Conditions: HIV Infections
Keywords: HIV treatment Treatment-naive Adult
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 51
Healthy volunteers: no

Brief summary:
CCTG 589 is a randomized, open-label, pilot study comparing the efficacy, safety and tolerability of RAL plus LPV/r to EFV plus TDF/FTC in HIV-infected, treatment-naïve subjects. Subjects will be ineligible if they have any evidence of drug resistant virus in the past or at the time of screening (if never previously tested). Those who are found to be eligible will be randomized 1:1 to initiate either LPV/r (400/100 mg) plus RAL (400mg), both given twice-daily, or fixed dose combination of EFV (600 mg), TDF (300 mg) and FTC (200 mg) given as once-daily Atripla® for 48 weeks.

Hypotheses

1. The novel nucleoside-sparing combination of LPV/r + RAL will have a faster phase 1 viral decay rate compared to standard-of-care therapy with EFV/TDF/FTC in antiretroviral-naïve patients.

   1. Faster phase 1 viral decay dynamics will be associated with improved longer-term (week 48) viral suppression.
   2. Faster phase 1 viral decay dynamics will be associated with accelerated early (Day 0-14) clearance of cell-associated HIV DNA.
   3. Faster phase 1 viral decay dynamics will be associated with greater early (baseline to week 12) CD4+ T-cell recovery.
2. The LPV/r + RAL arm will have greater decreases in early (baseline to week 4) CD4/CD8 T-cell immune activation and apoptosis which will be associated with greater late (week 12 to week 48) CD4+ T-cell recovery.
3. Subjects treated with LPV/r + RAL arm will have smaller changes in total cholesterol and triglycerides from baseline than those receiving EFV/TDF/FTC.

Detailed description:
The purpose of this study is to determine how well a new anti-HIV drug combination (RAL plus LPV/r) taken twice a day decreases the amount of HIV found in participants' blood (viral load) compared to taking the once-a-day combination pill Atripla®. This study will also try to determine if the new combination has fewer side effects and is tolerated better than Atripla®. Another reason this study is being done is to see if this new drug combination helps participants' body's CD4 cells recover differently and will also look at how well participants' bodies absorbs these drugs and how safe these drugs are when given together.

Arms:
arm 1: Kaletra (lopinavir/ritonavir 400/100 mg) + Isentress (Raltegravir 400 mg) twice-daily arm 2: Sustiva (EFV 600 mg), Viread (TDF 300 mg) and Emtriva (FTC 200 mg) taken as Atripla® once-daily

Interventions: intervention 1: Kaletra + Isentress intervention 2: Atripla
Intervention descriptions: intervention 1: kaletra 2 tabs twice a day + Raltegravir 1 tab twice a day intervention 2: Atripla 1 tab once a day

Protocol document:
Prot_SAP_000.pdf: 
 
 
CCTG 589 
 
 
Protocol version 1.0 
 
 
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CCTG 589 
 
 
Nucleoside-Sparing Combination Therapy with Lopinavir/ritonavir (LPV/r) + 
Raltegravir (RAL) vs. Efavirenz (EFV) + Tenofovir Disoproxil Fumarate + 
Emtricitabine (TDF/FTC) in Antiretroviral-Naïve Patients 
 
Sponsored by: 
 
 
The California HIV/AIDS Research Program (CHRP) 
 
 
 
Pharmaceutical Support Provided by: 
 
 
Abbott Laboratories 
and   
Merck Pharmaceuticals  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Co-chairs:  
 
 
Miguel Goicoechea, M.D. 
 
 
 
 
 
 
Gunter Rieg, M.D.     
 


 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .......................................................................................... 4 
PROTOCOL TEAM ROSTER ........................................................................................ 5 
SCHEMA ......................................................................................................................... 7 
1.0 STUDY OBJECTIVES .............................................................................................. 8 
1.1 Primary Objectives............................................................................................ 8 
1.2 Secondary Objectives........................................................................................ 8 
2.0 INTRODUCTION ..................................................................................................... 8 
2.1 Background ....................................................................................................... 8 
2.2    Rationale ......................................................................................................... 17 
3.0 STUDY DESIGN..................................................................................................... 19 
4.0 SELECTION AND ENROLLMENT OF SUBJECTS ............................................ 21 
4.1 Inclusion Criteria ............................................................................................ 21 
4.2 Exclusion Criteria ........................................................................................... 22 
4.3 Study Enrollment Procedures ......................................................................... 23 
4.4 Co-enrollment Guidelines ............................................................................... 23 
5.0 STUDY TREATMENT ........................................................................................... 24 
5.1 Dosing, Administration, and Duration ............................................................ 24 
5.2 Product Formulation and Preparation ............................................................. 24 
5.3 Product Supply, Distribution, and Pharmacy .................................................. 25 
5.4 Concomitant Medications ............................................................................... 25 
5.5 Adherence Assessment ................................................................................... 30 
6.0        CLINICAL AND LABORATORY EVALUATIONS ..................................... 31 
6.1 Schedule of Events – Clinical Evaluations ..................................................... 31 
6.2 Definitions for Schedule of Events – Timing of Evaluations ......................... 33 
6.3 Special Instructions and Definitions of Evaluations ....................................... 37 
6.4 Off-Drug Requirements .................................................................................. 43 
7.0 TOXICITY MANAGEMENT ................................................................................. 43 
8.0 CRITERIA FOR TREATMENT DISCONTINUATION ....................................... 48 
8.1 Criteria for Treatment Discontinuation ........................................................... 48 
8.2 Criteria for Discontinuation from the Study ................................................... 48 
9.0 STATISTICAL CONSIDERATIONS..................................................................... 49 
9.1 General Design Issues ..................................................................................... 49 
9.2 Endpoints ........................................................................................................ 49 
9.3 Sample Size ..................................................................................................... 50 
9.5 Monitoring ...................................................................................................... 52 
10.0 
DATA COLLECTION AND MONITORING AND ADVERSE 
EXPERIENCE REPORTING ........................................................................................ 52 
10.1 Records to Be Kept ......................................................................................... 53 
10.2 Role of Data Management .............................................................................. 53 
10.3 Clinical Site Monitoring and Record Availability .......................................... 53 
10.4 Serious Adverse Experience (SAE) Reporting ............................................... 53 
11.0 
HUMAN SUBJECTS ..................................................................................... 53 
11.1 Institutional Review Board (IRB) Review and Informed Consent ................. 53 


 
 
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11.2 Subject Confidentiality ................................................................................... 54 
11.3 Study Discontinuation ..................................................................................... 54 
12.0 
PUBLICATION OF RESEARCH FINDINGS .............................................. 54 
13.0 
BIOHAZARD CONTAINMENT ................................................................... 54 
14.0 
REFERENCES ............................................................................................... 54 
 


 
 
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LIST OF ABBREVIATIONS 
 
AE 
 
Adverse Event 
ALP 
 
Alkaline Phosphatase 
ALT 
 
Alanine Phosphatase 
ARV  
Antiretroviral Therapy 
AST 
 
Aspartate Phosphatase 
AUC  
Area Under the Curve 
BID 
 
Twice Daily 
BUN  
Blood Urea Nitrogen 
CCR5  
Chemokine Receptor 5 
CCTG 
California Collaborative 
Treatment Group 
CD4 
 
CD4 lymphocytes 
CRF 
 
Case Report Form 
CYP  
Cytochrome 
EFV 
 
Efaverenz 
FTC 
 
Emtricitabine 
HAART 
Highly Active 
Antiretroviral Therapy 
HBV  
Hepatitis B Virus 
HCV  
Hepatitis C Virus 
Hct 
 
Hematocrit 
HIV-1 
Human Immuno-
deficiency Virus - 1 
Hgb 
 
Hemoglobin 
IAS 
International AIDS 
Society 
IQR 
 
Interquartile Range 
ITT 
 
Intention To Treat 
LPV 
Lopinavir  
LPV/r 
Lopinavir/ ritonavir  
NNRTI 
Non-Nucleoside analogue 
Reverse Transcriptase 
Inhibitor  
NRTI 
Nucleoside analogue 
Reverse Transcriptase 
Inhibitor 
PBMC 
Peripheral Blood 
Mononuclear Cells 
PI 
 
Protease Inhibitor 
PK 
Pharmacokinetics  
QD 
Once Daily  
RAL 
Raltegravir  
RTV 
Ritonavir  
TDF 
Tenofovir disoproxil 
fumarate 
SAE 
 
Severe Adverse Reaction 
VD 
 
Viral Dynamics  
WBC  
White Blood Count 
 
 
 


 
 
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PROTOCOL TEAM ROSTER    
 
Co-Chairs 
 
Miguel Goicoechea, M.D. 
Assistant Professor of Medicine 
University of California, San Diego 
150 West Washington Street, 100 
San Diego, CA 92103 
Phone: (619) 543-8080 
Fax:   (619) 298-0177 
E-mail: mgoicoechea@ucsd.edu  
 
Gunter Rieg, M.D. 
Assistant Clinical Professor of Medicine 
David Geffen School of Medicine at 
UCLA Harbor-UCLA Medical Center 
1124 West Carson Street,  N24 
Torrance, CA 90502 
Phone: (310) 222 2467 
Fax: 
(310) 533 0447 
E-mail:  grieg@labiomed.org  
 
Vice Co-Chairs 
 
Richard Haubrich, M.D. 
Professor of Medicine 
University of California, San Diego 
150 West Washington Street, 100 
San Diego, CA  92103 
Phone:  (619) 543-8080 
Fax:   (619) 298-0177 
E-mail: rhaubrich@ucsd.edu 
 
