**MEMORANDUM**

DATE: April 14, 2003

TO: Advisory Committee Members and Guests

FROM: Atazanavir Review Team

THROUGH: Debra Birnkrant, M.D.

Division Director

Division of Antiviral Drug Products

SUBJECT: Background Package for NDA 21-567: atazanavir sulfate

I.  **Summary of Regulatory Issues and Purpose of Meeting**

This document provides background information for the May 13, 2003,
Antiviral Drugs Advisory committee meeting on atazanavir sulfate. On
this day, the committee will be asked to consider efficacy and safety
data submitted to support the approval of atazanavir for the treatment
of HIV infection.

The FDA analyses of the safety and efficacy data submitted in the NDA
support the applicant's findings. Phase 2 and 3 trials submitted in
support of this NDA provide evidence that the antiviral activity of
atazanavir is similar to nelfinavir or efavirenz in combination with two
NRTIs in treatment-naïve patients. In a registrational study of
treatment-experienced subjects, atazanavir was inferior to
lopinavir/ritonavir both in terms of viral load reduction and percentage
of patients with viral load below limits of quantification; however,
multiple analyses performed by FDA and the applicant support that
atazanavir has antiviral activity in this population.

Highly treatment-experienced subjects having failed at least two
regimens containing drugs from all three classes were enrolled in study
045. A ritonavir-boosted dose of atazanavir, and atazanavir given in
combination with saquinavir were compared to lopinavir/ritonavir, each
with tenofovir and an NRTI. Preliminary results support the similarity
of the ritonavir-boosted dose of atazanavir to lopinavir/ritonavir,
while the ATV/SQV arm appears to be inferior. These data are preliminary
and efficacy data from this trial will not be used to make a regulatory
decision on this NDA.

The Division is convening this meeting to solicit the committee's
comments on the breadth of the proposed treatment indication, and the
risk-benefit analysis of the use of atazanavir as it relates to the
following safety issues: 1) the incidence and degree of
hyperbilirubinemia seen in clinical trials, 2) prolongation of the QT
and PR interval, and 3) lipid profiles observed in atazanavir subjects
as compared to efavirenz and selected protease inhibitors. Given the
diversity of these issues, we have invited several committee guests with
expertise in fields relating to these safety issues.

The applicant is proposing a broad indication for the treatment of HIV
infection based on the results of the two registrational trials. While
atazanavir was comparable to currently marketed ARV medications in
treatment-naïve studies, it appeared inferior to lopinavir/ritonavir in
treatment-experienced patients. We would like to hear comments from the
committee regarding the proposed treatment indication for atazanavir.

With regard to safety issues, three areas of concern emerged during the
atazanavir development program. The first is the frequency of
hyperbilirubinemia seen in atazanavir-treated subjects; this adverse
event is dose dependent and appears to be due to inhibition of
UDP-glucuronosyl transferase, an enzyme responsible for the conjugation
of bilirubin. Over three-fourths of all patients experienced an
elevation of bilirubin while on treatment, and approximately five
percent of patients experienced grade 4 (five x upper limit of normal)
increases requiring dose modification per study protocols. Treatment
discontinuations for jaundice and/or scleral icterus were uncommon
despite a 15% incidence of these events.

The hyperbilirubinemia observed in atazanavir-treated subjects was
predominantly indirect, regardless of the degree of hyperbilirubinemia
observed. Significant elevations of direct bilirubin appeared to occur
predominantly in association with other indices of hepatic injury or
inflammation. Discontinuations due to abnormal LFTs or hepatotoxicity
(lactic acidosis syndrome/symptomatic hyperlactatemia \[LAS/SHL\] cases
were examined separately) appeared to occur with similar frequency
between atazanavir and comparator regimens.

In two phase 2 studies that compared atazanavir to nelfinavir, each with
identical NRTI background therapy, the frequency of all grades of
transaminase abnormalities was higher in atazanavir arms. The incidence
of grade 3-4 transaminase elevations was higher in atazanavir arms in
one of these studies, but lower in atazanavir arms in the second study.

In registrational study 034 which compared atazanavir to efavirenz in
treatment-naïve patients, the incidence of all grades of transaminase
abnormalities was similar between treatment arms. In registrational
study 043 of treatment-experienced patients, atazanavir subjects
experienced more grade 3-4 LFT abnormalities than lopinavir/ritonavir
subjects. Although there was an imbalance in hepatitis B or C
co-infection between treatment arms (ATV 20%, LPV/RTV 12%), this did not
explain the differences. Slight differences in background NRTI therapy
also existed in this study, with use of ddI and d4T being slightly more
common in atazanavir subjects.

In summary, the hyperbilirubinemia seen during the development program
of atazanavir did not appear to result in an increased incidence of
hepatotoxicity relative to selected PIs or to efavirenz. During the
meeting we will be seeking your assessment of the clinical data with
regard to hyperbilirubinemia and the risk of hepatotoxicity associated
with atazanavir use. We would like your general impression of the
clinical implications of these data and your recommendations for
additional preclinical or clinical studies to address the potential for
hepatotoxicity.

The second safety issue relates to effects of atazanavir on the QT and
PR interval. Effects of drugs on the QT interval have become an
increasing focus of the FDA; QT prolongation and the subsequent
development of Torsades de Pointes (TdP) have been one of the most
common reasons for drug withdrawal in recent years. While the
risk-benefit analysis of taking an antiretroviral medication versus the
possibility of developing an extremely rare but potentially
life-threatening arrhythmia may appear to be clear-cut, the Division
believes that we have moved into management of HIV infection as a
chronic disease. As such, all risks associated with medication use
should be well delineated.

Evaluation of the QT interval includes "correction" of the QT interval
for heart rate, as the QT interval decreases with increasing heart rate.
In this document, corrected QT intervals (QTc) were derived using a
correction formula known as Bazett's; this has been the correction
method historically used by the FDA and the one on which criteria for
evaluation of the QT interval have been based. Evaluation of the QT
interval is a specialized and evolving field and will not be discussed
at length in this document; further information will be provided at the
Advisory Committee meeting with the goal of allowing attendees to
participate in a discussion of the QT effects of atazanavir.

In brief, a placebo-controlled pharmacokinetic study designed to
evaluate effects of atazanavir on ECG parameters revealed a
dose-dependent prolongation of the QT interval. Prolongation that may be
considered a signal for increased risk for development of TdP was seen
at a dose of 800 mg given once daily. This dose produced an exposure
that is three-fold greater than that seen with the proposed dose of 400
mg. The ritonavir boosted dose of atazanavir 300 mg that is being
investigated for use in treatment-experienced patients has not been
fully evaluated in a placebo-controlled pharmacokinetic study, but data
suggest that this dose may also be associated with prolongation of the
QT interval.

In order to further evaluate cardiac risks, ECGs were collected from
five clinical trials. Use of atazanavir did not appear to result in an
increased incidence of QTc interval prolongation relative to
comparators. There were no clinical events of sudden death, or report of
arrhythmias that appeared to be related to prolongation of the QT
interval; however, these types of clinical events are rare, and likely
would not be seen in clinical trials of the size seen in this
application.

During evaluation of the effects of atazanavir on the QT interval it was
also found that atazanavir produced dose-dependent prolongation of the
PR interval. The incidence of first degree AV block was common and
occurred in over 50% of subjects receiving 800 mg of atazanavir.

In clinical trials of atazanavir first degree AV block was observed with
similar frequency in atazanavir subjects versus PI comparators. First
degree AV block appeared to be less common in subjects receiving
efavirenz. In study 034 bundle branch block was reported in one ATV
subject and one EFV subject. In the expanded access protocol a patient
taking atazanavir concomitantly with verapamil, delavirdine, and other
medications, was hospitalized with angina and a junctional rhythm.

In summary, while pharmacokinetic studies revealed moderate effects of
atazanavir on the PR interval, clinical events related to prolongation
of the PR interval were rare. First degree AV block was the most common
abnormality observed. Effects on the QT interval at the proposed dose
appeared to be minimal. We will be seeking comments from the Advisory
Committee on the risk-benefit analysis of the use of atazanavir with
regard to these issues.

The final safety issue relates to lipid metabolism. It was noted during
phase 2 studies of treatment-naïve subjects that treatment with
nelfinavir resulted in greater increases in lipid parameters relative to
atazanavir. These studies were not designed specifically to measure
these changes; however, this finding was confirmed in phase 3 studies of
both treatment-naïve and treatment-experienced patients.

The applicant analyzed lipid data from all studies in multiple ways.
Mean changes from baseline were calculated and categorical analyses were
performed using NCEP guidelines to define categories of lipid elevation.
Data regarding initiation of lipid-lowering agents during studies were
recorded. Calculations were made using Last Observation Carried Forward
(LOCF) for subjects initiating lipid lowering therapy during the trial
and sensitivity analyses were performed without using LOCF.

In general, atazanavir produced less change in total cholesterol,
fasting LDL, and triglycerides than all comparators; these differences
were found to be statistically significant. Atazanavir subjects
initiated lipid lowering therapy less frequently than patients on
comparator regimens. After 72 weeks of nelfinavir therapy, lipid levels
of subjects who switched from nelfinavir to atazanavir returned to
pretreatment levels.

Two concerns have emerged with regard to lipid parameters. The first is
whether this finding will be maintained over longer durations of therapy
and across multiple treatment regimens. In study 043 fasting
triglycerides did not appear to decrease significantly in the atazanavir
treatment arm to what may be considered pre-treatment (or treatment
naive) levels. This may suggest that other factors in addition to
protease inhibitor use may contribute to hypertriglyceridemia. The other
concern is whether this apparent lack of effect on lipid parameters will
translate into health benefits for patients in terms of a lower
incidence of lipodystrophy and cardiovascular disease. Spontaneous
reporting of lipodystrophy events in these clinical trials does not
suggest a reduction of these events in subjects taking atazanavir.

We will be seeking the committee's comments on this potential treatment
advantage of atazanavir.

## II. Clinical Development Summary

This NDA contains clinical data collected primarily from nine clinical
studies, including the two registrational studies, AI424034 (034) and
AI424043 (043). Study 034 was an international, multi-center,
double-blind, randomized, placebo-controlled trial comparing atazanavir
to efavirenz, each given with AZT/3TC, in treatment-naïve HIV-infected
subjects. Study 043 was an international, multi-center, randomized,
open-label trial comparing atazanavir to lopinavir/ritonavir, each with
an optimized NRTI background, in HIV-infected subjects who had failed a
PI-containing regimen.

Several supportive studies were also submitted, including studies
AI424007 (007) and AI424008 (008), two dose-finding studies comparing
atazanavir to nelfinavir. Studies AI434041 (041) and AI424044 (044) were
rollover studies for the dose-finding studies and were designed to
collect long-term safety data. Also notable is study AI424045 (045), a
multi-center, randomized open-label trial comparing a ritonavir-boosted
dose of atazanavir, and atazanavir given in combination with saquinavir,
to lopinavir/ritonavir, each with tenofovir and an NRTI, in highly
treatment-experienced HIV-infected subjects who had failed at least two
regimens containing ARV medications from all three classes.

Other trials include a PACTG pediatric protocol (020), an expanded
access protocol (900), and a small phase 2 trial of
treatment-experienced patients (009).

