steatohepatitis,    tenderness,                           
                                                                                   MAC                 dysarthria,                           
                                                                                                       arthralgias,                          
                                                                                                       myalgias, liver                       
                                                                                                       failure, multiple                     
                                                                                                       organ failure                         
  ----------------- ----------- -------- --------- ------- ------- --------------- ------------------- ------------------- ----------------- ---------

Table 1 (continued) Summaries of Fatal Outcomes from RESIST trials
including CPI/r rollover patients to 1182.17 (Pg 9 of 9)

  ----------------- ----------- -------- --------- ------- ------- --------------- -------------------- --------------------- ----------------- ---------
  **Pt Case         **Trial**   **Pt**   **Age**   **Bsl   **Bsl   **Treatment**   **Medical history**  **Intercurrent /      **Cause of        **Death
  Number**                                         VL**    CD4**                                        Concurrent            death**           Week**
                                                                                                        Illnesses**                             

  2003-BP-04672BP   17          121244   39 M      4.8     6       C to TPV/r      Cryptosporidiosis,   Colitis, hypovolemia, Renal failure     18.7
                                                                                   Kaposi's\' sarcoma   renal impairment,     acute             
                                                                                                        wasting,                                
                                                                                                        cryptosporidiosis,                      
                                                                                                        acute renal                             
                                                                                                        insufficiency,                          
                                                                                                        metabolic acidosis,                     
                                                                                                        volume depletion,                       
                                                                                                        staphylococcus                          
                                                                                                        aureus, resulting in                    
                                                                                                        bacteremia, worsening                   
                                                                                                        renal failure                           
                                                                                                        secondary to                            
                                                                                                        vancomycin , septic                     
                                                                                                        shock                                   

  2003-BP-07277BP   17          121543   40 M      4.4     253     C to TPV/r      Kaposi\'s, anemia    Splenomegaly,         Cardiopulmonary   1.0
                                                                                                        cardiopulmonary       failure           
                                                                                                        failure, lymphoma,                      
                                                                                                        AIDS                                    

  2004-NL-00039NL   17          482017   62 M      1.4     146     C to TPV/r      Lung cancer          Fatigue, liver        Liver scan        21.1
                                                                                                        metastases, anorexia, abnormal          
                                                                                                        weight loss                             

  2004-IT-00012IT   17          486039   40 M      2.3     16      C to TPV/r      Mycobacteriosis      Pneumonia,            Cardiac arrest    21.7
                                                                                   infection,           cardio-circulatory                      
                                                                                   pneumonia, CMV,      arrest                                  
                                                                                   retinitis, chronic                                           
                                                                                   hepatitis, DM                                                

  2004-BP-04244BR   17          489318   41 M      5.4     27      C to TPV/r      Mycobacterium        Aspiration pneumonia, Respiratory       
                                                                                   infection            neurotoxoplasmosis,   failure           
                                                                                                        headache, vomiting,                     
                                                                                                        mental confusion,                       
                                                                                                        psychomotor agitation                   
  ----------------- ----------- -------- --------- ------- ------- --------------- -------------------- --------------------- ----------------- ---------

[^1]: RESIST: **R**andomized **E**valuation of **S**trategic
    **I**ntervention in multi-drug re**S**istant patients with
    **T**ipranavir; Two randomized, controlled trials with RESIST-1
    conducted at North American and Australian sites and RESIST-2
    conducted in European and Latin American sites.

[^2]: Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten
    GA, Aschman DJ, Holmberg SD, HIV Outpatient Study Investigators.
    Declining morbidity and mortality among patients with advanced human
    immunodeficiency virus infection. N Engl J Med 1998;338(13):853-860.

[^3]: Richman DD, Morton SC, Wrin T, Hellmann N, Berry S, Shapiro MF,
    Bozzette SA. The prevalence of antiretroviral drug resistance in the
    United States. AIDS (Phila) 2004;18(10):1393-1401.

[^4]: Larder BA, Hertogs K, Bloor S, Eyne C van den, DeCian W, Yenyun W,
    et al. Tipranavir inhibits broadly protease inhibitor-resistant
    HIV-1 clinical samples. AIDS (Phila) 2000;14(13):1943-48.

[^5]: Bartlett JA. Addressing the challenges of Adherence. J Acq Immune
    Defic Syndr 2002; 29(Suppl 1):S2-S10.

[^6]: This date represents the cut-off for the Safety Update, for which
    comprehensive data have been collected and analyzed.