Eric Daar, M.D.  
Chief, Division of HIV Medicine 
Harbor-UCLA Medical Center 
Professor of Medicine 
David Geffen School of Medicine at 
UCLA 
1124 W. Carson St., N-24 
Torrance, CA 90502 
Phone: (310) 222-2467 
Fax: 
(310) 533-0447 
E-mail:EDaar@LABioMed.org 
 
Co-Investigators 
 
Mallory Witt, M.D. 
David Geffen School of Medicine at 
UCLA Harbor-UCLA Medical Center 
1000 W. Carson Street, Bldg N-24 
Torrance, CA 90509 
Tel: (310) 222-2467 
E-mail: mwitt@labiomed.org 
 
Jeremiah G. Tilles, M.D. 
Professor of Medicine 
UCI Dept. of Medicine, Bldg 11, Rte 81 
101 City Drive South 
Orange, CA 92868 
Tel: (714) 456-5915 
E-mail: jgtilles@uci.edu 
 
Catherine Diamond, M.D. 
UCI Dept. of Medicine, Bldg 11, Rte 81 
101 City Drive South 
Orange, CA 92868 
Tel: (714) 456-7612 
E-mail: diamondc@uci.edu 
 
Carol Kemper, M.D. 
Santa Clara Valley Medical Center 
751 S. Bascom Avenue 
San Jose, CA 95128 
Tel: (650) 934-7007 
cakemper@earthlink.net 
 
Robert Larsen, M.D. 
LAC+USC Medical Center 
2020 Zonal Avenue, Rm 632 
Los Angeles, CA 90033 
Tel: (323) 226-7194 
E-mail: rlarsen@usc.edu 
 
Michael Dube, M.D. 
LAC+USC Medical Center 
2020 Zonal Avenue, Rm 632 


 
 
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Los Angeles, CA 90033 
Tel: (323) 226-7194 
E-mail: mdube@usc.edu 
 
Statistician  
 
Sonia Jain, Ph.D. 
Assistant Professor 
Division of Biostatistics & 
Bioinformatics 
University of California, San Diego 
9500 Gilman Drive, MC 0717 
La Jolla, CA 92093-0717 
Phone: (858) 822-2388 
Fax: (858) 822-0617 
E-mail:  sojain@ucsd.edu 
 
Ronald G. Thomas, Ph.D. 
Professor and Chief Division of 
Biostatistics and Bioinformatics  
Director of the Biostatistics and 
Bioinformatics Laboratory 
University of California, San Diego 
9500 Gilman Drive, MC 0645 
La Jolla, CA 92093-0645 
Phone: (858) 822-3508 
Fax: (858) 822-5290 
E-mail:  rgthomas@ucsd.edu 
 
Industry Representatives 
 
Ashwaq Hermes, Pharm.D. 
Abbott Laboratories  
Sr. Clinical Science Manager 
200 Abbott Park Rd. 
Abbott Park, IL 60064 
Mobile 619.384-1997 
Fax 858.459-7124 
E-mail: ashwaq.hermes@abbott.com 
 
Kathleen Bailey, MS, NP 
Merck Laboratories 
E-mail: Kathleen_bailey@merck.com 
 
Protocol Data Center 
 
Fang Wang 
CCTG Data and Biostatistical Unit 
150 West Washington, Suite 100 
San Diego, CA 92103-8208 
(619) 543-8080 
(619) 298-1379 FAX 
 
Edward Seefried, R.N. 
Protocol Coordinator/Monitor 
CCTG Data and Biostatistical Unit  
150 West Washington, Suite 100  
San Diego, CA 92103-8208 
Phone: (619) 543-8080   
Fax: (619) 298-1379  


 
 
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SCHEMA    
 
Nucleoside-Sparing Combination Therapy with Lopinavir/ritonavir (LPV/r) + 
Raltegravir (RAL) vs. Efavirenz (EFV) + Tenofovir Disoproxil Fumarate + 
Emtricitabine (TDF/FTC) in Antiretroviral-Naïve Patients 
 
Design: 
CCTG 589 is a randomized, open-label, pilot study comparing the 
efficacy, safety and tolerability of RAL plus LPV/r to EFV plus 
TDF/FTC in HIV-infected, treatment-naïve subjects. Subjects will be 
ineligible if they have any evidence of drug resistant virus in the past 
or at the time of screening (if never previously tested). Those who 
are found to be eligible will be randomized 1:1 to initiate either 
LPV/r (400/100 mg) plus RAL (400mg), both given twice-daily, or 
fixed dose combination of EFV (600 mg), TDF (300 mg) and FTC 
(200 mg) given as once-daily Atripla® for 48 weeks. 
 
Duration: 
48 weeks 
 
Sample Size: 
50 subjects (25 per treatment arm) 
 
Study Population: 
HIV-1-infected treatment-naïve men and women (defined as having 
never received any HIV antiretroviral agents in the past) at least 18 
years of age with plasma HIV-1 RNA > 5,000 copies/mL and CD4+ 
T-cell count > 50 cells/mm3 with no evidence of drug resistant virus 
detected by genotype. 
 
Stratification: 
Subjects will be stratified based upon screening plasma HIV-1 RNA 
greater than or equal to, or below 100,000 copies/mL.   
 
Regimen: 
Subjects will be randomized 1:1 to initiate combination therapy 
either with LPV/r (400/100 mg) plus RAL (400mg twice-daily) or 
fixed dose combination of EFV (600 mg), TDF (300 mg) and FTC 
(200 mg) taken as Atripla® once-daily for 48 weeks. The study will 
provide LPV/r and RAL, however, Atripla® must be provided by 
prescription. 


 
 
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1.0 STUDY OBJECTIVES 
 
1.1 Primary Objectives 
 
1.1.1 To compare the phase 1 viral decay rates between LPV/r + RAL vs. 
EFV/TDF/FTC treatment combinations. 
 
1.2 Secondary Objectives 
 
1.2.1 To determine the antiviral efficacy of LPV/r + RAL compared to 
EFV/TDF/FTC after 48 weeks of treatment. 
 
1.2.2 To compare early (baseline to week 12) and late (week 12 to week 48) 
CD4+ T-cell recovery rates between treatment regimens. 
 
1.2.3 To evaluate the association of phase 1 viral decay dynamics (baseline to day 
14) on phase 1 (baseline to week 12) CD4+ T-cell recovery. 
 
1.2.4 To evaluate the association of early changes in immune subsets (baseline to 
week 4) on phase 2 (week 12 to week 48) CD4+ T-cell recovery. 
 
1.2.5 To compare the effect of LPV/r + RAL vs. EFV/TDF/FTC on change in 
fasting lipid profiles. 
 
1.2.6 To evaluate the safety and tolerability of this novel nucleoside-sparing 
combination of LPV/r + RAL compared to EFV/TDF/FTC therapy. 
 
2.0 INTRODUCTION 
 
2.1 Background 
 
Although current Department of Health and Human Services (DHHS) guidelines 
recommend either efavirenz (EFV) or a ritonavir-boosted protease-inhibitor (PI) in 
combination with two nucleoside reverse transcriptase inhibitors (NRTIs) as initial 
therapy of treatment-naïve patients [1], combinations of EFV + two NRTIs have 
been preferred by most practitioners. Specifically, the fixed dose combination of 
EFV/TDF/FTC is currently one the most prescribed regimen used in therapy-naïve 
patients. However, certain treatment-limiting toxicities have been associated with 
EFV and TDF-based therapy, including: renal [2], CD4+ T-cell decline [3], central 
nervous system [4] and lipatrophy [5]. Recently, new drug classes have been 
developed and potential new NRTI and NNRTI-sparing treatment options may be 
considered for treatment-naïve patients. 
 
The combination of LPV/r + RAL offers potential therapeutic advantages over 
current standard-of-care therapy that will be evaluated with the proposed study: 


 
 
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1. Antiviral Potency: Individually, LPV/r and RAL are potent antiretrovirals 
(ARVs) that act on distinct steps in viral replication. The combination of a late 
(i.e. LPV/r) and mid-cycle (i.e. RAL) viral target inhibitor could more 
efficiently stop viral replication from cell reservoirs leading to a more rapid 
early plasma viral decay rate than the combination of EFV/TDF/FTC which 
inhibits a common viral replication step. 
 
2.  Immune Recovery: Faster viral decay dynamics could result in greater phase 1 
(baseline to week 12) CD4+ T-cell recovery.  In addition, the inclusion of LPV/r 
may further decrease activation-induced apoptosis and enhance subsequent 
phase 2 (week 12 to 48) T-cell regeneration.  
 
 
2.1.1   Lopinavir/ritonavir (Kaletra®, LPV/r) 
 
LPV is a potent inhibitor of HIV-1 protease.  When coformulated with LPV, 
ritonavir inhibits the CYP3A-mediated metabolism of LPV, thereby 
providing increased plasma levels of LPV/r.  LPV/r has been evaluated and 
approved by the FDA for use in combination with other ARV agents for the 
treatment of HIV-1 infection.  LPV/r twice daily is one of the preferred PI in 
treatment-naïve HIV-infected patients in the DHHS HIV treatment guideline 
for adults and adolescents (DHHS 1-08).  
 