Summaries of these trials are provided in the table presented on the
following page:

## Summary of Clinical Trials

+----+--------+--------+---------+---------+------+---------+--------+
| S  | Design | Re     | Com     | Bac     | \#   | Pt      | En     |
| tu |        | gimens | parator | kground |      | Pop     | dpoint |
| dy |        |        |         |         | Enro | ulation |        |
|    |        | (mg)   | (mg)    |         | lled |         |        |
+----+--------+--------+---------+---------+------+---------+--------+
| 0  | Rand   | ATV    | Nel     | ddI/d4T | 420  | Tr      | TAD\*  |
| 07 | omized | 200    | finavir |         |      | eatment | in     |
|    | B      |        |         |         |      | naive   | log10  |
|    | linded | 400    | 750 tid |         |      |         | HIV    |
|    | to ATV |        |         |         |      |         | RNA    |
|    | dose   | 500    |         |         |      |         | from   |
|    |        |        |         |         |      |         | B/L    |
+----+--------+--------+---------+---------+------+---------+--------+
| 0  | Rand   | ATV    | Nel     | d4T/3TC | 467  | Tr      | TAD    |
| 08 | omized | 400    | finavir |         |      | eatment |        |
|    |        |        |         |         |      | naive   |        |
|    | B      | 600    | 1250    |         |      |         |        |
|    | linded |        | bid     |         |      |         |        |
|    | to ATV |        |         |         |      |         |        |
|    | dose   |        |         |         |      |         |        |
+----+--------+--------+---------+---------+------+---------+--------+
| 0  | Rand   | ATV    | RTV 400 | Op      | 85   | Tr      | TAD    |
| 09 | omized | 400    |         | timized |      | eatment |        |
|    |        |        | SQV 400 | bac     |      |         |        |
|    |        | SQV    |         | kground |      | expe    |        |
|    |        | 1200   |         |         |      | rienced |        |
|    |        |        |         |         |      |         |        |
|    |        | ATV    |         |         |      |         |        |
|    |        | 600    |         |         |      |         |        |
|    |        |        |         |         |      |         |        |
|    |        | SQV    |         |         |      |         |        |
|    |        | 1200   |         |         |      |         |        |
+----+--------+--------+---------+---------+------+---------+--------+
| 0  | Ro     | ATV    | NFV 750 | Bac     | 222  | S       | Coll   |
| 41 | llover | 400    | tid     | kground |      | ubjects | ection |
|    | study  |        |         | therapy |      | com     | of     |
|    | for    |        |         | r       |      | pleting | lon    |
|    | 007    |        |         | eceived |      | 007 and | g-term |
|    | and    |        |         | in      |      | 009     | safety |
|    | 009 to |        |         | p       |      |         | data   |
|    | c      |        |         | revious |      |         |        |
|    | ollect |        |         | trial   |      |         |        |
|    | lon    |        |         |         |      |         |        |
|    | g-term |        |         |         |      |         |        |
|    | safety |        |         |         |      |         |        |
|    | data   |        |         |         |      |         |        |
+----+--------+--------+---------+---------+------+---------+--------+
| 0  | Ro     | ATV    | P       | Bac     | 346  | S       | Coll   |
| 44 | llover | 400    | atients | kground |      | ubjects | ection |
|    | study  |        | re      | therapy |      | com     | of     |
|    | for    |        | ceiving | r       |      | pleting | lon    |
|    | 008 to |        | NFV in  | eceived |      | study   | g-term |
|    | c      |        | 008     | in      |      | 008     | safety |
|    | ollect |        | s       | p       |      |         | data   |
|    | addi   |        | witched | revious |      |         |        |
|    | tional |        | to ATV  | study   |      |         |        |
|    | safety |        | to      |         |      |         |        |
|    | data   |        | assess  |         |      |         |        |
|    |        |        | lipids  |         |      |         |        |
+----+--------+--------+---------+---------+------+---------+--------+
| 0  | Rand   | ATV    | EFV 600 | AZT/3TC | 810  | Tr      | P      |
| 34 | omized | 400    | mg      |         |      | eatment | ercent |
|    |        |        |         |         |      |         | BLQ    |
|    | Double |        |         |         |      | naïve   |        |
|    | -blind |        |         |         |      |         |        |
|    |        |        |         |         |      |         |        |
|    | P      |        |         |         |      |         |        |
|    | lacebo |        |         |         |      |         |        |
|    | cont   |        |         |         |      |         |        |
|    | rolled |        |         |         |      |         |        |
+----+--------+--------+---------+---------+------+---------+--------+
| 0  | Rand   | ATV    | LPV/RTV | Op      | 300  | P       | TAD    |
| 43 | omized | 400    |         | timized |      | atients |        |
|    |        |        |         | bac     |      | who     |        |
|    | Open   |        |         | kground |      | failed  |        |
|    | -label |        |         | of 2    |      | a PI    |        |
|    |        |        |         | NRTIs   |      | regimen |        |
+----+--------+--------+---------+---------+------+---------+--------+
| 0  | Rand   | ATV    | LPV/RTV | Te      | 358  | Highly  | TAD    |
| 45 | omized | 300    |         | nofovir |      | tr      |        |
|    |        | RTV    |         | and 1   |      | eatment |        |
|    | Open   | 100    |         | NRTI    |      | expe    |        |
|    | -label |        |         | based   |      | rienced |        |
|    |        | ATV    |         | on      |      | p       |        |
|    |        | 400    |         | results |      | atients |        |
|    |        |        |         | of      |      | having  |        |
|    |        | SQV    |         | phe     |      | failed  |        |
|    |        | 1200   |         | notypic |      | drugs   |        |
|    |        |        |         | testing |      | in all  |        |
|    |        |        |         |         |      | three   |        |
|    |        |        |         |         |      | classes |        |
+----+--------+--------+---------+---------+------+---------+--------+
| 9  | Ex     | ATV    | None    | Based   |      | Open    | None   |
| 00 | panded | 400    |         | on      |      | enr     |        |
|    | Access |        |         | ph      |      | ollment |        |
|    | Pr     | ATV    |         | ysician |      |         |        |
|    | otocol | 300    |         | choice  |      |         |        |
|    |        |        |         |         |      |         |        |
|    |        | RTV    |         |         |      |         |        |
|    |        | 100    |         |         |      |         |        |
+----+--------+--------+---------+---------+------+---------+--------+
| 0  | Ped    | ATV    | None    | Based   | 43   | Age 3   | PK/PD  |
| 20 | iatric | dose   |         | on MD   |      | mo to   | and    |
|    |        | r      |         | choice  |      | 21      | safety |
|    |        | anging |         |         |      | years   |        |
+----+--------+--------+---------+---------+------+---------+--------+

\*TAD -- Time-averaged difference from baseline

III. **Summary of Efficacy**

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A.  **Dose Selection**

A dose of 400 mg was chosen based on results from phase 2 dose-ranging
studies 007 and 008. No significant differences in efficacy were seen
after 48 weeks of treatment with 200 mg, 400 mg, 500 mg, and 600 mg
doses of atazanavir; however, an initial two-week monotherapy treatment
phase with atazanavir showed that doses of 400 mg or greater had higher
probabilities of producing a 1.5 log~10~ reduction from baseline. The
choice of 400 mg provided a balance between efficacy and the incidence
of hyperbilirubinemia.

B.  **Study Design and Baseline Demographics for Registrational Trials**

As mentioned previously, study 034 was an international, multi-center,
double-blind, randomized, placebo-controlled trial comparing atazanavir
to efavirenz, each given with AZT/3TC, in treatment-naïve HIV-infected
subjects. Study 043 was an international, multi-center, randomized,
open-label trial comparing atazanavir to lopinavir/ritonavir, each with
an optimized NRTI background, in HIV-infected subjects who had failed a
PI containing regimen.

Baseline characteristics of subjects enrolled in these studies are
summarized on the following page.

**Baseline Characteristics: Studies 034 and 043**

+---------------------------+-----------------+------------------------+
|                           | **Study 034**   | **Study 043**          |
+---------------------------+-----------------+------------------------+
| **\# of Subjects          | 810             | 300                    |
| Randomized**              |                 |                        |
+---------------------------+-----------------+------------------------+
| **\# of Subjects          | 805             | 290                    |
| Treated**                 |                 |                        |
+---------------------------+-----------------+------------------------+
| **Age (Years)**           | 34              | 38                     |
|                           |                 |                        |
| **Mean**                  | 33              | 37                     |
|                           |                 |                        |
| **Median**                | 18, 73          | 20, 65                 |
|                           |                 |                        |
| **Range**                 |                 |                        |
+---------------------------+-----------------+------------------------+
| **Sex (%)**               | 65              | 79                     |
|                           |                 |                        |
| **Male**                  | 35              | 21                     |
|                           |                 |                        |
| **Female**                |                 |                        |
+---------------------------+-----------------+------------------------+
| **Race (%)**              | 33              | 41                     |
|                           |                 |                        |
| **Caucasian**             | 37              | 52                     |
|                           |                 |                        |
| **Hispanic**              | 13              | 7                      |
|                           |                 |                        |
| **Black**                 | 17              | \<1                    |
|                           |                 |                        |
| **Asian/Other**           |                 |                        |
+---------------------------+-----------------+------------------------+
| **CD4 Cell Count          | 322             | 320                    |
| (cells/mm^3^)**           |                 |                        |
|                           | 282             | 268                    |
| **Mean**                  |                 |                        |
|                           |                 |                        |
| **Median**                |                 |                        |
+---------------------------+-----------------+------------------------+
| **HIV RNA**               | 4.84            | 4.14                   |
|                           |                 |                        |
| **(log~10~ copies/mL)**   | 4.88            | 4.19                   |
|                           |                 |                        |
| **Mean**                  | 58              | 83                     |
|                           |                 |                        |
| **Median**                | 42              | 17                     |
|                           |                 |                        |
| **N \< 100,000 (%)**      |                 |                        |
|                           |                 |                        |
| **N 100,000 (%)**         |                 |                        |
+---------------------------+-----------------+------------------------+
| **Mean Time on Prior      | N/A             | 144 (100% of subjects) |
| Antiretroviral Therapy**  |                 |                        |
|                           |                 | 184 (100% of subjects) |
| **(weeks)**               |                 |                        |
|                           |                 | 94 (14% of subjects)   |
| **PIs**                   |                 |                        |
|                           |                 |                        |
| **NRTIs**                 |                 |                        |
|                           |                 |                        |
| **NNRTIs**                |                 |                        |
+---------------------------+-----------------+------------------------+

C.  **Primary Efficacy Endpoints**

The primary efficacy endpoint in study 034 was percentage of patients
with HIV RNA levels below the limit of quantification of 400 copies/mL
at 48 weeks. The primary efficacy endpoint for study 043 was the
magnitude of viral suppression as assessed by the change from baseline
in plasma HIV RNA levels (expressed in log10) through 24 weeks. Multiple
secondary analyses were performed for each study.

D.  **HIV RNA Results**

The following two tables summarize efficacy results for selected trials.
The first table provides efficacy results for atazanavir 400 mg in
studies 007, 008, and 034. In these studies, atazanavir was similar to
efavirenz and nelfinavir in a Time to Loss of Virologic Response (TLOVR)
analysis using both 400 copies/mL and 50 copies/mL as limits of
detection.

At 24 weeks in study 043, subjects receiving atazanavir had a mean
decrease of 1.73 log10 c/mL as compared to a mean decrease of 2.16 log10
copies/mL for lopinavir/ritonavir patients. The time-averaged difference
(TAD) estimate (ATV - LPV/RTV) for the change from baseline in HIV RNA
level through 24 weeks was 0.31 log10 c/mL (97.5% CI: 0.06, 0.55),
favoring lopinavir/ritonavir.

Preliminary efficacy results at 16 weeks of a limited number of enrolled
subjects in study 045 were provided in this NDA. A ritonavir-boosted
dose of atazanavir 300 mg appeared to be similar to LPV/RTV, each given
with tenofovir and an optimized NRTI. Atazanavir given in combination
with saquinavir appeared to be inferior.