[^7]: Baxter JD, Mayers DL, Wentworth DN, Neaton JD, Hoover ML, Winters
    MA, Mannheimer SB, Thompson MA, Abrams DI, Brizz BJ, Ioannidis JPA,
    Merigan TC, CPCRA 046 Study Team for the Terry Beirn Community
    Programs for Clinical Research on AIDS. A randomized study of
    antiretroviral management based on plasma genotypic antiretroviral
    resistance testing in patients failing therapy. AIDS (Phila) 2000;
    14(9):F83‑F93.

[^8]: Larder BA, Hertogs K, Bloor S, Eyne C van den, DeCian W, Yenyun W,
    Freimuth WW, Tarpley G. Tipranavir inhibits broadly PI-resistant
    HIV-1 clinical samples. AIDS (Phila) 2000;14(13):1943-1948

[^9]: The 33 mutation was not included in the eligibility criteria for
    BI 1182.52. It was added to the list to determine eligibility for
    the RESIST studies after being found to be heavily selected both *in
    vitro* and in clinical HIV-1 isolates from patients failing TPV/r in
    other Phase II clinical studies.

[^10]: The results of the sensitivity analyses performed are shown in
    Section 6.3.3. These analyses demonstrate that the trial design
    issues did not affect the primary endpoint efficacy analyses.

[^11]: The panel had two main objectives; to ensure that the most
    susceptible CPI on the resistance report was pre-selected by
    investigators, and to assist investigators in their individual
    patient drug selections. It was mandatory for investigators to
    consult the panel if they wished to deviate from the "best choice"
    on the genotype report provided. Investigators could also seek an
    optional consult to assist in individual patient drug selection;
    overall, the resistance expert panel was consulted by investigators
    in approximately 34% of patient cases.

[^12]: Amendment #2 was implemented prior to any patient randomizations
    in response to numerous investigator requests. Without this
    amendment, many of the patients screened for the studies would not
    have been eligible and study completion would have been very slow.

[^13]: Due to Amendment #2, the initially planned non-inferiority
    comparison of TPV/r and CPI/r in the statistical analysis plan with
    sequential testing for superiority was deemed inappropriate and
    demonstration of TPV/r superiority was considered essential to
    establish the efficacy of TPV/r.

[^14]: The combination of APV and TPV/r was associated with an increased
    rate of Grade 3 or 4 ALT/AST elevations.

[^15]: Fluconazole dosage increases to above 200 mg QD should be
    carefully monitored.

[^16]: Studies between TPV/r and these alternative lipid-lowering agents
    have not been conducted, but would not be expected to be
    substantially increased.

[^17]: While the entry criteria for BI 1182.52 permitted only two
    mutations, some patients with three mutations were entered into the
    study due to mutations at protease codon 33 or at 82 other than L or
    T.

[^18]: Patients in the CPI/r arms of the RESIST studies were permitted
    to discontinue and receive TPV/r in BI 1182.17 only if objectively
    confirmed virologic failure occurred. Since AEs may be considered
    'subjective,' RESIST CPI/r patients could not rollover in BI 1182.17
    if discontinuation was exclusively due to AEs.

[^19]: From the TruGene report, viral isolates were "genotypically
    available" if they were listed as "no evidence of resistance," or
    "possible resistance." From the Virtual Phenotype report, viral
    isolates were "genotypically available" if they were listed as
    "within normal susceptible range or resistance unlikely."

[^20]: Relevant protocol deviations were determined by the individual
    trial teams prior to the unblinding of data and were those that may
    have potentially affected the primary or secondary endpoint results.

[^21]: FAS is the 'full analysis set' for all patients who were
    randomized and received at least one dose of treatment. PPS is the
    'per-protocol set' where patients with relevant protocol deviations
    have been omitted.

[^22]: Larder BA, Hertogs K, Bloor S, Eyne C van den, DeCian W, Yenyun
    W, et al. Tipranavir inhibits broadly protease inhibitor-resistant
    HIV-1 clinical samples. AIDS (Phila) 2000;14(13):1943-48.

[^23]: The PLATO Collaboration. Predictors of trend in CD4-positive T
    cell counts and mortality among HIV-1 infected individuals with
    virological failure to all three antiretroviral-drug classes. Lance
    2004;364:51-62.

[^24]: In the Safety Update, a total of 298 patients who failed
    virologically on CPI/r of the RESIST trials entered BI Trial
    1182.17.