2.1.1.1 Efficacy 
 
The efficacy of LPV/r has been studied in ARV-naïve and ARV-
experienced HIV-1 infected patients. The M97-720 study, a phase II study 
of LPV/r in combination with NRTIs in ARV- naïve HIV-1-infected 
subjects, was a randomized, dose-blinded, multicenter trial with two groups 
of subjects enrolled [6].  Group I subjects (n=32) were randomly assigned to 
200 mg LPV/100 mg RTV Q12H or 400 mg LPV/100 mg RTV Q12H 
monotherapy. On day 22, all subjects added stavudine (d4T) and lamivudine 
(3TC).  Group II subjects (n=70) were randomly assigned to 400 mg 
LPV/100 mg RTV Q12H or 400 mg LPV/200 mg RTV Q12H and received 
d4T and 3TC beginning on day 1. After 48 weeks, all subjects converted to 
open-labeled LPV/r 400mg/100mg BID dosing. At year 6, d4T / 3TC was 
substituted with TDF in combination with LPV/r in 37 subjects.  Similar 
efficacy was observed across all dosing groups. However, a trend towards 
higher lipid levels and increased rates of gastrointestinal adverse events was 
seen in the highest dose group, 400 mg LPV/200 mg RTV.  Based on a 
review of this and other phase I/II data, a dose of 400 mg LPV with 100 mg 
RTV BID was selected for development.  After week 48, all subjects were 
converted to this dose. 
 


 
 
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At week 360 (7 year data), by intent-to-treat missing=failure (ITT M=F) 
analysis, 61% of all participants had HIV-1 RNA <400 copies/mL, while the 
corresponding on-treatment (OT) analysis showed 98% suppressed to this 
level.  By ITT M=F analysis, 59% of study subjects had HIV-1 RNA <50 
copies/mL (OT: 95%). During 7 years of treatment with LPV/r, there were 
18 subjects that met the criteria for loss of virologic response, and 11 
participants had at least one “blip” after week 24.  Resistance tests were 
performed on 29 subjects.  In 19 individuals with available results, no LPV 
or d4T resistance was observed.  Four individuals demonstrated 3TC 
resistance with six demonstrating a new secondary mutation/ polymorphism 
in protease at rebound, but phenotypic LPV susceptibility was not affected.  
 
In a phase III M98-863 study, the safety and efficacy of LPV/r versus 
nelfinavir (NFV) both in combination with d4T and 3TC was evaluated in 
ARV-naïve subjects. The M98-863 study was a randomized, double-blind, 
multicenter, international trial [6]. Overall, 326 subjects were assigned to the 
LPV/r group and 327 to the NFV group. The superior antiviral activity of 
LPV/r was demonstrated by the analysis of the proportion of subjects 
achieving a plasma HIV-1 RNA below 400 copies/mL at week 48 (75% vs. 
63% respectively, ITT, p<0.001) and the analysis of the proportion of 
subjects achieving a plasma HIV-1 RNA below 50 copies/mL at week 48 
(67% vs. 52% respectively, ITT, p<0.001).  In the analysis of the time to 
loss of virologic response through week 48, superior antiviral activity of 
LPV/r was also demonstrated (p<0.001, Cox proportional hazards model) 
with 84% of LPV/r and 66% of NFV-treated subjects maintaining virologic 
suppression.  Samples from 51 (69%) LPV/r-treated and 96 (78%) NFV-
treated subjects could be amplified for resistance testing.  No primary 
protease mutations were detected in the rebound sample from any of the 
LPV/r-treated subjects through week 108.  In contrast, new protease 
mutations developed in 43 of 96 samples from NFV-treated subjects, and PI 
resistance was confirmed by phenotypic analysis.  Resistance to 3TC and 
d4T was also significantly higher in NFV- than LPV/r-treated subjects. 
 
2.1.1.2 Impact on CD4+ T-cell Recovery 
 
In both of these trials in ARV- naïve patients, LPV/r led to a significant 
recovery of CD4 cells. In the M97-720 study, the mean increase in CD4+ T-
cell counts between baseline and week 360 was 501 cells/mm3.  In the M98-
863 study, LPV/r led to a similar CD4+ T-cell cell recovery in the LPV/r 
group than in the NFV group. The mean change in CD4+ T-cell count at 
week 48 was 207 cells/mm3 for the LPV/r-treated group and 195 cells/mm3 
for the NFV-treated group. 
 
 
 
 


 
 
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2.1.1.3 Safety and Tolerability 
 
LPV/r is generally well tolerated. In the M97-720 study, 38 subjects 
discontinued at or prior to week 360.  Reasons for discontinuation probably 
or possibly due to study drugs include: AST/ALT increases (n=2), diarrhea 
(n=1), liver pain/enlargement, fatty deposits (n=1), arthralgia (n=1), elevated 
lipids (n=2), fat redistribution (n=5), and death of unknown cause (n=1) (10 
days after thoracic spinal surgery with perioperative myocardial infarction).  
The most frequent adverse events of moderate or severe intensity and 
probable, possible, or unknown relationship to LPV/r in both M97-720 
treatment groups were diarrhea (28%), nausea (16%), lipodystrophy (12%), 
abdominal pain (11%). The most frequent Grade ≥3 laboratory 
abnormalities were cholesterol >300 mg/dL (27%), triglycerides >750 
mg/dL (29%), and AST/ALT >5 x ULN (11%).   
 
The safety and tolerability of LPV/r and NFV were also assessed in the 
M98-863 study.  In this study, only 3% of subjects in the LPV/r treatment 
group and 4% of the subjects in the NFV group discontinued therapy at or 
before week 48 due to study drug-related adverse events.  Diarrhea and 
nausea were the most frequently reported adverse events in both treatment 
groups.  However, study drug interruptions and discontinuations related to 
diarrhea or nausea were infrequent, occurring in less than 2% of subjects in 
either treatment group.  Adverse events consistent with body fat 
composition changes were reported in 5% of LPV/r and 6% of NFV-treated 
subjects through week 48.  Five individuals receiving LPV/r and three NFV 
died.  One death due to pancreatitis was considered possibly related to 
LPV/r; with the person also having lactic acidosis.  Clinically significant 
laboratory abnormalities were infrequent in both treatment groups.  Grade 3 
or 4 elevations of cholesterol were noted in 9% of LPV/r-treated and 5% of 
NFV-treated subjects.  Grade 3 or 4 triglyceride elevations were noted more 
frequently in LPV- than NLF-treated subjects (9% vs. 1%, respectively, p 
<0.001). However, Grade 3 or 4 elevations of lipids were generally 
intermittent with the majority of subjects who experienced such elevations 
not having persistent elevations above Grade 2.  No subjects discontinued 
the study due to lipid elevations. 
 
2.1.1.4 Drug Interactions and Special Populations 
 
 
LPV is metabolized by CYP3A. Drugs that induce CYP3A activity are 
expected to increase the clearance of LPV resulting in lower plasma levels 
while those that inhibit CYP3A are expected to increase plasma levels of 
LPV (see Section 5.4 Concomitant Medications). 
 
LPV/r has a pregnancy category C rating.   
 


 
 
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2.1.2 Raltegravir (Isentress®, RAL) 
 
RAL is the first FDA approved agent in the class of integrase inhibitors. 
RAL targets the HIV-1 integrase enzyme which is required for viral 
replication. HIV-1 encoded integrase catalyzes the insertion of the HIV-1 
DNA into the genome of the host cell. Raltegravir acts at the step of strand 
transfer and prevents transfer of HIV DNA into the host DNA. 
 
2.1.2.1 Efficacy 
 
RAL has been evaluated in several clinical trials in ARV- naïve and – 
experienced HIV-1 infected patients. The protocol 004 is a multicenter, 
double-blinded, randomized 2-part, dose ranging study. In part I, RAL was 
given as one of four different doses (100mg, 200mg, 400mg, 600mg BID) as 
monotherapy to 35 patients for 10 days. In part II, RAL was given as one of 
four different doses and compared to EFV both in combination with TDF + 
3TC for 48 weeks. After 48 weeks, participants who received RAL at 
different doses, were continued at a RAL dose of 400mg BID combined 
with TDF/3TC and compared with the group receiving EFV/TDF/3TC.  
RAL was found efficacious when given as monotherapy in all evaluated 
doses with a mean decrease of HIV RNA from baseline to day 10 of 1.7 – 
2.2 log10 copies/mL (Part I) [7]. The 48 week analysis of part II included 
198 patients, 160 participants receiving RAL and 38 EFV [8]. At weeks 2, 4, 
and 8, the proportion of patients achieving an HIV-1 RNA level <50 
copies/mL was greater in each of the RAL treated groups than in the EFV 
group. By week 24, all treatment groups appeared similar, with plasma HIV-
1 RNA levels <400 copies/mL in 85% - 98% of subjects in the RAL group 
and 95% in the EFV group and <50 copies/mL in 85 - 95% of patients of 
subjects in the RAL groups and 92% in the EFV group. These viral load 
reductions were maintained through week 48 in 85% to 98% of patients and 
in 83% to 88% of patients, respectively. In a time-to-event analysis, patients 
receiving RAL at any dose achieved an HIV-1 RNA level < 50 copies/mL 
earlier than patients receiving EFV (log-rank test p<0.05).  Five (3%) 
patients on RAL and 1 (3%) on EFV experienced virologic failure before 
week 48. In two patients with virologic failure on RAL, the N155H 
mutation was detected in the HIV-1 integrase region. NNRTI and NRTI 
mutations (including the K65R mutation) were found in the one patient 
failing in the EFV group.   
 
Two phase III randomized controlled trials of treatment-experienced 
subjects have also been reported.  These studies, BENCHMRK 1 and 2 were 
conducted in Europe, Asia/Pacific, Peru, and North and South America [9, 
10]. In these studies, triple class resistant subjects were randomized 2:1 to 
RAL 400 mg BID or placebo plus optimized background therapy (OBT).  


 
 
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Results showed that 64% and 34% of subjects in the RAL and placebo arms, 
respectively, had plasma HIV-1 RNA < 50 copies/mL at 48 weeks.  
A cross-sectional analysis of integrase resistance data from the 
BENCHMRK-1 and 2 studies have been presented. Mutations in the 
integrase region of HIV pol at Q148 or N155 in combination with at least 
one other mutation were associated with virological failure.  
 