## Time to Loss of Virologic Response (TLOVR)

The TLOVR analysis is an intent-to-treat analysis that examines
endpoints using the following definitions of treatment failure for
patients who have achieved HIV RNA levels below the limit of
quantification:

For all subjects with confirmed HIV RNA levels below an assay limit, the
time to failure is the earliest time when a specific event had occurred.
These events are

-   Death

-   Permanent discontinuation of the study drug or loss to follow-up

-   Introduction of a new ARV drug (unless a background drug is changed
    for reasons of toxicity or intolerance that are clearly attributable
    to that drug)

-   Confirmed HIV RNA levels above or equal to an assay

## 

## 

## Summary of Efficacy Treatment-Naïve Studies

Time to Loss of Virologic Response (TLOVR)

+----------+---+---------+---------+--------+--------+---------+---------+
|          | * |         |         | *      |        | **Study |         |
|          | * |         |         | *Study |        | 008**   |         |
|          | S |         |         | 007**  |        |         |         |
|          | t |         |         |        |        |         |         |
|          | u |         |         |        |        |         |         |
|          | d |         |         |        |        |         |         |
|          | y |         |         |        |        |         |         |
|          | 0 |         |         |        |        |         |         |
|          | 3 |         |         |        |        |         |         |
|          | 4 |         |         |        |        |         |         |
|          | * |         |         |        |        |         |         |
|          | * |         |         |        |        |         |         |
+----------+---+---------+---------+--------+--------+---------+---------+
| ###      | * |         | **EFV** | *      | *      | **ATV** | **NLF** |
|  HIV RNA | * |         |         | *ATV** | *NLF** |         |         |
|          | A |         | **AZ    |        |        | **d4    | **d4    |
|          | T |         | T/3TC** | **ddI  | **ddI  | T/3TC** | T/3TC** |
|          | V |         |         | /d4T** | /d4T** |         |         |
|          | * |         |         |        |        |         |         |
|          | * |         |         |        |        |         |         |
|          |   |         |         |        |        |         |         |
|          | * |         |         |        |        |         |         |
|          | * |         |         |        |        |         |         |
|          | A |         |         |        |        |         |         |
|          | Z |         |         |        |        |         |         |
|          | T |         |         |        |        |         |         |
|          | / |         |         |        |        |         |         |
|          | 3 |         |         |        |        |         |         |
|          | T |         |         |        |        |         |         |
|          | C |         |         |        |        |         |         |
|          | * |         |         |        |        |         |         |
|          | * |         |         |        |        |         |         |
+----------+---+---------+---------+--------+--------+---------+---------+
|          |   | Number  |         |        |        |         |         |
|          |   | of      |         |        |        |         |         |
|          |   | Subject |         |        |        |         |         |
|          |   | s/Total |         |        |        |         |         |
|          |   | (%)     |         |        |        |         |         |
+----------+---+---------+---------+--------+--------+---------+---------+
|          |   |         |         |        |        |         |         |
+----------+---+---------+---------+--------+--------+---------+---------+
| **\< 400 | 2 |         | 258/401 | 48/78  | 50/82  | 123/181 | 54/91   |
| cop      | 8 |         | (64)    |        |        |         |         |
| ies/mL** | 1 |         |         | \(62\) | \(61\) | \(68\)  | \(59\)  |
|          | / |         |         |        |        |         |         |
|          | 4 |         |         |        |        |         |         |
|          | 0 |         |         |        |        |         |         |
|          | 4 |         |         |        |        |         |         |
|          | ( |         |         |        |        |         |         |
|          | 7 |         |         |        |        |         |         |
|          | 0 |         |         |        |        |         |         |
|          | ) |         |         |        |        |         |         |
+----------+---+---------+---------+--------+--------+---------+---------+
| **\< 50  | 1 |         | 150/401 | 26/78  | 23/82  | 60/181  | 35/91   |
| cop      | 3 |         | (37)    |        |        |         |         |
| ies/mL** | 1 |         |         | \(33\) | \(28\) | \(33\)  | \(38\)  |
|          | / |         |         |        |        |         |         |
|          | 4 |         |         |        |        |         |         |
|          | 0 |         |         |        |        |         |         |
|          | 4 |         |         |        |        |         |         |
|          | ( |         |         |        |        |         |         |
|          | 3 |         |         |        |        |         |         |
|          | 2 |         |         |        |        |         |         |
|          | ) |         |         |        |        |         |         |
+----------+---+---------+---------+--------+--------+---------+---------+
| **T      | - |         | -2.74   | -2.42  | -2.33  | -2.51   | -2.31   |
| AD~48~** | 2 |         |         |        |        |         |         |
|          | . |         |         |        |        |         |         |
|          | 6 |         |         |        |        |         |         |
|          | 7 |         |         |        |        |         |         |
+----------+---+---------+---------+--------+--------+---------+---------+

**Summary of Efficacy -- Treatment-Experienced Studies**

Time to Loss of Virologic Response (TLOVR)

+----------+----------+----------+-----------+-----------+-----------+
|          | ### Stud |          | ### Stu   |           |           |
|          | y 043 -  |          | dy 045 -- |           |           |
|          | 24 weeks |          |  16 weeks |           |           |
+----------+----------+----------+-----------+-----------+-----------+
| ##       | **ATV**  | **L      | **ATV     | **ATV     | **LOP**   |
|  HIV RNA |          | PV/RTV** | 300**     | 400**     |           |
|          | **2      |          |           |           | **RTV**   |
|          | NRTIs**  | **2      | **RTV     | **SQV     |           |
|          |          | NRTIs**  | 100**     | 1200**    | **T       |
|          | ###      |          |           |           | NF/NRTI** |
|          |          |          | **T       | **T       |           |
|          |          |          | NF/NRTI** | NF/NRTI** |           |
+----------+----------+----------+-----------+-----------+-----------+
|          | Number   |          |           |           |           |
|          | of       |          |           |           |           |
|          | Subjec   |          |           |           |           |
|          | ts/Total |          |           |           |           |
|          | (%)      |          |           |           |           |
+----------+----------+----------+-----------+-----------+-----------+
|          |          |          |           |           |           |
+----------+----------+----------+-----------+-----------+-----------+
| **\< 400 | 69/114   | 93/115   | 21/37     | 17/34     | 21/35     |
| cop      |          |          |           |           |           |
| ies/mL** | \(61\)   | \(81\)   | \(57\)    | \(50\)    | \(60\)    |
+----------+----------+----------+-----------+-----------+-----------+
| **\<     | 47/114   | 60/115   | 14/37     | 10/34     | 7/35      |
| 50**     |          |          |           |           |           |
|          | \(41\)   | \(52\)   | \(38\)    | \(29\)    | \(20\)    |
| **cop    |          |          |           |           |           |
| ies/mL** |          |          |           |           |           |
+----------+----------+----------+-----------+-----------+-----------+
| **T      | \-\--    | \-\--    | -1.74     | -1.70     | -1.87     |
| AD~16~** |          |          |           |           |           |
+----------+----------+----------+-----------+-----------+-----------+
| **T      | -1.73    | -2.16    | \-\--     | \-\--     | \-\--     |
| AD~24~** |          |          |           |           |           |
+----------+----------+----------+-----------+-----------+-----------+

######## CD4 Cell Counts

In general, CD4 counts increased over time across all treatment regimens
and were comparable between treatment arms within each study. In study
034, the mean increase at week 48 was 176 cells/mm^3^ on the ATV regimen
and 160 cells/mm^3^ on the EFV regimen. In study 043, the mean increase
from baseline in CD4 cell count at week 24 was 101 cells/mm^3^ on the
ATV treatment regimen and 121 cells/mm^3^ on the LPV/RTV treatment
regimen. While each of these differences was statistically significant,
they are not felt to have clinical significance due to the small
magnitude of the differences.

IV. **Drug Interactions**

The following two tables summarize the results of drug interactions
studies performed by the applicant. Drugs were chosen for study based on
the likelihood that drugs would be co-administered with atazanavir and
the potential for clinically relevant drug interactions.

+------------+----------------+-------------+---+----------+---------+
| Table 1:   |                |             |   |          |         |
| Drug       |                |             |   |          |         |
| Int        |                |             |   |          |         |
| eractions: |                |             |   |          |         |
| Pharm      |                |             |   |          |         |
| acokinetic |                |             |   |          |         |
| Parameters |                |             |   |          |         |
| for        |                |             |   |          |         |
| Atazanavir |                |             |   |          |         |
| in the     |                |             |   |          |         |
| Presence   |                |             |   |          |         |
| of         |                |             |   |          |         |
| Coad       |                |             |   |          |         |
| ministered |                |             |   |          |         |
| Drugs (3A4 |                |             |   |          |         |
| inhibitor, |                |             |   |          |         |
| inducer,   |                |             |   |          |         |
| or drugs   |                |             |   |          |         |
| affecting  |                |             |   |          |         |
| QTc and PR |                |             |   |          |         |
| intervals) |                |             |   |          |         |
+------------+----------------+-------------+---+----------+---------+
| Coad       | Coadministered | TRADENAME   | n | Ratio    |         |
| ministered | Drug           | Do          |   | (90%     |         |
| Drug       | Dose/Schedule  | se/Schedule |   | Co       |         |
|            |                |             |   | nfidence |         |
|            |                |             |   | I        |         |
|            |                |             |   | nterval) |         |
|            |                |             |   | of       |         |
|            |                |             |   | At       |         |
|            |                |             |   | azanavir |         |
|            |                |             |   | Pharmac  |         |
|            |                |             |   | okinetic |         |
|            |                |             |   | Pa       |         |
|            |                |             |   | rameters |         |
|            |                |             |   | with     |         |
|            |                |             |   | /without |         |
|            |                |             |   | Coadmi   |         |
|            |                |             |   | nistered |         |
|            |                |             |   | Drug; No |         |
|            |                |             |   | Effect = |         |
|            |                |             |   | 1.00     |         |
+------------+----------------+-------------+---+----------+---------+
|            |                |             |   | C~max~   | AUC     |
+------------+----------------+-------------+---+----------+---------+
| Atenolol   | 50 mg QD,      | 400 mg QD,  | 1 | 1.00     | 0.93    |
| (prolongs  |                |             | 9 |          |         |
| PR         | d 7-11 and d   | d 1-11      |   | (0.89,   | (0.85,  |
| interval)  | 19-23          |             |   | 1.12)    | 1.01)   |
+------------+----------------+-------------+---+----------+---------+
| clar       | 500 mg QD,     | 400 mg QD,  | 2 | 1.06     | 1.28    |
| ithromycin |                |             | 9 |          |         |
|            | d 7-10 and d   | d 1-10      |   | (0.93,   | (1.16,  |
|            | 18-21          |             |   | 1.20)    | 1.43)   |
+------------+----------------+-------------+---+----------+---------+
| didanosine | ddI: 200 mg x  | 400 mg x 1  | 3 | 0.11     | 0.13    |
| (ddI)      | 1 dose,        | dose        | 2 |          |         |
| (buffered  |                |             | ^ | (0.06,   | (0.08,  |
| tablets)   | d4T: 40 mg x 1 | sim         | a | 0.18)    | 0.21)   |
| plus       | dose           | ultaneously | ^ |          |         |
| stavudine  |                | with ddI    |   |          |         |
| (d4T)      |                | and d4T     |   |          |         |
+------------+----------------+-------------+---+----------+---------+
|            | ddI: 200 mg x  | 400 mg x 1  | 3 | 1.12     | 1.03    |
|            | 1 dose,        | dose        | 2 |          |         |
|            |                |             | ^ | (0.67,   | (0.64,  |
|            | d4T: 40 mg x 1 | 1 hour      | a | 1.18)    | 1.67)   |
|            | dose           | after ddI + | ^ |          |         |
|            |                | d4T         |   |          |         |
+------------+----------------+-------------+---+----------+---------+
| Diltiazem  | 180 mg QD,     | 400 mg QD,  | 3 | 1.04     | 1.00    |
| (prolongs  |                |             | 0 |          |         |
| PR         | d 7-11 and d   | d 1-11      |   | (0.96,   | (0.95,  |
| interval)  | 19-23          |             |   | 1.11)    | 1.05)   |
+------------+----------------+-------------+---+----------+---------+
| Efavirenz  | 600 mg QD,     | 400 mg QD,  | 2 | 0.41     | 0.26    |
| (3A4       |                |             | 7 |          |         |
| inducer)   | d 7-20         | d 1-20      |   | (0.33,   | (0.22,  |
|            |                |             |   | 0.51)    | 0.32)   |
+------------+----------------+-------------+---+----------+---------+
| efavirenz  | efavirenz 600  | 400 mg QD,  | 1 | 1.14     | 1.39    |
| and        | mg QD          |             | 3 |          |         |
| ritonavir  |                | d 1-6 then  |   | (0.83,   | (1.02,  |
|            | 2 h after      |             |   | 1.58)    | 1.88)   |
|            | TRADENAME and  | 300 mg QD   |   |          |         |
|            | ritonavir 100  |             |   |          |         |
|            | mg QD          | d 7-20      |   |          |         |
|            | simultaneously |             |   |          |         |
|            | with           |             |   |          |         |
|            | TRADENAME, d   |             |   |          |         |
|            | 7-20           |             |   |          |         |
+------------+----------------+-------------+---+----------+---------+
| Ke         | 200 mg QD,     | 400 mg QD,  | 1 | 0.99     | 1.10    |
| toconazole |                |             | 4 |          |         |
| (3A4       | d 1-13         | d 7-13      |   | (0.77,   | (0.89,  |
| inhibitor) |                |             |   | 1.28)    | 1.37)   |
+------------+----------------+-------------+---+----------+---------+
| Rifabutin  | 150 mg QD,     | 400 mg QD,  | 7 | 1.34     | 1.15    |
| (3A4       |                |             |   |          |         |
| inducer)   | d 15-28        | d 1-28      |   | (1.14,   | (0.98,  |
|            |                |             |   | 1.59)    | 1.34)   |
+------------+----------------+-------------+---+----------+---------+
| Ritonavir  | 100 mg QD,     | 300 mg QD,  | 2 | 1.86     | 3.38    |
| (3A4       |                |             | 8 |          |         |
| inhibitor) | d 11-20        | d 1-20      |   | (1.69,   | (3.13,  |
|            |                |             |   | 2.05)    | 3.63)   |
+------------+----------------+-------------+---+----------+---------+
| ^a^ One    |                |             |   |          |         |
| subject    |                |             |   |          |         |
| did not    |                |             |   |          |         |
| receive    |                |             |   |          |         |
| TRADENAME. |                |             |   |          |         |
+------------+----------------+-------------+---+----------+---------+

+------------+-----------+----------+----+--------------+------------+
| Table 2:   |           |          |    |              |            |
| Drug       |           |          |    |              |            |
| Int        |           |          |    |              |            |
| eractions: |           |          |    |              |            |
| Pharm      |           |          |    |              |            |
| acokinetic |           |          |    |              |            |
| Parameters |           |          |    |              |            |
| for        |           |          |    |              |            |
| Coad       |           |          |    |              |            |
| ministered |           |          |    |              |            |
| Drugs (3A4 |           |          |    |              |            |
| s          |           |          |    |              |            |
| ubstrates, |           |          |    |              |            |
| drugs      |           |          |    |              |            |
| affecting  |           |          |    |              |            |
| QTc and PR |           |          |    |              |            |
| intervals) |           |          |    |              |            |
| in the     |           |          |    |              |            |
| Presence   |           |          |    |              |            |
| of         |           |          |    |              |            |
| TRADENAME  |           |          |    |              |            |
+------------+-----------+----------+----+--------------+------------+
| Coad       | Coadm     | T        | n  | Ratio (90%   |            |
| ministered | inistered | RADENAME |    | Confidence   |            |
| Drug       | Drug      | Dose/    |    | Interval) of |            |
|            | Dose      | Schedule |    | Co           |            |
|            | /Schedule |          |    | administered |            |
|            |           |          |    | Drug         |            |
|            |           |          |    | Pha          |            |
|            |           |          |    | rmacokinetic |            |
|            |           |          |    | Parameters   |            |
|            |           |          |    | with/without |            |
|            |           |          |    | TRADENAME;   |            |
|            |           |          |    | No effect =  |            |
|            |           |          |    | 1.00         |            |
+------------+-----------+----------+----+--------------+------------+
|            |           |          |    | C~max~       | AUC        |
+------------+-----------+----------+----+--------------+------------+
| Atenolol   | 50 mg QD, | 400 mg   | 19 | 1.34         | 1.25       |
| (prolongs  |           | QD,      |    |              |            |
| PR         | d 7-11    |          |    | (1.26, 1.42) | (1.16,     |
| interval,  | and       | d 1-11   |    |              | 1.34)      |
| not        |           |          |    |              |            |
| m          | d 19-23   |          |    |              |            |
| etabolized |           |          |    |              |            |
| by 3A)     |           |          |    |              |            |
+------------+-----------+----------+----+--------------+------------+
| clar       | 500 mg    | 400 mg   | 21 | 1.50         | 1.94       |
| ithromycin | QD,       | QD,      |    |              |            |
|            |           |          |    | (1.32, 1.71) | (1.75,     |
|            | d 7-10    | d 1-10   |    |              | 2.16)      |
|            | and       |          |    | OH-cla       |            |
|            |           |          |    | rithromycin: | OH-clari   |
|            | d 18-21   |          |    |              | thromycin: |
|            |           |          |    | 0.28         |            |
|            |           |          |    |              | 0.30       |
|            |           |          |    | (0.24, 0.33) |            |
|            |           |          |    |              | (0.26,     |
|            |           |          |    |              | 0.34)      |
+------------+-----------+----------+----+--------------+------------+
| didanosine | ddI: 200  | 400 mg   | 3  | ddI: 0.92    | ddI: 0.98  |
| (ddI)      | mg        |          | 2^ |              |            |
| (buffered  |           | x 1 dose | a^ | (0.84, 1.02) | (0.92,     |
| tablets)   | x 1 dose, |          |    |              | 1.05)      |
| plus       |           | simu     |    | d4T: 1.08    |            |
| stavudine  | d4T: 40   | ltaneous |    |              | d4T: 1.00  |
| (d4T)      | mg        |          |    | (0.96, 1.22) |            |
|            |           | with ddI |    |              | (0.97,     |
|            | x 1 dose  | and d4T  |    |              | 1.03)      |
+------------+-----------+----------+----+--------------+------------+
| Diltiazem  | 180 mg    | 400 mg   | 28 | 1.98         | 2.25       |
|            | QD,       | QD,      |    |              |            |
|            |           |          |    | (1.78, 2.19) | (2.09,     |
|            | d 7-11    | d 1-11   |    |              | 2.16)      |
|            | and d     |          |    | desacety     |            |
|            | 19-23     |          |    | l-diltiazem: | desacetyl- |
|            |           |          |    |              | diltiazem: |
|            |           |          |    | 2.72         |            |
|            |           |          |    |              | 2.65       |
|            |           |          |    | (2.44, 3.03) |            |
|            |           |          |    |              | (2.45,     |
|            |           |          |    |              | 2.87)      |
+------------+-----------+----------+----+--------------+------------+
| ethinyl    | Or        | 400 mg   | 19 | ethinyl      | ethinyl    |
| estradiol  | tho-Novum | QD,      |    | estradiol:   | estradiol: |
|            | 7/7/7 QD, |          |    | 1.15         | 1.48       |
| &          |           | d 16-29  |    |              |            |
| nor        | d 1-29    |          |    | (0.99, 1.32) | (1.31,     |
| ethindrone |           |          |    |              | 1.68)      |
|            |           |          |    | no           |            |
|            |           |          |    | rethindrone: | nore       |
|            |           |          |    | 1.67         | thindrone: |
|            |           |          |    |              | 2.10       |
|            |           |          |    | (1.42, 1.96) |            |
|            |           |          |    |              | (1.68,     |
|            |           |          |    |              | 2.62)      |
+------------+-----------+----------+----+--------------+------------+
| Rifabutin  | 300 mg    | 600 mg   | 3  | 1.18         | 2.10       |
| (3A4       | QD,       | QD^b^,   |    |              |            |
| substrate) |           |          |    | (0.94, 1.48) | (1.57,     |
|            | d 1-10    | d 11-20  |    |              | 2.79)      |
|            |           |          |    | 2            |            |
|            | then 150  |          |    | 5-O-desacety | 25-O-      |
|            | mg QD,    |          |    | l-rifabutin: | desacetyl- |
|            |           |          |    | 8.20         | rifabutin: |
|            | d 11-20   |          |    |              | 22.01      |
|            |           |          |    | (5.90,       |            |
|            |           |          |    | 11.40)       | (15.97,    |
|            |           |          |    |              | 30.34)     |
+------------+-----------+----------+----+--------------+------------+
| saquinavir | 1200 mg   | 400 mg   | 7  | 4.39         | 5.49       |
| (soft      | QD,       | QD,      |    |              |            |
| gelatin    |           |          |    | (3.24, 5.95) | (4.04,     |
| capsules)  | d 1-13    | d 7-13   |    |              | 7.47)      |
+------------+-----------+----------+----+--------------+------------+
| la         | 150 mg    | 400 mg   | 19 | lamivudine:  | l          |
| mivudine + | lam       | QD,      |    | 1.04         | amivudine: |
| zidovudine | ivudine + |          |    |              | 1.03       |
|            | 300 mg    | d 7-12   |    | (0.92, 1.16) |            |
|            | z         |          |    |              | (0.98,     |
|            | idovudine |          |    | zidovudine:  | 1.08)      |
|            |           |          |    | 1.05         |            |
|            | BID,      |          |    |              | z          |
|            |           |          |    | (0.88, 1.24) | idovudine: |
|            | d 1-12    |          |    |              | 1.05       |
|            |           |          |    | zidovudine   |            |
|            |           |          |    |              | (0.96,     |
|            |           |          |    | glucuronide: | 1.14)      |
|            |           |          |    | 0.95         |            |
|            |           |          |    |              | zidovudine |
|            |           |          |    | (0.88, 1.02) | gl         |
|            |           |          |    |              | ucuronide: |
|            |           |          |    |              | 1.00       |
|            |           |          |    |              |            |
|            |           |          |    |              | (0.97,     |
|            |           |          |    |              | 1.03)      |
+------------+-----------+----------+----+--------------+------------+
| ^a^ One    |           |          |    |              |            |
| subject    |           |          |    |              |            |
| did not    |           |          |    |              |            |
| receive    |           |          |    |              |            |
| TRADENAME. |           |          |    |              |            |
|            |           |          |    |              |            |
| ^b^ Not    |           |          |    |              |            |
| the        |           |          |    |              |            |
| r          |           |          |    |              |            |
| ecommended |           |          |    |              |            |
| t          |           |          |    |              |            |
| herapeutic |           |          |    |              |            |
| dose of    |           |          |    |              |            |
| a          |           |          |    |              |            |
| tazanavir. |           |          |    |              |            |
+------------+-----------+----------+----+--------------+------------+

V.  **Summary of Clinical Virology**

HIV-1 resistant to ATV was selected from *in vitro* selection
experiments in three different HIV-1 strains. These ATV-resistant HIV-1
isolates showed a 6-to 183-fold decrease in susceptibility to ATV
compared to wild type. Genotypic analyses indicated that I50L, A71V,
N88S, M46I and I84V substitutions appeared to be key changes with
possible roles in ATV resistance. Direct evidence for a role of the I50L
mutation in ATV resistance was obtained by constructing recombinant
viruses with the protease gene from clinical isolates. ATV resistance
corresponded to the presence of I50L and A71V in the protease coding
sequence. Results showed that the I50L mutation, sometimes combined with
A71V and other changes, appears to be a signature substitution for ATV
and mediates increased susceptibility to other PIs by an unknown
mechanism.

Genotypic and phenotypic evaluation of clinical isolates from
ATV-treated patients designated as virologic failures with decreased ATV
susceptibility (\>2.5-fold) demonstrated that ATV can display different
resistance patterns depending on the PI-treatment experience of the
patient population. When ATV was used as the only PI in patients with no
previous antiretroviral experience, clinical isolates developed a unique
I50L mutation frequently accompanied by an A71V mutation. The I50L
mutation resulted in ATV resistance, impaired viral growth and increased
*in vitro* susceptibility to other approved PIs including amprenavir
where resistance is mediated through the I50V mutation.