2.1.2.2 CD4+ T-cell Recovery 
 
The mean increase in CD4+ T-cell count in Study 004 ranged from 70-104 
cells/mm3 across all treatment groups and continued to increase through 
week 32. The mean CD4+ T-cell increase was comparable between the 
different RAL groups and EFV.  
 
2.1.2.3 Safety and Tolerability 
 
RAL was overall well tolerated. In the study 004, there were overall fewer 
drug related clinical adverse events in the RAL group than in the EFV group 
(p=0.04 for 100mg , 400mg and p=0.07 for 200mg RAL). The most frequent 
drug related adverse events were nausea, headache, dizziness. Serious 
adverse event occurred in 6% in the RAL group experienced and 5% in the 
EFV group. None of the serious adverse events were considered drug related 
or led to treatment discontinuation. 
 
In the BENCHMRK trials, there was overall no difference in the clinical or 
laboratory toxicity between those receiving OBT with RAL than with 
placebo.  Drug-related clinical AEs were reported in >5% of subjects 
receiving RAL in BENCHMRK 1 for diarrhea (6.9%), with this occurring in 
14.4% of controls.  In BENCHMRK 2 clinical AEs occurring in >5% of 
RAL-treated subjects included diarrhea (13.9% versus 10.1% of controls), 
nausea (9.6% versus 9.2% ), fatigue (5.2% versus 2.5%) and headache 
(8.7% versus 5.0%). Laboratory abnormalities reported in > 5% of the RAL-
treated subjects in BENCHMRK 1 included LDL>190 mg/dL (7.8% versus 
6.4%), triglycerides >750 mg/dL (7.7% versus 2.5%), and alanine 
aminotransferase (ALT) >5.1 times ULN (6.5% versus 4.2%).  In contrast, 
for BENCHMRK 2 such laboratory abnormalities were only seen at >5% of 
individuals for triglycerides >750 mg/dL (10.6% versus 7.6%) and creatine 
kinase > 10 times ULN (6% versus 4.2%). 
 
2.1.2.4 Special Populations 
 
RAL has a pregnancy category C rating. 
 
 
2.1.3   Pharmacokinetic Compatibility of Lopinavir/ritonavir and Raltegravir 
 


 
 
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Data about potential pharmacokinetic interactions between LPV/r and RAL 
are available from healthy volunteer studies. In a PK study of 15 healthy 
volunteers RAL (400 mg twice-daily) and LPV/r (400/100 mg twice-daily) 
were given each as monotherapy followed by a combination of both drugs. 
The plasma concentrations of each drug were measured during monotherapy 
and while given in combination. 
 
The LPV concentration was not influenced by the addition of RAL. 
However, RAL trough concentrations were 30% lower when LPV/r was 
given in combination (12 hour concentration of 49.4 ng/mL when given as 
monotherapy and 34.3.ng/mL when given in combination with LPV/r), but 
still above the estimated IC95 for wild-type virus of 15ng/mL. Additionally, 
elimination half-life of RAL was shortened from 5.9 hours when given as 
monotherapy to 3.6 hours when given in combination with LPV/r.  In 12 out 
of 13 participants who completed the study, the trough level remained above 
the estimated 95% inhibitory concentration of RAL of 14.6 ng/mL. In one 
participant, the trough level was measured below the 95% inhibitory 
concentration of RAL. Of note, in part 1 of study 004 [7], RAL was given as 
one of four different doses (100mg, 200mg, 400mg, 600mg BID) as 
monotherapy to 35 patients for 10 days. All four arms had similar 
magnitudes of HIV viral decay, suggesting that RAL is sufficiently potent 
even at lower concentrations. The authors do not recommend any dose 
adjustment when using RAL in combination with LPV/r [11]. 
 
2.1.4 Atripla® (EFV/TDF/FTC) 
 
Atripla® is fixed dose combination of EFV, TDF and FTC. Atripla® has 
been approved by the FDA in July 2006 for the treatment of HIV-1 infection 
in adults.  Atripla® is one of the preferred NNRTI containing regimens for 
treatment-naïve HIV-infected patients in the DHHS HIV treatment guideline 
for adults and adolescents [1].  
 
2.1.4.1 Efficacy 
 
Several prospective clinical trials have demonstrated that EFV-based 
therapy is as effective or more effective than the drugs it has been compared 
with, including indinavir (IDV), nelfinavir (NFV), nevirapine (NVP), 
atazanavir (ATV), Trizivir® (fixed dose ZDV/3TC/ABC) [12-14].  For 
example, in a randomized, 48 week, open label study, in ARV–naïve HIV-1 
Infected patients, more subjects randomized to efavirenz + AZT + 3TC had 
a HIV-1 RNA < 400copies/ml than subjects assigned to Indinavir + 
zidovudine + lamivudine (70% versus 48% ITT, p<0.05) or efavirenz + 
indinavir (70% versus 53% ITT, p<0.05) [14]. 
 
A randomized, double blinded study comparing EFV versus ATV, both 
combined with AZT and 3TC showed no differences in HIV-1 RNA levels 


 
 
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after 48 weeks (70% for ATV versus 64% for EFV) [12]. The ACTG 5095 
study compared a triple NRTI regimen (ZDV +3TC+ ABC) versus two EFV 
based regimens (one in comniation ZDV+ 3TC and a second combination 
with ZDV+3TC+ABC) [13]. The EFV containing treatment groups had a 
much higher rate of HIV-1 viral suppression (61% for the triple NRTI arm 
and 89% for the combined EFV arms (p< <0.001). Twenty one percent of 
subjects in the triple NRTI arm failed this regimen which led to the 
discontinuation of this arm. 
 
Study 934 is a phase III, randomized, open-label, multicenter study designed 
to compare EFV with either TDF 300 mg + FTC 200 mg QD or ZDV 300 
mg + 3TC 150 mg BID as fixed-dose combination Combivir® [15]. After 
144 weeks of treatment, 71% of subjects in the EFV + TDF + 3TC had HIV-
1 viral load < 400 copies/mL in comparison to 58% of subjects in the EFV + 
ZDV + 3TC group (n=0.004 using the time to loss of virologic response 
algorithm). In general, resistance to an EFV-based regimen can developed 
within weeks when plasma HIV-1 RNA levels are not suppressed to below 
the assay limits of quantification. Mutation at codon 103 develops most 
often with the use of EFV which is associated with cross-resistance to many 
available NNRTIs. 
 
2.1.4.2 CD4+ T-cell recovery 
 
In the study 934, the mean increase of CD4 cell from baseline to week 144 
was 312 cells/mL in the EFV/TDF/FTC group and 271 cell/mL in the 
efavirenz / combivir group. The mean CD4 cell increase was 176 cell/mm3 
versus 160 cell/mm3 for ATZr versus EFV [12]and 201, 185, 180 cell/mm3 
for EFV + ZDV+3TC, EFV+ IDV and IDV + AZT+3TC [14]. 
 
2.1.4.3 Safety and Tolerability 
 
The most common side effects of EFV are central nervous system (CNS) 
symptoms and rash. Fifty-three percent of subjects receiving EFV reported 
CNS symptoms, including but not limited to dizziness, impaired 
concentration, somnolence, abnormal dreams, and insomnia. Symptoms 
usually begin during the first or second day of therapy and generally resolve 
after 2 to 4 weeks of therapy. In clinical trials, 2.1% of EFV-treated subjects 
discontinued therapy because of CNS side effects.  There have been reports 
(approximately 1 or 2 per thousand EFV-treated patients) of delusions and 
aberrant behavior, predominantly in those with a history of mental illness or 
substance abuse. Severe acute depression (including suicidal 
ideation/attempts) has also been infrequently reported in both EFV-treated 
(0.9%) and control-treated (0.5%) subjects.  Subjects who experience these 
symptoms should contact their doctor immediately to assess the possibility 
that the symptoms may be related to EFV. 
 


 
 
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In controlled clinical trials, 26% (266/1008) of subjects treated with EFV 
600 mg QD experienced new onset skin rash compared with 17% (111/635) 
of subjects treated in control groups (see the Sustiva® package insert). Rash 
associated with blistering, moist desquamation, or ulceration occurred in 
0.9% (9/1008) of subjects treated with EFV. Among approximately 2200 
treated subjects in all studies and expanded access, the incidence of Grade 4 
rash (e.g., erythema multiforme and Stevens-Johnson syndrome) was 0.14%. 
The median time to onset of rash in adults was 11 days, and the median 
duration was 16 days. The discontinuation rate for rash in clinical trials was 
1.7% (17/1008). EFV should be discontinued in subjects developing severe 
rash associated with blistering, desquamation, mucosal involvement, or 
fever; milder rashes often resolve with continued dosing, with 
antihistamines or transient corticosteroids given for symptomatic relief. 
 
The most common adverse events in patients receiving TDF with other 
ARV therapy in clinical trials were mild to moderate gastrointestinal events, 
such as nausea, diarrhea, vomiting, and flatulence. Less than 1% of patients 
discontinued participation in the clinical studies because of gastrointestinal 
adverse events. Laboratory abnormalities observed in these studies occurred 
with similar frequency in the TDF and placebo-treated groups.  
 
In rare cases, hypophosphatemia, proteinuria, glycosuria, and reduced 
creatinine clearance have been seen, and several cases of renal tubular injury 
have been reported.  In a retrospective review, the rate of TDF 
discontinuation due to increased creatinine was evaluated in a review of a 
clinical database which included drug treatment, demographic, and 
laboratory data of 563 HIV-1-infected subjects who had been treated with 
TDF.  Of these subjects, 11 (2%) had discontinued TDF due to elevated 
creatinine after a median of 4 months (range 2-9); of the 9 for whom renal 
biopsy was available, all showed evidence of acute tubular injury.  Lactic 
acidosis and severe hepatomegaly with steatosis, including fatal cases have 
been reported with the use of nucleoside analogues alone or in combination, 
including TDF, and other ARVs.   
 