In contrast to naïve patients, isolates from experienced patients
treated with ATV and SQV did not contain the I50L mutation but acquired
several additional amino acid changes including I84V, L90M, M46I or
N88S/D. These additional mutations in protease also conferred
cross-resistance to other PIs. A higher percentage of the clinical
isolates from ATV treatment arms with the PI mutations I84V, L90M, A71V,
N88S/D or M46I at baseline were virologic failures compared to isolates
from other treatment arms. These results suggest that these mutations in
the HIV-1 protease are unfavorable to ATV antiviral activity and may
reduce virologic response to ATV treatment clinically.

Out of 551 PI-experienced clinical isolates evaluated, ATV
susceptibility was retained against \> 80% of isolates resistant to 1-2
other PIs, primarily NFV-resistant isolates. There was a clear trend
toward loss of ATV susceptibility as isolates demonstrated resistance to
three or more PIs. ATV sensitivity was retained against only 5% of
isolates resistant to five PIs. Therefore, ATV susceptibility of
clinical isolates resistant to one or more PIs from patients never
exposed to ATV decreased as the level of cross-resistance to other PIs
increased. ATV-resistant isolates were highly cross-resistant to NFV,
IDV, SQV, and RTV and moderately cross-resistant to APV and LPV. From
treatment-experienced trials, 63% percent of the isolates that developed
ATV-resistance remained susceptible to APV and 53% of the isolates were
susceptible to LPV while less than 20% of these isolates remained
susceptible to IDV, RTV, or SQV and none remained susceptible to NFV.

In summary, mutations I50L, A71V, N88S/D, I84V, and L90M appear to
confer ATV resistance and reduce the clinical response to ATV. ATV is
cross-resistant with other PIs and there is clear trend toward loss of
ATV susceptibility with isolates resistant to three or more PIs.

VI. **Safety Summary**

**Study 034 - General Safety**

Clinical adverse events were common in study subjects; at least 95% of
all subjects on both treatment regimens reported at least one adverse
event. The majority of all AEs were mild to moderate only (Grade 1 - 2).
Grade 3 - 4 events occurred in about 16% of subjects on both regimens.

The most common adverse events of any grade that were reported with a
comparable incidence on both treatment regimens were infection, nausea,
headache, vomiting, diarrhea, abdominal pain, somnolence, insomnia, and
fever.

Adverse events that occurred with a higher frequency on the ATV regimen
included jaundice (11% vs. 0%) and scleral icterus (11% vs. 2%). Adverse
events that occurred with a higher frequency on the EFV regimen included
dizziness (39% vs. 13%), abnormal dreams (10% vs. 6%), nervousness (3%
vs. \< 1%), rash (29% vs. 23%), and vasodilatation (7% vs. 3%).

Sixty-five subjects discontinued therapy because of adverse events (28
subjects on the ATV regimen and 37 subjects on the EFV regimen). The
most frequent events leading to discontinuation in the ATV regimen were
anemia (2%), nausea (1%) and vomiting (1%). Three subjects on the ATV
regimen discontinued for scleral icterus or jaundice. The most frequent
events leading to discontinuation on the EFV regimen were rash (2%), CNS
events (2%), and nausea (1%).

**Study 043 - General Safety**

The regimens appeared to be well-tolerated with 2 subjects in each
treatment arm discontinuing for adverse events prior to the week 24
visit (one atazanavir subject discontinued for scleral icterus and
lipoatrophy, and the second atazanavir subject discontinued for grade 4
transaminases and grade 3 bilirubin). The majority of AEs were mild to
moderate in severity; Grade 3 - 4 adverse events were observed in
approximately 10% of subjects in each treatment arm.

The most common adverse events of any grade that were reported with a
comparable incidence between the treatment regimens were headache,
nausea, peripheral neurologic symptoms, abdominal pain, fatigue,
insomnia, vomiting, and lipodystrophy.

Adverse events that were observed more frequently on the ATV treatment
regimen as compared with the LPV/RTV treatment regimen included rash
(13% vs. 7%), dizziness (8%; vs. 3%), extremity pain (8% vs. 1%),
jaundice (10% vs. 0%), and scleral icterus (6% vs. 0%). Adverse events
that were observed more frequently on the LPV/RTV treatment regimen as
compared with the ATV treatment regimen included diarrhea (32% vs. 10%),
infection (40% vs. 35%), somnolence (9% vs. 3%), and anorexia (5% vs.
\<1%).

**Special Safety Considerations**

## Lipid Profiles

As mentioned previously it was noted during phase 2 studies of
treatment-naïve subjects that treatment with nelfinavir resulted in
greater increases in lipid parameters relative to atazanavir. This
finding was confirmed in phase 3 studies of both treatment-naïve and
treatment-experienced patients. In addition, subjects who switched from
nelfinavir to atazanavir after 72 weeks of treatment experienced a
return to baseline lipid parameters by 12 weeks on treatment.

The following tables summarize the means of data collected at each
timepoint for lipid parameters during studies 034 and 043.

+---------------------+------------------------+----------------------+
| **Lipid Parameters  |                        |                      |
| -- Study 034**      |                        |                      |
+---------------------+------------------------+----------------------+
|                     |                        |                      |
+---------------------+------------------------+----------------------+
| #                   | **Atazanavir**         | **Efavirenz**        |
+---------------------+------------------------+----------------------+
|                     | **AZT/3TC**            | **AZT/3TC**          |
+---------------------+------------------------+----------------------+
|                     | **N=404**              | **N=401**            |
+---------------------+------------------------+----------------------+
|                     | # Mean                 |                      |
+---------------------+------------------------+----------------------+
|                     | N=386                  | N=379                |
+---------------------+------------------------+----------------------+
| **Total Chol --     | 164                    | 162                  |
| B/L**               |                        |                      |
+---------------------+------------------------+----------------------+
|                     | N=321                  | N=302                |
+---------------------+------------------------+----------------------+
| **48 weeks**        | 168                    | 195                  |
+---------------------+------------------------+----------------------+
|                     |                        |                      |
+---------------------+------------------------+----------------------+
|                     | N=383                  | N=378                |
+---------------------+------------------------+----------------------+
| **Fasting LDL -     | 98                     | 98                   |
| B/L**               |                        |                      |
+---------------------+------------------------+----------------------+
|                     | N=283                  | N=264                |
+---------------------+------------------------+----------------------+
| **48 weeks**        | 98                     | 114                  |
+---------------------+------------------------+----------------------+
|                     |                        |                      |
+---------------------+------------------------+----------------------+
|                     | N=386                  | N=379                |
+---------------------+------------------------+----------------------+
| **HDL -- B/L**      | 39                     | 38                   |
+---------------------+------------------------+----------------------+
|                     | N=321                  | N=302                |
+---------------------+------------------------+----------------------+
| **48 weeks**        | 43                     | 46                   |
+---------------------+------------------------+----------------------+
|                     |                        |                      |
+---------------------+------------------------+----------------------+
|                     | N=384                  | N=379                |
+---------------------+------------------------+----------------------+
| **Fasting TG --     | 138                    | 129                  |
| B/L**               |                        |                      |
+---------------------+------------------------+----------------------+
|                     | N=283                  | N=266                |
+---------------------+------------------------+----------------------+
| **48 weeks**        | 124                    | 168                  |
+---------------------+------------------------+----------------------+

+----------------------+-----------------------+----------------------+
| **Lipid Parameters   |                       |                      |
| -- Study 043**       |                       |                      |
+----------------------+-----------------------+----------------------+
|                      |                       |                      |
+----------------------+-----------------------+----------------------+
|                      | **Atazanavir**        | **L                  |
|                      |                       | opinavir/Ritonavir** |
+----------------------+-----------------------+----------------------+
|                      | **Dual NRTI           | **Dual NRTI          |
|                      | background**          | background**         |
+----------------------+-----------------------+----------------------+
|                      | N=109                 | N=114                |
+----------------------+-----------------------+----------------------+
|                      | # Mean                |                      |
+----------------------+-----------------------+----------------------+
|                      |                       |                      |
+----------------------+-----------------------+----------------------+
|                      | N=109                 | N=114                |
+----------------------+-----------------------+----------------------+
| ######               | 179                   | 172                  |
| #  Total Chol -- B/L |                       |                      |
+----------------------+-----------------------+----------------------+
|                      | N=94                  | N=84                 |
+----------------------+-----------------------+----------------------+
| **24 weeks**         | 169                   | 199                  |
+----------------------+-----------------------+----------------------+
|                      |                       |                      |
+----------------------+-----------------------+----------------------+
|                      | N=109                 | N=114                |
+----------------------+-----------------------+----------------------+
| **Fasting LDL --     | 104                   | 100                  |
| B/L**                |                       |                      |
+----------------------+-----------------------+----------------------+
|                      | N=91                  | N=83                 |
+----------------------+-----------------------+----------------------+
| **24 weeks**         | 92                    | 106                  |
+----------------------+-----------------------+----------------------+
|                      |                       |                      |
+----------------------+-----------------------+----------------------+
|                      | N=109                 | N=114                |
+----------------------+-----------------------+----------------------+
| **HDL -- B/L**       | 37                    | 37                   |
+----------------------+-----------------------+----------------------+
|                      | N=94                  | N=84                 |
+----------------------+-----------------------+----------------------+
| **24 weeks**         | 41                    | 45                   |
+----------------------+-----------------------+----------------------+
|                      |                       |                      |
+----------------------+-----------------------+----------------------+
|                      | N=109                 | N=114                |
+----------------------+-----------------------+----------------------+
| **Fasting TG --      | 207                   | 196                  |
| B/L**                |                       |                      |
+----------------------+-----------------------+----------------------+
|                      | N=92                  | N=83                 |
+----------------------+-----------------------+----------------------+
| **24 weeks**         | 207                   | 260                  |
+----------------------+-----------------------+----------------------+

**LDL Cholesterol**

In treatment naïve studies, subjects receiving efavirenz and nelfinavir
treatment regimens had substantial increases in LDL cholesterol by week
12; these increases persisted through 48 weeks for efavirenz and 72
weeks for nelfinavir in studies 007/008. Data from rollover study
007/041 confirmed that atazanavir produced less effect on lipid
parameters than nelfinavir through 108 weeks of treatment.

In treatment-naïve study 034, the mean increase from baseline in LDL
cholesterol for efavirenz-treated subjects was 18 % as compared to 1%
for ATV-treated subjects (p \< .0001). At week 48 for study 034, more
subjects on the efavirenz regimen had fasting LDL cholesterol 160 mg/dL
as compared to atazanavir (8% versus 3%, p \< .005).

At week 24, in treatment-experienced study 043, the mean increase in LDL
cholesterol for LPV/RTV-treated subjects was 8% compared to a mean
decrease of 6% for ATV-treated patients. By week 24, 7% of LPV/RTV
subjects had fasting LDL \> 160 mg/dL as compared to none of the
atazanavir subjects.

**HDL Cholesterol**

In study 034, mean baseline HDL cholesterol concentrations were similar
between atazanavir and efavirenz treatment arms. By week 48, the
efavirenz regimen had a significantly higher mean increase from baseline
in HDL cholesterol as compared to atazanavir (24% versus 13%, p
\<0.0001).

In study 043 mean increases in HDL were similar (ATV 14%, LPV/RTV 13%).

**Fasting Triglycerides**

In study 034, baseline fasting mean triglyceride concentrations were
slightly lower on the efavirenz regimen (129 mg/dL) as compared to the
atazanavir regimen (138 mg/dL). At week 48, significant mean increases
(p \< 0.0001) were observed for efavirenz-treated subjects (23%) as
compared to atazanavir-treated subjects, who experienced a small
decrease in triglyceride concentrations (-9%).

In studies 007/008 combined, substantial mean increases were observed in
triglycerides for NFV-treated subjects relative to ATV-treated subjects
(45% versus 9%). These differences were seen by week 4 and were
sustained throughout the treatment period.

At week 24 in study 043, the mean increase in serum triglycerides for
LPV/RTV-treated subjects was 57 % compared to a mean decrease of 2% for
ATV-treated subjects (p \< .0001). Despite this, triglyceride levels of
atazanavir patients appeared to be higher than levels seen in
atazanavir-treated patients enrolled in naïve studies. This may suggest
that factors other than current protease inhibitor use also contribute
to hyperlipidemia in HIV-infected subjects.

## Lipodystrophy

Review of lipodystrophy events in this document will be limited to
treatment-naïve studies 007 and 034. Data on lipodystrophy events in
treatment-experienced trials may be confounded by prior ARV therapy and
by variable NRTI backgrounds.

Lipodystrophy events were inconsistently reported; some were reported
only as lipodystrophy, while other reports were specific as to the area
of weight loss or weight gain. Because of this, reports were not grouped
by categories of lipoatrophy, lipohypertrophy or both. As some events
may have been reported simply as weight loss or weight gain due to lack
of awareness of these events at the time studies were conducted, these
reports were also reviewed.

Spontaneous reports of any event of lipodystrophy, generalized weight
loss or weight gain appeared to be similar between atazanavir and
comparators in these trials. Events did appear to increase with
increasing duration of therapy.

Incidence of Lipodystrophy, Weight Loss, and Weight Gain

+-------------+--------+--------+--------+--------+--------+--------+
| **Study**   | *      |        | *      |        | **007  |        |
|             | *034** |        | *007** |        | /041** |        |
+-------------+--------+--------+--------+--------+--------+--------+
|             | *      | *      | *      | **NFV  | *      | **NFV  |
|             | *ATV** | *EFV** | *ATV** | 2500   | *ATV** | 2500   |
|             |        |        |        | mg**   |        | mg**   |
|             | **400  | **600  | **all  |        | **all  |        |
|             | mg**   | mg**   | d      | **ddI  | d      | **ddI  |
|             |        |        | oses** | /d4T** | oses** | /d4T** |
|             | **AZT  | **AZT  |        |        |        |        |
|             | /3TC** | /3TC** | **ddI  | **N    | **ddI  | **N    |
|             |        |        | /d4T** | =100** | /d4T** | =100** |
|             | **N    | **N    |        |        |        |        |
|             | =404** | =401** | #      |        | **N    |        |
|             |        |        |  N=310 |        | =310** |        |
+-------------+--------+--------+--------+--------+--------+--------+
|             | **     |        |        |        |        |        |
|             | Number |        |        |        |        |        |
|             | of     |        |        |        |        |        |
|             | su     |        |        |        |        |        |
|             | bjects |        |        |        |        |        |
|             | (%)**  |        |        |        |        |        |
+-------------+--------+--------+--------+--------+--------+--------+
| Any Event   | 61     | 47     | 46     | 11     | 68     | 18     |
|             | (15)   | (12)   | (15)   | (11)   | (22)   | (18)   |
+-------------+--------+--------+--------+--------+--------+--------+
| Li          | 37 (9) | 29 (7) | 14 (4) | 4 (4)  | 41     | 10     |
| podystrophy |        |        |        |        | (13)   | (10)   |
+-------------+--------+--------+--------+--------+--------+--------+
| Weight gain | 12 (3) | 3 (1)  | 4 (1)  | 1 (1)  | 4 (1)  | 1 (1)  |
+-------------+--------+--------+--------+--------+--------+--------+
| Weight loss | 12 (3) | 16 (4) | 31     | 7 (7)  | 41     | 11     |
|             |        |        | (10)   |        | (13)   | (11)   |
+-------------+--------+--------+--------+--------+--------+--------+

In summary, use of atazanavir appeared to have less of an impact on
lipid parameters as compared to efavirenz and selected protease
inhibitors. Fasting triglycerides in treatment-experienced subjects in
study 043 did not return to levels seen in treatment-naive subjects,
suggesting that factors other than protease inhibitor use may also
contribute to the development of hyperlipidemia. In addition, the
favorable lipid profile did not appear to result in fewer reported
lipodystrophy events in atazanavir-treated subjects as compared to
efavirenz and nelfinavir.

**Special Safety Considerations -- Hyperbilirubinemia**

Elevations in bilirubin in subjects receiving atazanavir were noted
early during the phase 1 development of ATV and confirmed in phase 2 and
3 studies. In order to elucidate the mechanism of hyperbilirubinemia,
studies were conducted by the applicant to investigate the following
potential causes:

1\) Increased production of bilirubin in spleen and peripheral tissues.

2\) Displacement of bilirubin from albumin during transport to the
liver.

3\) Decreased uptake of bilirubin by liver cells from plasma.

4\) Displacement of bilirubin from cytosolic binding protein (ligandin)
in liver cells.

5\) Inhibition of bilirubin conjugation mediated by the uridine
diphosphate-glucuronosyl

transferase 1A1 (UGT 1A1) isozyme.

Data from evaluations of these mechanisms supported an unconjugated
hyperbilirubinemia. Elevated total bilirubin, when fractionated, was
primarily indirect (unconjugated) and reversible upon discontinuation of
ATV. This finding suggested that the mechanism of hyperbilirubinemia
attributable to ATV occurs prior to glucuronidation (conjugation). At
clinically relevant concentrations, ATV, bound to purified UGT 1A1
isozymes, inhibited the conjugation of bilirubin. Evidence for
hemolysis, another potential cause of unconjugated hyperbilirubinemia,
was not seen; clinical markers such as LDH, reticulocytes, and
hemoglobin were stable. Displacement from carriers (e.g., albumin, GST)
was not observed. By elimination, these experiments suggested that the
predominant mechanism of the primarily unconjugated hyperbilirubinemia
seen with ATV exposure is inhibition of UGT 1A1.

For the following discussion, please note that the following toxicity
grading scale for hyperbilirubinemia was used for grading
hyperbilirubinemia in the atazanavir clinical development program:

Grade 1 -- 1.1 -- 1.5 x ULN

Grade 2 -- 1.6 -- 2.5 x ULN

Grade 3 -- 2.6 -- 5.0 x ULN

Grade 4 -- \> 5.0 x ULN

Standard normal ranges of laboratory values may vary slightly from lab
to lab, however, for total bilirubin levels the normal range is
generally defined as 1 - 1.5 mg/dL. The normal range for direct
bilirubin is generally defined as 0.2 - 0.5 mg/dL. For purposes of this
review, the normal range of total bilirubin is 1.0 mg/dL and the normal
range for direct bilirubin is 0.2 mg/dL.

Increases in total bilirubin levels were observed in the vast majority
of subjects treated with ATV in contrast to relatively few subjects
treated with comparator regimens. The mean total bilirubin for
ATV-treated subjects was approximately 3-fold higher at week 48 as
compared to baseline.

The following table summarizes total and direct bilirubin levels
collected at all timepoints in study 034. Regardless of the degree of
hyperbilirubinemia observed at a given timepoint, minimal changes were
seen in direct bilirubin, supporting inhibition of UDP-glucuronosyl
transferase as the mechanism of hyperbilirubinemia. Mean direct
bilirubin levels for ATV-treated subjects increased slightly from
baseline. This was generally observed regardless of the degree of
elevation in total bilirubin. When significant elevations of direct
bilirubin were observed they generally occured simultaneously with other
indices of hepatic injury or inflammation.

+------------------------------------------+---------------------------+
| **Mean Total and Direct Bilirubin of All |                           |
| Bilirubin Measurements in Study 034**    |                           |
|                                          |                           |
| **by Categorical Analysis**              |                           |
+------------------------------------------+---------------------------+
|                                          |                           |
+------------------------------------------+---------------------------+
| **Total Bilirubin**                      | N=3170                    |
|                                          |                           |
| **\< 2.5 mg/dL**                         |                           |
+------------------------------------------+---------------------------+
| Mean total bilirubin (SD)                | 1.2 (.58)                 |
+------------------------------------------+---------------------------+
| Mean direct bilirubin (SD)               | 0.22 (.10)                |
+------------------------------------------+---------------------------+
|                                          |                           |
+------------------------------------------+---------------------------+
| **Total Bilirubin**                      | N=634                     |
|                                          |                           |
| **2.5 - 5 mg/dL**                        |                           |
+------------------------------------------+---------------------------+
| Mean total bilirubin (SD)                | 3.3 (.64)                 |
+------------------------------------------+---------------------------+
| Mean direct bilirubin (SD)               | 0.36 (.14)                |
+------------------------------------------+---------------------------+
|                                          |                           |
+------------------------------------------+---------------------------+
| **Total Bilirubin**                      | N=66                      |
|                                          |                           |
| **\> 5 mg/dL**                           |                           |
+------------------------------------------+---------------------------+
| Mean total bilirubin (SD)                | 6.3 (1.4)                 |
+------------------------------------------+---------------------------+
| Mean direct bilirubin (SD)               | 0.35 (.52)                |
+------------------------------------------+---------------------------+

The incidence of hyperbilirubinemia was clearly dose-dependent as
demonstrated in dose-finding phase 2 studies. Please note that dose
reduction as a management strategy for grade 4 hyperbilirubinemia was
utilized in clinical trials of atazanavir, however, insufficient data
was obtained from clinical trials on the efficacy of a reduced dose of
atazanavir to support its use in clinical practice.

+-------------+-------------+-------------+-------------+-------------+
| **Incidence |             |             |             |             |
| of Grade    |             |             |             |             |
| 3--4        |             |             |             |             |
| Hyperbi     |             |             |             |             |
| lirubinemia |             |             |             |             |
| and Dose    |             |             |             |             |
| Reduction   |             |             |             |             |
| by ATV      |             |             |             |             |
| Dose**      |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| **Number of |             |             |             |             |
| Sub         |             |             |             |             |
| jects/Total |             |             |             |             |
| (%)**       |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| **Dose**    | **200 mg**  | **400 mg**  | **500 mg**  | **600 mg**  |
+-------------+-------------+-------------+-------------+-------------+
| **Study**   | **007**     | **007/008** | **007**     | **008**     |
+-------------+-------------+-------------+-------------+-------------+
|             | N= 101      | N=277       | N=104       | N=195       |
+-------------+-------------+-------------+-------------+-------------+
|             |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| **Grade     | 20/101 (20) | 114/277     | 51/104 (49) | 113/195     |
| 3-4**       |             | (41)        |             | (58)        |
|             |             |             |             |             |
| **          |             |             |             |             |
| Bilirubin** |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| **Dose      | 0/102 (0)   | 15/277 (5)  | 10/107 (9)  | 24/195 (12) |
| Reduction   |             |             |             |             |
| for Grade   |             |             |             |             |
| 4**         |             |             |             |             |
|             |             |             |             |             |
| **          |             |             |             |             |
| Elevation** |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+

Jaundice and scleral icterus were reported for subjects treated with ATV
but rarely for subjects treated with comparators. The incidence of these
two adverse events in ARV treatment-naive and treatment-experienced
trials for patients receiving ATV 400 mg is shown in the following
table:

+-----------------+-----------------+-----------------+-----------------+
| # Ataza         |                 |                 |                 |
| navir -- 400 mg |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| **Number of     |                 |                 |                 |
| Subjects (%)**  |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| **Study**       | **007/41**      | **034**         | **043**         |
|                 |                 |                 |                 |
|                 | **008/44**      | **N=404**       | **N=109**       |
|                 |                 |                 |                 |
|                 | **N=277**       |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
|                 |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Jaundice        | 26 (9)          | 45 (11)         | 14 (10)         |
+-----------------+-----------------+-----------------+-----------------+
| Scleral Icterus | 22 (8)          | 45 (11)         | 8 (6)           |
+-----------------+-----------------+-----------------+-----------------+
|                 |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Total           | 45 (16)         | 58 (14)         | 21 (15)         |
| Subjects\*      |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

\* Subjects may have reported one or both of these adverse events.

The incidence of jaundice was similar for ARV treatment-naive (9% - 11%)
and

treatment-experienced subjects (10%), however, follow-up for subjects in
the treatment-experienced trials was significantly shorter. The
incidence of jaundice was not increased on the ATV 300 mg/RTV 100 mg
(10%) treatment regimen relative to treatment with ATV 400 mg (5% - 11%)
through the 16 weeks of follow-up available for study 045.