2.1.4.4 Drug Interactions and Special Populations 
 
The U.S. FDA use-in-pregnancy category for EFV has been changed from 
Category C (Risk of Fetal Harm Cannot Be Ruled Out) to Category D 
(Positive Evidence of Fetal Risk).  This change is a result of four 
retrospective reports of neural tube defects in infants born to women with 
first trimester exposure to EFV, including three cases of meningomyelocele 
and one of Dandy Walker syndrome.  As EFV may cause fetal harm when 
administered during the first trimester to a pregnant woman, pregnancy 
should be avoided in women receiving EFV.  Women of reproductive 
potential should be counseled on the possible risks associated with 
pregnancy. Women should be instructed not to breast-feed while taking 


 
 
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EFV.  If a woman becomes pregnant while taking EFV during the first 
trimester of pregnancy, she should be apprised of the potential harm to the 
fetus. 
 
For additional information concerning atripla, please refer to the AtriplaTM 
U.S.  package insert. 
 
 
2.2    Rationale 
 
 
 
2.2.1 Antiviral and Metabolic Outcomes  
 
Raltegravir is an HIV-1 integrase inhibitor that has been shown to be 
efficacious, safe and well-tolerated [9, 10, 16, 17]. Studies of early viral 
decay kinetics, a surrogate measure of overall regimen potency and 
predictor of long-term viral suppression [18], demonstrate that  RAL has 
viral decay rates that exceed those observed with PIs, NNRTIs or NRTIs 
[7]. In a dose-finding, comparative study of RAL (four dose arms: 100 mg 
to 600 mg daily) vs. EFV in combination with 2 NRTIs, a similar proportion 
of patients achieved plasma HIV-1 RNA less than 50 copies/mL at week 24 
(RAL arms: 85 – 95% vs. EFV: 92%). These reductions in viral load 
persisted through 48 weeks of therapy with no significant difference in the 
long-term rates of viral suppression between the two arms. One explanation 
for these faster early viral decay rates is that already reverse transcribed pre-
integration complexes can proceed through the replication cycle and 
generate RNA containing virions for the lifetime of the infected cell while 
RAL will block such complexes from integrating and generating RNA 
containing virions. Importantly, total cholesterol, low-density lipoprotein 
and triglyceride levels were relatively unchanged in the RAL groups. By 
contrast, all three of these lipid markers increased from baseline in the 
efavirenz subjects. Although large phase 3 trials comparing RAL- vs. EFV-
based regimens in treatment-naïve patients are not yet available, preliminary 
data with 48 weeks of follow-up demonstrate a comparable degree of 
antiviral efficacy of RAL-based therapy compared with standard of care 
therapy with EFV-based regimens.  
 
Comparisons between LPV/r- and EFV-based regimens have been less 
clear-cut. In one study, virologic response was similar between EFV and 
LPV/r [19], however a recent ACTG study, A5142 [20], demonstrated 
significantly better viral control rates with EFV-based regimens. A5142 is a 
prospective study that randomized 753 treatment-naïve patients to either an 
NRTI-containing regimen of LPV/r (400/100 mg twice-daily) or EFV (600 
mg once-daily) combined with 3TC and a second NRTI, or a NRTI-sparing 
regimen of LPV/r (533/133 mg twice-daily) and EFV (600 mg once-daily) 
for 96 weeks.  The EFV arm had a greater proportion of subjects with HIV 
RNA levels < 50 copies/ml than the LPV/r group (89% vs. 77%; P=0.003, 


 
 
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respectively). While median increases from baseline in total cholesterol 
were similar between nucleoside-containing regimens (33 mg/dL vs. 33 
mg/dL), LPV/r-treated subjects had greater increases in triglycerides than 
those in the efavirenz arm (47 mg/dL vs. 14 mg/dL, P<0.01). In contrast, 
EFV-treated subjects had a higher proportion of protocol-defined 
lipoatrophy than the LPV/r group (32% vs. 18%, P<0.01) [21]. 
 
2.2.2 Immunologic Benefits  
 
Suboptimal CD4+ T-cell recovery during antiretroviral therapy is a common 
clinical dilemma. Several studies have demonstrated greater CD4+ T-cell 
recovery during viral suppression in patients receiving LPV/r-based 
regimens compared to other combination therapies [12, 22-24].  Although A 
5142 demonstrated  that the EFV arm had a greater proportion of patients 
with plasma HIV RNA levels below 50 copies/mL, both LPV/r-containing 
treatment arms showed significantly higher absolute CD4+ T-cell gains after 
96 weeks than patients receiving EFV (284 cells/mm3 and 268 cells/mm3 vs. 
241 cells/mm3; P=0.01) [24]. The mechanisms by which PI-based therapies 
may improve CD4+ T cell recovery are poorly understood. Interestingly, 
some PIs have been shown to inhibit lymphocyte apoptosis [25, 26].  Since 
CD4+ T-cell activation and apoptosis continues despite control of HIV-1 
replication, PI-based regimens may improve T cell survival, and long term 
T-cell reconstitution. In addition, faster viral decay rates have been 
associated with more robust early CD4+ T-cell recovery [27]. Potentially, 
the addition of RAL may result in a more rapid viral clearance and 
consequently improved early CD4+ T-cell recovery than currently 
recommended EFV-based regimens. 
 
2.2.3 Justification for an NRTI-sparing regimen 
 
NRTIs in combination with PIs / NNRTIs have been the backbone of potent 
antiretroviral drug combinations since the introduction of HAART.  
However, NRTIs are associated with significant toxicity such as 
mitochondrial toxicity, lipoatrophy and others.  Therefore, novel, NRTI-
sparing and potent antiretroviral combinations are appealing. The feasibility 
using NRTI-sparing antiretroviral therapies has been demonstrated in the 
ACTG 5142 trial which compared LPV/r + EFV with EFV + NRTIs and 
LPV/r + NRTIs [28].  In this study, the NRTI-sparing arm was as effective 
as the EFV + NRTI arm and superior to the LPV/r + NRTI arm. However, a 
higher rate of laboratory abnormalities, especially elevated lipid levels, was 
reported in the LPV + EFV combination and limits its use.  
RAL is a new and potent antiretroviral agent. Its ability to reduce HIV viral 
load is comparable to EFV with the additional benefit to decrease HIV RNA 
level faster to < 50 copies/mL than EFV [7]. In contrast to EFV, RAL 
showed no adverse effects on cholesterol and triglyceride lipids.  Therefore, 
the combination of RAL + LPV/r is very appealing by providing a potent 


 
 
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NRTI sparing ARV regimen and with a lower risk of worsening blood lipid 
levels.  Additionally, the high genetic barrier of LPV/r provides protection 
against mutations affecting RAL which has a low genetic barrier.  
  
2.2.4 Hypotheses 
 
1. The novel nucleoside-sparing combination of LPV/r +  
  
RAL will have a faster phase 1 viral decay rate compared to  
  
standard-of-care therapy with EFV/TDF/FTC in antiretroviral-naïve 
 
patients. 
 
a. Faster phase 1 viral decay dynamics will be associated with 
improved longer-term (week 48) viral suppression.  
b. Faster phase 1 viral decay dynamics will be associated with 
accelerated early (Day 0-14) clearance of cell-associated HIV DNA. 
c. Faster phase 1 viral decay dynamics will be associated with greater 
early (baseline to week 12) CD4+ T-cell recovery.  
 
2. The LPV/r + RAL arm will have greater decreases in  
  
early (baseline to week 4) CD4/CD8 T-cell immune activation and 
 
apoptosis which will be associated with greater late (week 12 to  
  
week 48) CD4+ T-cell recovery.  
 
3. Subjects treated with LPV/r + RAL arm will have smaller  
  
changes in total cholesterol and triglycerides from baseline than those  
  
receiving EFV/TDF/FTC.  
 
3.0 STUDY DESIGN 
 
 
 
CCTG 589 is a randomized, open-label, 48-week pilot study comparing the 
efficacy, safety and tolerability of RAL plus LPV/r to EFV/TDF/FTC in HIV-
infected, treatment naïve subjects (defined as having never received any HIV 
antiretroviral agents in the past) with plasma HIV-1 RNA >5000 copies/mL and 
CD4+ T-cells >50 cells/mm3 at or within 90 days of screening.  Additional 
screening safety laboratories must be obtained within 30 days of study entry. Drug 
resistance testing is required prior to entry and can include any available test done 
prior to entry.  Subjects will be ineligible if they have any evidence of drug resistant 
virus in the past or at the time of screening (if never previously tested).  All 
resistance test results should be scanned and uploaded to the online data collection 
system for review and approval by the protocol team ant the site’s investigator prior 
to enrollment.  Those who are found to be eligible will be randomized 1:1 to initiate 
either LPV/r (400/100 mg) plus RAL (400mg), both given twice-daily, or fixed 
dose combination of EFV (600 mg), TDF (300 mg) and FTC (200 mg) given as 
once-daily Atripla® for 48 weeks. The study will provide LPV/r and RAL, however, 
Atripla® must be provided by prescription. 
 


 
 
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Eligible subjects will be HIV-1-infected, at least 18 years of age, treatment-naïve 
and have no evidence of drug resistant virus (per Inclusion Criteria, Section 4.1.) 
detected by any previous resistance test or at screening if not previously performed.  
Subjects must have CD4+ T-cell counts greater than or equal to 50 cells/mm3 and 
screening plasma HIV-1 RNA greater than or equal to 5,000 copies/mL at or within 
90 days of study screening. 
 