While clinical jaundice and/or scleral icterus were reported in roughly
15% of patients, these symptoms or laboratory confirmed grade 4
hyperbilirubinemia led to dose reduction and/or discontinuation of
atazanavir in 5% of patients. From the perspective of patient
acceptability this side-effect appears to be well-tolerated; however, it
may be postulated that more discontinuations may occur in general
clinical practice as patients enrolled in clinical trials have unique
motivations to continue treatment and the strategy of dose reduction
will not be recommended.

Three of the clinical trials (007, 008, and 034) had subjects receiving
identical nucleoside analogue background therapy allowing for direct
comparison of the rate of LFT abnormalities on treatment. Hepatitis B
and C status in studies 007 and 008 were comparable across treatment
regimens. In study 007 at 72 weeks of follow-up, more subjects receiving
atazanavir had any grade elevation of LFTs as compared to nelfinavir.
This finding was also observed in study 008, although the overall
incidence of LFT abnormalities was lower, likely reflecting the
different NRTI background therapy. In 007 grade 3-4 abnormalities were
more frequent in atazanavir arms, while in study 008, they were more
common in the nelfinavir arm. In registrational study 034, with the
expected exception of bilirubin elevations, abnormalities of serum liver
function tests were comparable between ATV-treated subjects and
EFV-treated subjects.

In study 043, an imbalance existed at baseline between the two treatment
regimens in the number of subjects with a history of hepatitis B or C
(ATV 20%, LPV/RTV 12%); slight differences in NRTI background therapy
also existed between the two regimens. The majority of liver function
test abnormalities on study were Grade 1 - 2 and were comparable between
the treatment regimens. Grade 3 -- 4 ALT and AST elevations occurred in
6% and 3% of subjects, respectively, on the ATV treatment regimen and \<
1% and 1% of subjects, respectively, on the LPV/RTV treatment regimen.
Grade 3 - 4 elevations in ALT were more common among hepatitis negative
subjects treated with ATV (5%) than subjects treated with LPV/RTV (\<
1%). One subject with hepatitis B receiving atazanavir/ddI EC/d4T
discontinued for grade 3-4 LFTs.

No increase in discontinuations and/or death due to hepatotoxicity
relative to comparators was apparent in clinical trials of ATV. The
following table summarizes discontinuations due to the development or
worsening of hepatitis, liver function abnormalities or damage
(excluding lactic acidosis syndrome/symptomatic hyperlactatemia cases
\[LAS/SHL\]):

+----------+-----------+-----------+----------+----------+----------+
| ### D    |           |           |          |          |          |
| iscontin |           |           |          |          |          |
| uations  |           |           |          |          |          |
| and/or D |           |           |          |          |          |
| eaths Du |           |           |          |          |          |
| e to Hep |           |           |          |          |          |
| atic Abn |           |           |          |          |          |
| ormaliti |           |           |          |          |          |
| es (w/o  |           |           |          |          |          |
| LAS/SHL) |           |           |          |          |          |
+----------+-----------+-----------+----------+----------+----------+
| **Phase  |           |           |          |          |          |
| 2 and 3  |           |           |          |          |          |
| Clinical |           |           |          |          |          |
| S        |           |           |          |          |          |
| tudies** |           |           |          |          |          |
+----------+-----------+-----------+----------+----------+----------+
|          |           |           |          |          |          |
+----------+-----------+-----------+----------+----------+----------+
|          | **Number  |           |          |          |          |
|          | of        |           |          |          |          |
|          | Subjects  |           |          |          |          |
|          | (%)**     |           |          |          |          |
+----------+-----------+-----------+----------+----------+----------+
| **ARV    | **034**   | **034**   | **       | **0      |          |
| Trea     |           |           | 007/41** | 07/041** |          |
| tment-** |           |           |          |          |          |
|          |           |           | **       | **008**  |          |
| **Naive  |           |           | 008/44** |          |          |
| S        |           |           |          |          |          |
| tudies** |           |           |          |          |          |
+----------+-----------+-----------+----------+----------+----------+
|          | **ATV     | **EFV     | **ATV**  | **NFV**  |          |
|          | 400**     | 600**     |          |          |          |
|          |           |           | **all    |          |          |
|          |           |           | doses**  |          |          |
+----------+-----------+-----------+----------+----------+----------+
|          | **N =     | **N =     | **N =    | **N =    |          |
|          | 404**     | 401**     | 673**    | 191**    |          |
+----------+-----------+-----------+----------+----------+----------+
|          |           |           |          |          |          |
+----------+-----------+-----------+----------+----------+----------+
| D/C      | 2 (\<1)   | 1 (\<1)   | 11 (2)   | 4 (2)    |          |
+----------+-----------+-----------+----------+----------+----------+
| Death    | 0         | 0         | 1 (\< 1) | 0        |          |
+----------+-----------+-----------+----------+----------+----------+
|          |           |           |          |          |          |
+----------+-----------+-----------+----------+----------+----------+
| **ARV    | **043**   | **043**   | **045**  | **045**  | **045**  |
| Trea     |           |           |          |          |          |
| tment-** |           |           |          |          |          |
|          |           |           |          |          |          |
| **Exper  |           |           |          |          |          |
| ienced** |           |           |          |          |          |
|          |           |           |          |          |          |
| ##       |           |           |          |          |          |
|  Studies |           |           |          |          |          |
+----------+-----------+-----------+----------+----------+----------+
|          | ##        | **        | **ATV    | **ATV    | **L      |
|          |  ATV 400  | LPV/RTV** | 300**    | 400**    | PV/RTV** |
|          |           |           |          |          |          |
|          |           |           | **RTV    | **SQV    |          |
|          |           |           | 100**    | 1200**   |          |
+----------+-----------+-----------+----------+----------+----------+
|          | **N =     | **N =     | **N =    | **N =    | **N =    |
|          | 144**     | 146**     | 119**    | 109**    | 117**    |
+----------+-----------+-----------+----------+----------+----------+
|          |           |           |          |          |          |
+----------+-----------+-----------+----------+----------+----------+
| D/C      | 1 (\<1)   | 0         | 1 (\<1)  | 0        | 0        |
+----------+-----------+-----------+----------+----------+----------+
| Death    | 0         | 0         | 0        | 0        | 0        |
+----------+-----------+-----------+----------+----------+----------+
|          |           |           |          |          |          |
+----------+-----------+-----------+----------+----------+----------+
| **ARV    | **009**   | **009**   | **009**  |          |          |
| Trea     |           |           |          |          |          |
| tment-** |           |           |          |          |          |
|          |           |           |          |          |          |
| **Exper  |           |           |          |          |          |
| ienced** |           |           |          |          |          |
|          |           |           |          |          |          |
| ##       |           |           |          |          |          |
|  Studies |           |           |          |          |          |
+----------+-----------+-----------+----------+----------+----------+
|          | **ATV     | **ATV     | **RTV    |          |          |
|          | 400**     | 600**     | 400**    |          |          |
|          |           |           |          |          |          |
|          | **SQV     | **SQV     | **SQV    |          |          |
|          | 1200**    | 1200**    | 400**    |          |          |
+----------+-----------+-----------+----------+----------+----------+
|          |           |           |          |          |          |
+----------+-----------+-----------+----------+----------+----------+
|          |           |           |          |          |          |
+----------+-----------+-----------+----------+----------+----------+
|          | **N= 32** | **N=27**  | **N=23** |          |          |
+----------+-----------+-----------+----------+----------+----------+
| D/C      | 0         | 0         | 3 (13)   |          |          |
+----------+-----------+-----------+----------+----------+----------+
| Death    | 0         | 0         | 0        |          |          |
+----------+-----------+-----------+----------+----------+----------+

One atazanavir 200 mg subject in study 007 died four weeks after
treatment discontinuation with the immediate cause of death specified as
liver failure; this was described as hepato-renal syndrome secondary to
multi-organ failure and complications of HIV disease, possibly
non-Hodgkin\'s lymphoma (autopsy indeterminate). With the exception of
five deaths related to lactic acidosis (four ATV, one NFV), no other
subjects died due to causes associated with hepatotoxicity; LAS/SHL are
adverse events attributed to the mitochondrial toxicity of NRTIs.

Of the 15 subjects discontinuing atazanavir for worsening of liver
function or hepatitis (without LAS/SHL) on therapy, 10 had chronic
hepatitis B or C. One subject had acute hepatitis B. One subject had a
prior history of hepatic steatosis. The three remaining subjects had no
apparent risk factors for hepatotoxicity.

Five of the eight subjects discontinuing treatment for worsening of
liver function on comparator regimens had chronic hepatitis B or C, one
subject was hepatitis B core antibody positive but surface antigen and
antibody negative, and one subject had acute hepatitis B. One subject
receiving ritonavir/saquinavir had no apparent risk factors for
hepatotoxicity.

In summary, hyperbilirubinemia seen in clinical trials was predominantly
indirect, and resulted in dose reduction and/or treatment
discontinuation in relatively few subjects ( 5%). With the exception of
hyperbilirubinemia, the incidence of LFT abnormalities and
discontinuations for hepatotoxicity, hepatitis, or LFT abnormalities in
subjects receiving atazanavir appeared to fall within the range of that
seen with other marketed protease inhibitors and non-nucleoside reverse
transcriptase inhibitors.

## Cardiac Issues

As mentioned previously in this document, evaluation of the QT interval
includes "correction" of the QT interval for heart rate, as the QT
interval decreases with increasing heart rate. Corrected QT intervals
(QTc) were derived using a correction formula known as Bazett's; this
has been the correction method historically used by the FDA and the one
on which criteria for evaluation of the QT interval have been based.
Several weeks ago, the Division requested that the applicant recalculate
data from two studies using a correction formula known as Fridericia's;
while this correction formula has not been used by the FDA to evaluate
potential QT effects in the past, it was felt that presentation of this
data would provide a balanced analysis of QT effects. This data will be
presented only by the applicant.

Several pharmacokinetic studies were undertaken by the applicant to
evaluate the effects of atazanavir on the QT interval after preclinical
studies revealed a weak signal for potential to prolong the QT interval.
We will focus here on study 076, a three-treatment, three-period
crossover study in which 72 subjects were randomized to receive multiple
once-daily doses of atazanavir at 400 mg, 800 mg, or a placebo in six
different sequences, with a washout period between doses of 14 days. The
results we will focus on here will be changes in the average Bazett's
corrected QT interval over 24 hours of dosing (QTcB Avg) and the changes
in the Bazett's corrected QT interval at the time of maximal atazanavir
concentration (QTcB at Tmax).

The following two graphs display the means of the QTc interval across a
24-hour period prior to dosing and then at day 6 of drug administration.

Plot of Mean QTcB From Time of Dosing on Day --1 (Baseline)\
Study 076

![](media/image1.png){width="5.6in" height="3.761111111111111in"}

Plot of Mean QTcB from Time of Dosing on Day 6\
Study 076

![](media/image2.png){width="4.8in" height="3.6in"}

As can be seen in the previous figures, differences in the mean QTcB
interval become apparent at the 800 mg dose at the time that corresponds
to the maximum concentration of atazanavir (Tmax \[2-2.5 hrs\]). An
analysis of covariance of QTcB changes from baseline showed that the
placebo-corrected difference in the mean changes from baseline of the
average QTcB interval between 800 mg and placebo was 5.4 msec (95% CI
2.4, 8.3). The difference in the mean changes from baseline in the QTcB
interval at Tmax was 7.9 msec (95% CI 2.8, 12.9).

Changes in mean QTcB intervals of \> 5 msec are considered potentially
clinically significant. While these signals were seen only at the 800 mg
dose, co-administration of atazanavir with other medications metabolized
by CYP 3A4 may lead to drug levels that could potentially result in
significant prolongation of the QT interval.

Summary statistics for derived QTcB changes from baseline in each
treatment group are summarized in the following table. A scatter plot of
QTc Avg changes from baseline versus ATV concentration follows this
table.

+-----------------+-------------+------------------+-------------------+
| # Summary o     |             |                  |                   |
| f Selected Deri |             |                  |                   |
| ved QTcB Change |             |                  |                   |
| s from Baseline |             |                  |                   |
+-----------------+-------------+------------------+-------------------+
| Dose            | Subjects    | QTcB Avg (msec)  | QTcB at Tmax      |
|                 | (#)         |                  | (msec)            |
|                 |             | Mean (SD)        |                   |
|                 |             |                  | Mean (SD)         |
+-----------------+-------------+------------------+-------------------+
|                 |             |                  |                   |
+-----------------+-------------+------------------+-------------------+
| Placebo         | 67          | -2.5 (10)        | -15 (20)          |
+-----------------+-------------+------------------+-------------------+
| 400 mg          | 65          | -3.0 (10)        | -17 (20)          |
+-----------------+-------------+------------------+-------------------+
| 800 mg          | 66          | 2.9 (13)         | -4 (22)           |
+-----------------+-------------+------------------+-------------------+

Scatter Plot and Fitted Regression Line of Derived QTc Avg Changes from
Baseline vs. Measures of Average ATV Concentration

![](media/image3.png){width="5.0in" height="3.520138888888889in"}

# Summary of Cardiovascular Evaluation of the QT Interval in Clinical Trials

Phase 3 studies 043 and 045 (antiretroviral-experienced subjects) were
designed to evaluate ECG parameters by obtaining a baseline ECG
measurement prior to study drug administration and by measuring serial
ECG parameters (pre-dose, 2 -3 hours post-dose, and 6 - 12 hours
post-dose) multiple times over the 48 week treatment period. However,
these studies did not include a washout period prior to enrollment, and
therefore, prior drugs may have influenced the baseline measurement.

The rollover phase 2 studies 007/041 and 008/044, and the phase 3 study
of treatment-naive subjects (034), were amended to include ECG
measurements. Three serial ECGs (pre-dose \[trough\], 2 -3 hours
post-dose, and 6 - 12 hours post-dose) were collected. Interpretation of
the ECG results was limited by several factors. First, no pre-study
baseline measurement was available for comparison and in addition, many
subjects had been receiving concomitant medications for various
durations at the time of the ECG recordings. Secondly, the timing of the
ECGs did not take into account diurnal variation. And lastly, a single
baseline ECG measure likely does not provide an accurate measure of a
baseline value from which to calculate delta signals.

For this section categories of QT prolongation will be reviewed, using
the following categories to assess potential signals for QT
prolongation:

## Normal QTc Interval Criteria

  ----------------------- ----------------------- -----------------------
  **QTc Interval (msec)** **Males**               **Females**

                                                  

  Normal                  \< 430                  \< 450

  Borderline              430 -- 450              450 -- 470

  Prolonged               \> 450                  \> 470
  ----------------------- ----------------------- -----------------------

#### Absolute QTc Signals

QTc \> 450 msec

QTc \> 470 msec

QTc \> 500 msec

#### 

#### Changes from Baseline (Delta) Signals

QTc increase from baseline 30 msec

QTc increase from baseline 60 msec

## Study 034 - In study 034 subjects from each treatment arm had similar numbers of subjects with QTc prolongation.

Maximum Post-Dose QTc (msec)

  ---------------- ------------------ ------------------- -----------------
                                      **Females**         

                   **\< 450**         **450 -- 470**      **\> 470**

  Atazanavir       121/127 (95)       6/127 (5)           0/127 (0)

  Efavirenz        99/103 (96)        3/103 (3)           1/103 (1)

                                                          

                                      **Males**           

                   **\< 430**         **430 -- 450**      **\>450**

  Atazanavir       202/225 (90)       19/225 (8)          4/225 (2)

  Efavirenz        198/221 (90)       17/221 (8)          6/221 (3)
  ---------------- ------------------ ------------------- -----------------

One male subject receiving efavirenz experienced a QTc \> 500 msec. Nine
of the eleven subjects with QTc prolongation were receiving drugs
mentioned as possible contributors to QTc interval prolongation in the
literature, specifically trimethoprim/sulfamethoxasole, amitriptyline,
and fluconazole; their contribution to QT prolongation in this
population is unknown.

###### Changes from Trough QTc to Post-Dose Maximum QTc

  ---------------- ------------------ ------------------- -----------------
                   **30**             **30 - 60**         **60**

                                                          

  Atazanavir       304/352 (86)       44/352 (13)         4/352 (1)

                                                          

  Efavirenz        303/324 (94)       21/324 (6)          0/324 (0)
  ---------------- ------------------ ------------------- -----------------

##### 

In study 034 no cardiovascular (CV) events led to death and no events of
sudden death were reported. CV events leading to treatment
discontinuation occurred only in the efavirenz arm (1 event each of MI,
HTN, syncope, palpitations, and vasodilatation). Four CV events coded as
SAEs by investigators occurred and all were in efavirenz arm (1 MI, 2
syncope, 1 HTN). Grade 3-4 CV events occurred in 3 atazanavir treated
patients (1 event each of hypotension, syncope, and bradycardia). The 3
events occurring in atazanavir were related to one event of
meningoencephalitis (bradycardia), and two events of grade 3-4 anemia
(hypotension and syncope).

All other CV events occurred with roughly equal frequency between arms
with the exception of vasodilatation which was more frequent in the EFV
arm. AEs potentially related to arrhythmia were reviewed (w/exception of
dizziness) and found to be generally mild, self-limiting, and
attributable to causes other than arrhythmia.

**Study 043** -- In this study two atazanavir subjects and seven
lopinavir/ritonavir subjects had post-baseline QTc prolongation. None of
these subjects were on concomitant medications known to prolong the QT
interval. Slightly more patients on LPV/RTV had post-dose maximum
changes from baseline QTc greater than 60 msec.

###### Changes From Trough QTc to Post-Dose Maximum QTc

  --------------------- ---------------- ---------------- ---------------
                        **30**           **30 - 60**      **60**

                                                          

  Atazanavir            77/107 (72)      28/107 (26)      2/107 (2)

                                                          

  Lopinavir/Ritonavir   77/115 (67)      31/115 (27)      7/115 (6)
  --------------------- ---------------- ---------------- ---------------

No cardiovascular events led to death or discontinuation from study. One
LPV/RTV subject experienced an MI on study; no other CV events were
reported as SAEs or as grade 3-4 events. Other reported CV events that
were considered to be potentially related to study therapy by
investigators included one event of extrasystole in an ATV patient and
one event of palpitations in a LPV/RTV patient; no ECGs were recorded at
the time of these events.

## PR Interval

Evaluation of the effects of atazanavir on the PR interval in the
previously described study 076 revealed a moderate dose-dependent
prolongation of the PR interval. The following table summarizes mean
changes in the maximum PR interval and the incidence of first degree AV
block seen in study 076.

+-------+-------+-----------+-----------+------------+--------------+
| **Ch  |       |           |           |            |              |
| anges |       |           |           |            |              |
| in    |       |           |           |            |              |
| Ma    |       |           |           |            |              |
| ximum |       |           |           |            |              |
| PR    |       |           |           |            |              |
| Inter |       |           |           |            |              |
| val** |       |           |           |            |              |
|       |       |           |           |            |              |
| **And |       |           |           |            |              |
| Inci  |       |           |           |            |              |
| dence |       |           |           |            |              |
| of    |       |           |           |            |              |
| First |       |           |           |            |              |
| D     |       |           |           |            |              |
| egree |       |           |           |            |              |
| AV    |       |           |           |            |              |
| Block |       |           |           |            |              |
| --    |       |           |           |            |              |
| Study |       |           |           |            |              |
| 076** |       |           |           |            |              |
+-------+-------+-----------+-----------+------------+--------------+
| Dose  | \# of | Baseline  | PR Max    | PR Max     | Subjects w/  |
|       | Sub   |           |           |            |              |
|       | jects | PR Max    | Mean (SD) | from       | AV block     |
|       |       |           |           | Baseline   |              |
|       |       | Mean (SD) |           |            | Eva          |
|       |       |           |           | Mean (SD)  | luable/Total |
|       |       |           |           |            | (%)          |
+-------+-------+-----------+-----------+------------+--------------+
|       |       |           |           |            |              |
+-------+-------+-----------+-----------+------------+--------------+
| Pl    | 67    | 154 (17)  | 166 (17)  | 13 (11)    | 1/67 (1)     |
| acebo |       |           |           |            |              |
+-------+-------+-----------+-----------+------------+--------------+
| 400   | 65    | 155 (19)  | 180 (18)  | 24 (15)    | 9/65 (14)    |
| mg    |       |           |           |            |              |
+-------+-------+-----------+-----------+------------+--------------+
| 800   | 66    | 152 (17)  | 212 (31)  | 60 (25)    | 39/66 (59)   |
| mg    |       |           |           |            |              |
+-------+-------+-----------+-----------+------------+--------------+

PR intervals \> 250 msec were observed in eight subjects receiving 800
mg of atazanavir in study 076. A PR interval of 324 msec was observed in
one female subject receiving the 800 mg dose.

In another pharmacokinetic study designed to study ECG effects, a female
subject was discontinued from the study when she developed an
asymptomatic prolongation of the PR interval of \> 400 msec on an 800 mg
dose of ATV.

**Study 034** - At trough drug concentrations, the mean PR interval was
5 msec shorter for subjects receiving EFV compared with subjects
receiving ATV. Minimal changes in the mean post-dose PR intervals from
trough were observed on both treatment regimens. Maximum recorded PR
intervals on atazanavir ranged from 265-307 msec.

Seven of 324 evaluable subjects (2.2%) treated with EFV and 16 of 352
evaluable subjects (4.5%) treated with ATV experienced first degree AV
block (PR \> 200 msec) on at least one ECG. One subject receiving
atazanavir reported bundle branch block and one patient receiving
efavirenz reported bifasicular block. Neither event was reported as a
Grade 3-4 event, an SAE, or resulted in discontinuation from therapy.

**Study 043** -- No differences in mean PR intervals were noted between
atazanavir and lopinavir/ritonavir subjects. Mean PR intervals at all
time points were similar. The mean PR interval at the time corresponding
to Cmax for atazanavir was 157 msec for both ATV and LPV/RTV. Six
percent of subjects in both treatment arms experienced first degree AV
block. No other conduction abnormalities were reported in this study.

As mentioned previously in this document, one subject receiving
atazanavir in combination with DLV/TNF/3TC through the expanded access
protocol was hospitalized with atypical angina and a junctional rhythm.
Medications included verapamil and mirtazapine; ARV medications were
discontinued following hospital admission, however, verapamil and other
medications were continued. Junctional rhythm persisted despite
discontinuation of atazanavir. The patient was found unresponsive during
hospital admission with an idioventricular rhythm; preliminary autopsy
revealed a 95% LAD without evidence of infarct.

It is likely the junctional rhythm in this patient was multifactorial.
It may have been due, in part, to high serum levels of both verapamil
and atazanavir that occurred with co-administration of delavirdine, a
CYP 3A4 inhibitor. Persistence of this rhythm after discontinuation of
atazanavir would suggest that factors other than atazanavir use
contributed to the development of this rhythm in this patient.

In summary, while pharmacokinetic studies designed to evaluate effects
of atazanavir revealed moderate effects on the PR interval, clinical
events related to prolongation of the PR interval were uncommon. First
degree AV block was the most common abnormality observed. Effects on the
QT interval appeared to be minimal.

VII. **Questions for the Advisory Committee**

Listed below are a number of questions for you to consider during the
discussion period.

1)  Are the available data sufficient to support approval of atazanavir
    for the treatment of HIV infection?

> If no, what additional studies are recommended?
>
> If yes, please address the following questions.

2)  Does the degree of hyperbilirubinemia seen with atazanavir
    administration raise any significant safety concerns?

3)  Does prolongation of the PR and QT interval raise any significant
    safety concerns?

4)  Does the committee believe that the effect of atazanavir on lipid
    parameters offers patients a unique advantage over other treatment
    options?

5)  Please provide your risk/benefit assessment of atazanavir and its
    implications for clinical use.

6)  Please provide us with recommendations for any Phase 4 studies of
    atazanavir.