Fifty subjects will be enrolled over approximately 48 weeks. Subjects will be 
stratified based upon screening plasma HIV-1 RNA (greater than or equal to or 
below 100,000 copies/mL) and will be followed for a total of 48 weeks.  Subjects 
will have plasma HIV-1 RNA and CD4+ T-cell count measured at pre-entry and 
entry.  The geometric and arithmetic means, respectively, of these measurements 
will be used to establish their baseline values.  During the initial 2-week period, 
subjects will undergo intensive monitoring of viral decay dynamics with plasma 
HIV-1 RNA measured at baseline and days 2, 7, 10 and 14. Changes in CD4+ T-
cells will be measured from baseline to week 12 (Phase 1) and week 12 to week 48 
(Phase 2).  In addition, extended immune phenotyping for activation, maturation 
and apoptosis markers will be measured on CD4+/CD8+ T-cells obtained from 
baseline, week 4 and week 24. From weeks 2 to 48, subjects will be monitored for 
treatment efficacy, including changes in CD4+ T-cells and plasma HIV-1 RNA 
levels, as well as for safety and tolerability with laboratories for hematology, 
chemistry, fasting lipids and a symptom questionnaire.  Serial plasma and PBMCs 
will be stored for future studies.  Genotypic drug resistance testing will be 
performed at screening (test not provided by study) if never performed in the past as 
well as at the time of virologic failure. Virologic failure will be defined as:  
 
• 
Week 4: 
Confirmed failure to achieve ≤50 copies/ml or, if >50 copies/ml, a 1 log10 
copies/ml reduction from the baseline level; 
 
• 
Week 12: 
Confirmed failure to achieve ≤50 copies/ml or, if >50 copies/ml, a 2 log10 
copies/ml reduction from baseline level;  
OR, if the Week 4 value is >50 copies/ml, confirmed rebound from the Week 4 
value by >0.5 log10 copies/ml; 
OR, if the Week 4 value is ≤50 copies/ml, confirmed rebound to >50 copies/ml  
 
• 
Week 24: Confirmed value >50 copies/ml. 
 
Subjects who meet criteria for confirmed virologic failure will undergo real-time 
genotypic resistance testing (testing not provided by study) and an alternative 
regimen will be chosen by the site investigator with recommendations of the 
protocol team. Follow-up intervals will continue per study protocol, but the site 
investigator may schedule additional non-study, safety visits as necessary. The 
patient will be followed off study medication but on study for the remainder of the 
48 weeks of study. 


 
 
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Adherence to all study drugs will be monitored by self-report as per the Schedule of 
Events.  During the viral dynamics visits, all study medication dosing times and 
dates will be recorded by the study coordinator at each visit. All subjects should be 
provided adherence reinforcement throughout the study, according to local standard 
practice.  Subjects who modify their study regimen or miss more than one-day dose 
of medication or miss more than one visit during the viral dynamics sequence (days 
2, 7, 10 and 14) will need to be replaced. However, subjects who discontinue/ 
change study medication after day 14 will not need to be replaced.  For all subjects 
discontinued from the study for any reason a premature discontinuation visit should 
done within 4 weeks (see section 6.2.3 and 6.2.4). 
 
4.0 SELECTION AND ENROLLMENT OF SUBJECTS  
 
4.1 Inclusion Criteria 
4.1.1 HIV-1 infection, as documented by any licensed screening antibody test, 
such as ELISA, and confirmed by a second antibody test, such as Western 
blot, at any time prior to study entry. HIV-1 culture, HIV-1 antigen, two 
plasma HIV-1 RNA > 2,000 copies/mL.  HIV-1 infection can also be 
documented by two plasma HIV-1 RNA > 2,000 copies/mL. 
 
4.1.2 Treatment naïve (defined as having never received any HIV antiretroviral 
agents in past).  
 
4.1.3 CD4+ T-cell count greater than or equal to 50 cells/mm3 determined by site 
clinical laboratory at or within 90 days of screening. 
 
 
NOTE:  Obtained locally in a CLIA-certified laboratory.  
 
4.1.4 Screening plasma HIV-1 RNA greater than or equal to 5,000 copies/mL 
determined by site clinical laboratory at or within 90 days of screening. 
 
NOTE:  Obtained locally in a CLIA-certified laboratory.  
 
4.1.5 Laboratory values obtained by screening laboratories within 30 days of 
entry: 
 
• Absolute neutrophil count (ANC) ≥ 750/mm3. 
• Hemoglobin ≥ 8.0 g/dL. 
• Platelet count ≥ 50,000/mm3. 
• Calculated creatinine clearance (CrCl) > 60 mL/min as estimated by the 
Cockcroft-Gault equation:   
* For men, (140 - age in years) x (body weight in kg) ÷ (serum 
creatinine in mg/dL x 72) = CrCl (mL/min) 
* For women, multiply the result by 0.85 = CrCl (mL/min)  


 
 
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• AST (SGOT), ALT (SGPT), and alkaline phosphatase ≤ 5 x ULN. 
• Total bilirubin ≤ 2.5 x ULN. 
 
4.1.7 Females of childbearing potential must have a negative serum pregnancy 
test at screening and agree to use a double-barrier method of contraception 
throughout the study period. 
 
4.1.8 Karnofsky performance score ≥ 70.  
 
4.1.9 Men and women age ≥ 18 years. 
 
4.1.10 Ability to obtain prescription for HIV antiretroviral medications and to have 
required prescriptions filled prior to entry. 
 
4.1.11 Ability and willingness of subject to give written informed consent. 
 
4.2 Exclusion Criteria 
4.2.1 Pregnancy or breast-feeding 
 
4.2.2 Use of any of the prohibited medications (section 5.4.2) within 30 days of 
study entry. 
 
4.2.3 Known hypersensitivity to any of the study drugs. 
 
4.2.4 Serious illness requiring systemic treatment and/or hospitalization until 
subject either completes therapy or is clinically stable on therapy, in the 
opinion of the investigator, for at least 30 days prior to study entry (day 0). 
 
4.2.5 Acute therapy for serious infection or other serious medical illnesses (in the 
judgment of the site investigator) requiring systemic treatment and/or 
hospitalization within 14 days prior to study entry (day 0). 
 
4.2.6 Evidence of HIV seroconversion within 6 months prior to study entry. 
 
4.2.7 Evidence of any major resistance-associated mutation on any genotype 
performed prior to study entry or at the time of screening.  Resistance 
testing results must be available for review by the site investigator and study 
protocol team prior to enrollment to ensure that there are no exclusionary 
resistance mutations.  All resistance testing results should be scanned and 
uploaded to the on-line data collecting system 
(https://cfar.ucsd.edu/intranet).  
 
NOTE: Subjects will be excluded if genotype shows presence of any HIV-
associated resistance mutations listed per the Internation AIDS 


 
 
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Society-USA mutation list (update lists can be found at: 
http://www.iasusa.org). 
 
4.2.8 History of chronic hepatitis C (defined as HCV antibody positive and HCV 
RNA detectable). 
4.2.9 History of chronic active hepatitis B (defined as surface antigen positive 
and/or HBV DNA detectable). 
 
4.2.10 Active drug or alcohol use or dependence that, in the opinion of the 
investigator, would interfere with adherence to study requirements. 
 
4.2.11 Use of any immunomodulator, HIV vaccine, or investigational therapy 
within 30 days of study entry. 
 
4.2.12 Use of human growth hormone within 30 days prior to study entry. 
 
4.2.13 Initiation of testosterone or anabolic steroids within 30 days prior to study 
entry. (Exception: Chronic replacement dosages in patient’s with diagnosed 
hypogonadism is allowed). 
 
4.3 Study Enrollment Procedures 
4.3.1 Prior to implementation of this protocol, sites must have the protocol and 
consent form approved by their local institutional review board (IRB). Sites 
must be registered with and approved by the CCTG Data and Biostatistical 
Unit. Site registration must occur before any subjects can be enrolled in this 
study. 
 
Once a candidate for study entry has been identified, details will be carefully 
discussed with the subject. The subject will be asked to read and sign the 
consent form that was approved by both the local IRB and the CCTG Data 
Center. 
 
4.3.2 A patient identification number (PID) will be assigned to each patient 
screened for the study.  PIDs will include a site code and three-digit 
extension.  PIDs should not be reassigned even if the patient fails to enter 
the study.  The PID must be included on every CRF and patient blood 
sample.  Each site must maintain a master list of PIDs in a central location.  
The patient registration and inclusion/exclusion CRF must be completed on 
the online system (https://cfar.ucsd.edu/intranet).  
 
4.4 Co-enrollment Guidelines  
Co-enrollment in this study and other studies will be discussed with the protocol 
team and will be decided on a case by case basis. 


 
 
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5.0 STUDY TREATMENT            
 
Study medications include  
• Raltegravir (Isentress®) 
• Lopinavir/ritonavir (Kaletra®) 
• Efavirenz / Tenofovir / Emtricitabine (Atripla®). 
 
5.1 Dosing, Administration, and Duration 
5.1.1   Dosing  
 
5.1.1.1 Raltegravir (Isentress®): 
Each tablet contains 400 mg of RAL and will be administered 
twice a day, with or without food. 
 
5.1.1.2 Lopinavir/ritonavir (Kaletra®):  co-formulated tablet.   
Each tablet contain 200 mg of LPV and 50 mg RTV. LPV/RTV 
will be dosed 400mg of LPV and 100mg RTV twice daily (two 
Kaletra® tablets twice a day). Kaletra needs to be administered 
with food. 
 
5.1.1.3 Efavirenz / tenofovir disoproxil fumarate/ emtricitabine 
(Atripla®): co-formulated tablet.  
Each tablet contain 600mg of EFV, 300mg of TDF and 200mg of 
FTC. Atripla® will be dose one tablet once a day without food.  
 
 
5.1.2 Administration 
 
At study entry, subjects will be randomized 1:1 to one of two treatment 
arms: 
 
• LPV 400mg/RTV 100mg + RAL 400mg twice-daily 
• Atripla® (EFV 600mg + TDF 300mg + FTC 200mg) once-daily. 
 
5.1.3 Duration 
 
Subjects will receive study treatment for 48 weeks.  
 
5.2 Product Formulation and Preparation  
5.2.1 Isentress® tablets should be stored at room temperature (250C / 770F). Do 
not store above 300C / 860F and protect from moisture. 
  


 
 
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5.2.2  Kaletra® film coated tablets should be stored at 20-25oC (69-77oF),  
excursion permitted to 15-30oC (59-86oF.) 
 
5.2.3 Atripla® should be stored at 250C (770F), excursion permitted to 15-300C 
(59-860F). 
 
5.3 Product Supply, Distribution, and Pharmacy 
5.3.1 Study Product Acquisition 
 
Study medication Isentress® will be provided by Merck and Kaletra® will 
be provided by Abbott Laboratories.  
AtriplaTM will not be supplied by the study, but will be made available to 
patients via prescription at cost to the patient and/or patient’s health 
insurance.  
 
5.3.2 Investigational Agent Accountability 
 
The clinical site pharmacist is required to maintain complete records of all 
study products received from this study. All unused LPV/r and RAL 
products must be returned to the sponsors after the study is completed or 
terminated. 
 
5.4 Concomitant Medications 
5.4.1   Required Medications 
 
5.4.1.1 Study medications (RAL + LPV/r or EFV/TDF/FTC). 
 
5.4.1.2    PCP prophylaxis for CD4+ T-cells <200 cells/mm3 is strongly  
  
recommended. 
 
5.4.2   Prohibited Medications 
 
  
5.4.2.1 All investigational drugs. 
 
 
5.4.2.2 All HIV vaccines 
 
5.4.2.3 Any immunomodulators 
 
5.4.2.4 Systemic cytotoxic chemotherapy 
 
5.4.2.5 All herbal products should be avoided because of the unknown 
drug interactions between herbal products and the antiretroviral 
drugs used in this study. 


 
 
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5.4.2.6   All of the following systemic drugs: 
 
Table 1:  Prohibited with LPV/r: 
 
 
Agent by Class 
Agents 
 
 
Alternative/Complementary 
St. John’s wort (Hypericum perforatum) 
 
 
Antiarrhythmics 
Amiodarone 
 
Bepridil (Bepadin, Vascor) 
 
Flecainide (Tambocor) 
 
Propafenone (Rythmol) 
 
Quinidine 
 
 
Antihistamines 
Astemizole (Hismanal) 
 
Terfenadine (Seldane) 
 
 
Anti-infectives 
Rifampin (Rifadin, Rimactane, 
Rifamate, Rifater) 
 
Voriconazole (VfendTM) 
 
 
GI Motility 
Cisapride (Propulsid) 
 
 
HMG Co Reductase Inhibitors  
Lovastatin (Mevacor) 
 
Simvastatin (Zocor ®) 
 
 
Sedative/hypnotics 
Midazolam (Versed)  
 
Triazolam (Halcion) 
 
 
Other 
Alfuzosin 
 
Dihydroergotamine (Migranal  
and others) 
 
Ergonovine  
 
 
Table 2:  Prohibited with RAL:  
 
Agent by Class 
Agents 
 
 
Anticonvulsants 
Dilantin 
 
Phenobarbitol 
 
 
Anti-infectives 
Rifampin 
 


 
 
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Table 3:  Prohibited with Atripla® (EFV / TDF / FTC) 
 
Agent by Class 
Agents 
 
 
Alternative / Complementary 
St. John’s wort (Hypericum perforatum) 
 
 
Antihistamines 
Astemizole (Hismanal) 
 
Terfenadine (Seldane) 
 
 
Anti-infectives 
Voriconazole (Vfend) 
 
 
GI Motility 
Cisapride (Propulsid) 
 
 
Sedative/hypnotics 
Midazolam (Versed)  
 
Triazolam (Halcion) 
 
 
Other 
Dihydroergotamine (Migranal)  
and others) 
 
Ergonovine  
 
Ergotamine 
 
Methylergonovine 
 
 
5.4.1 Precautionary Medications 
 
NOTE:   Refer to the individual package inserts for additional information 
regarding potential drug interactions that may require therapeutic drug 
monitoring and/or adjustment of concomitant medications.  Competition for 
primary CYP3A metabolism or other mechanisms by study drugs could 
result in inhibition or stimulation of the metabolism of these drugs and 
create the potential for serious and/or life-threatening reactions such as 
cardiac arrhythmias, prolonged or increased sedation, and respiratory 
depression. 
 
Table 4:  Precautionary Medications with LPV/r: 
 
 
Agent by Class 
Agents 
 
 
Analgesics 
Methadone / Propoxyphene (Darvon and 
others) / Tramadol (Ultram) 
 
 
Antiarrhythmics 
Disopyramide (Norpace) / Lidocaine 
(systemic) (Xylocaine) / Mexilitine 
(Mexitil) 


 
 
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Agent by Class 
Agents 
 
 
 
 
Anticonvulsants 
Carbamazepine (Tegretol) / 
Lamotrigine (Lamictal) / Phenobarbitol/ 
Phenytoin (Dilantin) / Valproic Acid 
 
 
Antacids, H2 blockers,  
Proton Pump Inhibitor 
Cimetidine (Tagamet) / Famotidine 
(Pepcid) / Nizatidine (Axid) / Ranitidine 
(Zantac) 
 
 
Anti-infectives 
Atovaquone (Meprone) / Caspofungin 
(CancidasTM) / Clindamycin (CleocinTM) / 
Clarithromycin (Biaxin) / Miconazole 
(Monistat TM) / Rifabutin (requires dose 
reduction) 
 
 
Anti migraine Agents 
Eleptriptan / Zolmitriptan 
 
 
Beta Blockers 
Alprenlol / Atenolol / Bisoprolol \ 
(ZebetaTM) / Carvedilol (Coreg TM) / 
Esmolol (Brevibloc TM) / Labetolol  
(Normodyne TM) / Metoprolol  
(LopressorTM / ToprolTM) / Pindolol  
Visken TM) / Propanolol (Inderal TM) /  
Timolol (Bocadren TM) 
 
 
Calcium Channel Blockers 
Amlodipine (Norvasc TM) / Aranidipine  
Cilnidipine / Diltiazem / Felodipine  
(Plendil TM) / Isradipime (Lacipil TM) /  
Lacidipine (Lacipil TM) / Lercandipine /  
Manidipine / Nicardipine (Cardene TM) /  
Nifedipine / Nivadipine / Nimodipine  
(Nimotop TM) / Nisoldipine (Sular TM) /  
Nitrendipine (Nitrendipine TM) /  
Verapamil   
 
 
Chemotherapeutic Agnets 
Cyclophosphamide / Irinotecan  
Ifosfamide / Etoposide 
 
 
Hormonal Agents 
Estrogens / Progesterones /  
Glucocorticoids 
 
 
Hypoglycemics 
Pioglitazone (Actos TM) 


 
 
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Agent by Class 
Agents 
 
 
 
 
HMG Co Reductase Inhibitors  
Atorvastatin (Lipitor) 
 
 
Psychiatric Medications 
Clozapine (Clozaril TM) / Buproprion 
(Wellbutrin, Zyban TM) / Fluoxetine / 
Paroxetine (Paxil TM) / Risperidone 
(Risperdal TM) / Venlafexine (Effexor TM) / 
Nefazadone (Serzone TM)  
 
 
Tricyclic antidepressants 
Amitripyiline / Desipramine / Imipramine/  
Nortriptyline 
 
 
Sedative/hypnotics 
Alprazolam (Xanax TM) / Diazepam 
(Valium TM) / Estolam ( ProSom TM) /  
Clorazepate / Flurazepam (Dalmane TM) /  
Oxazepam (Seraz TM) / Temazepam  
(RestorilTM) / Buspirone (BusparTM),  
Trazodone, Zalpeplon (SonataTM),  
Zolpedim (AmbienTM)  
 
 
Other 
Cyclosporine A / Digoxin / Rapamycin / 
Tacrolimus 
 
 
 
Table 5:  Precautionary Medications with Atripla® (EFV / TDF / FTC) 
 
Agent by Class 
Agents 
 
 
Alternative/Complementary 
Milk Thistle (Silymarin, Silybum,  
marianum) 
 
 
Anti-convulsants 
Carbamazepine (TegretolTM) / Phenytoin 
(DilantinTM) / Phenobarbitol 
 
 
Anti-infectives 
Caspofungin (CancidasTM) /  
Clarithromycin (Biaxin TM) / Itraconazole  
(Sporonox TM) / Ketoconazole / Rifampin  
and Rifabutin / Quinupristin/Dalfopristin  
(Synercid TM) 
 
 
Antimigraine 
Eletriptan (Relpax) 
 
 


 
 
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Agent by Class 
Agents 
 
 
HMG Co Reductase Inhibitors  
Lovastatin (Mevacor) /  Simvastatin  
(Zocor ®) 
 
 
Hypoglycemics 
Pioglitazone (ActosTM) 
 
 
Sedative/hypnotics 
Alprazolam (Xanax TM) / Diazepam  
(Valium TM) / Estazolam (ProSom TM) /  
Flurazepam (Dalmane TM) / Oxazepam  
(Serax TM) / Temazepam (Restoril TM) /  
Lorazepam (Ativan TM) / Buspirone  
(BuSpar TM) / Zaleplon (Sonata TM) /  
Zolpidem (Ambien TM) 
 
 
 
Other 
Warfarin 
 
Nephrotoxic agents such as  
amphotericinB, aminoglycosides,  
cidofovir, acyclovir, ganciclovir,  
vancomycin 
 
Methadone 
 
Sildenafil / Vardenafil / Tadalafil 
 
Sertraline 
 
Anyacids / H2-blockers / Proton Pump  
Inhibitors 
NOTES: Drugs without trade names either have many marketed forms,  
• or are not available in the US.  Web-based information is available at:  
http://www.hiv-druginteractions.org/drug/pdf/pi_col.pdf 
 
5.5 Adherence Assessment 
Throughout the study, the documentation of adherence to study drugs and 
concomitant HIV medications is essential. During the viral dynamics visits an 
adherence diary will be completed by study personal that will include the date and 
time all study medications were taken. Afterwards a separate adherence 
questionnaire will be completed during each study visit at weeks 2, 8, 12, 24, 36 
and 48. 


 
 
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6.0        CLINICAL AND LABORATORY EVALUATIONS 
 
 
 
6.1 Schedule of Events – Clinical Evaluations 
 
 
 
Screen 
 
Pre 
Entry 
Viral Dynamics 
Follow-up 
 
Within 30 
days of 
entry 
 
Day 
 0 
(Entry) 
Day 
2 
+1 day 
Day 
7 
+1 day 
Day 
10 
+1 day 
Day 
14 
+1 day 
Week 
4 
+1 wk 
Week 
8 
+1 wk 
Week 
12 
+1 wk 
Week 
16 
+1 wk 
Week 
24 
+2 wk 
Week 
36 
+2 wk 
Week 
48 
+2 wk 
Virologic 
Failure, Tox or 
Premature D/C 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
§ Documentation of prior 
HIV drug resistance 
testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Medication 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Documentation of HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessment / AE 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Physical Exam 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted Physical Exam 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Start Drug/ Dispense Drug 
 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Complete Adherence 
Diary or Questionnaire 
 
 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
§ Resistance testing results obtained anytime in the past is acceptable. If not available, then resistance testing should be done at screening (test not provided by 
study). Subject must have no evidence of major HIV drug-associated mutations to be eligible for the study (see Exclusion Criteria section 4.2.7). 
  


 
 
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Schedule of Events – Laboratory Evaluations 
 
 
Screen 
 
Pre 
Entry 
Viral Dynamics 
Follow-up 
 
Within 30 
days of 
entry 
 
Day 
 0 
(Entry) 
Day 
2 
+1 day 
Day 
7 
+1 day 
Day 
10 
+1 day 
Day 
14 
+1 day 
Week 
4 
+1 wk 
Week 
8 
+1 wk 
Week 
12 
+1 wk 
Week 
16 
+1 wk 
Week 
24 
+2 wk 
Week 
36 
+2 wk 
Week 
48 
+2 wk 
Virologic 
Failure, Tox or 
Premature D/C 
Hematology (local lab) 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
Chem / LFT (local lab) 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
Fasting Lipids (local lab) 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
Pregnancy test (local lab) 
X 
 
      X      and whenever suspected 
 
Immunology: 
CD4+/CD8+  
 
X 
X 
 
 
 
 
X 
X 
X 
 
X 
X 
X 
X 
§ CD4 >50 cells/mm3  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
§ HIV RNA  >5000 
cells/mL  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ΨHIV-1 RNA (local lab) 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
ΨHIV-1 RNA load 
(UCSD lab) 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
†Extended flow cytometry 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
† Proviral HIV DNA 
 
X 
X 
X 
X 
 
X 
X 
 
 
 
X 
 
X 
 
† PBMCs collection  
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
Ψ Plasma for storage 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
† Ambient ship to UCSD 
 
X 
X 
X 
X 
 
X 
X 
 
 
 
X 
 
X 
 
Ψ Dry-ice ship to UCSD 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
§ If available within 90 days of screen then do not need to repeat laboratory test and can use value obtained within 90 days as screen value 
 
Ψ Plasma for HIV RNA loads for the viral decay dynamics (pre-entry to day 14) needs to be stored and shipped in batch to UCSD on day 14. Thereafter, all subsequent HIV RNA loads 
need to be done at the site’s local lab and stored plasma can be shipped in batch after the subject completes week 48 or at time of premature study discontinuation.  
 
† Samples for extended flow cytometry, proviral HIV DNA and PBMCs do not require local lab processing. All samples should be shipped immediately after collection with an 
ambient overnight to UCSD.  


 
 
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6.2 Definitions for Schedule of Events – Timing of Evaluations 
6.2.1 Pre-Entry Evaluations 
 
Occur prior to the subject taking any study medications, treatments, or 
interventions.  
 
Patient Registration 
 
A patient identification number (PID) will be assigned to each patient 
screened for the study.  PIDs will include a site code and three-digit extension.  
PIDs should not be reassigned even if the patient fails to enter the study.  The 
PID must be included on every case report form (CRF) and patient blood 
sample.  Each site must maintain a master list of PIDs in a central location.  
The patient registration and inclusion/exclusion CRF must be completed on 
the online system (https://cfar.ucsd.edu/intranet).  
 
Screening Site Clinical Labs 
 
If plasma HIV-1 RNA and CD4+ T-cell counts were obtained at a CLIA-
approved lab no more than 90 days prior to screening and results are available 
then these labs do not need to be repeated. Otherwise, a plasma HIV-1 RNA 
level and a CD4 cell count measurement need to be done at screening. Please 
record actual dates laboratories were done in the CRF.  
 
All other study screening laboratories must be determined within 30 days of 
study entry (Day 0). Screening and entry evaluations must be separated by at 
least 48 hours. Hematology, chemistry and pregnancy testing will be 
coordinated through the site’s local laboratory and results will be tracked by 
the CCTG Data Center.   
 
Once the screening laboratories have been done the patient will be evaluated 
for study eligibility if all other entry criteria are satisfied.   
 
The total blood volume for screening labs is 10 mL. 
 
If the HIV RNA or other laboratory values are outside the eligible range, the 
site may re-screen a patient on one occasion. However, the study will not pay 
for additional re-screening laboratories.  
 
Pre-Entry 
 
Specimens for proviral HIV DNA need to be shipped by each site in real-time 
to the central laboratory (UCSD).  
 


 
 
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Plasma HIV-1 RNA and CD4+ T-cell counts should be obtained at the Pre-
Entry visit. The CD4 cell count should be done at the site’s local laboratory in 
real-time. However, the plasma for the HIV-1 RNA should be collected, 
stored then shipped in batch at Day 14 of study along with other phase 1 viral 
dynamic specimens. 
 
The total blood volume for pre-entry labs is 30 mL. 
 
Randomization  
 
The screen HIV RNA value will be used to stratify the patient (at or above 
versus below 100,000 copies/mL) prior to randomization. 
 
If the subject is randomized to the Atripla® arm, then this subject should be 
contacted and supplied with a prescription for Atripla®. Please remind the 
subject to fill medication as soon as possible and he/she must present with 
medication in hand on day of study entry. The entry visit for all subjects 
should occur within 7 days of randomization.  
 
Entry 
 
The entry evaluation should be scheduled within 30 days of the screening 
visit.  The randomization should be completed and a 30-day supply of 
treatment medication should be provided. If the subject is randomized to the 
LPV/r arm, then study medications will be supplied by the study and 
dispensed by the site’s pharmacy on day of entry. However, if the subject is 
randomized to the EFV/TDF/FTC arm, then a prescription must be provided 
prior to entry and the subject must present with medications in hand on day of 
entry. The first dose of LPV/r + RAL study medication should be given and 
witnessed by the study coordinator after drawing the baseline laboratories. 
The first dose of EFV/TDF/FTC should be taken the evening of study entry as 
a non-witnessed dose. A 14-day adherence diary should be completed by 
study personal during the viral dynamics sequence. 
 
6.2.2 On-Study Evaluations 
 
Evaluations should be counted from entry (Day 0).  Start dates for the viral 
decay sequence can occur on Monday thru Wednesday.  Viral dynamic 
visits should occur on days 2, 7, 10 and 14 or within a visit window of + 1 
day. Since blood for proviral HIV DNA needs to be shipped in real-time 
for all visits (except day 10) viral dynamic visits should be planned in 
ahead to occur only from Monday to Thursday – avoiding Fridays. 
Thereafter, while on follow-up phase of the therapy, study evaluations will 
occur on weeks 4 (+ 1 week), 8 (+ 1 week), 12 (+ 1 week), 16 (+ 1 week), 24 
(+ 2week), 36 (+ 2 week) and 48 (+ 2 week). In instances of virologic failure 


 
 
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and/or premature treatment discontinuation evaluations would also need to 
occur within 4 weeks. 
 
Total blood volume for laboratory evaluations for viral dynamics sequence 
(entry to day 14) will be approximately 167 mL.  
 
Total blood volume for laboratory evaluations for follow-up phase (week 4 to 
week 48) will be approximately 266 mL.  
 
6.2.3 Evaluations and plan for randomized or registered subjects that do not 
complete the viral dynamics portion of the study:  
 
a. Those subjects that do not start treatment will be replaced and will 
have no follow-up evaluations performed. 
 
b. Subjects on the viral dynamics (entry to Day 14) portion of the study 
that discontinue antiretroviral therapy before end of Day 14 will be 
replaced and will have no follow-up evaluations performed. 
 
c. Subjects on the viral dynamics (entry to Day 14) portion of the study 
that miss more than one scheduled visit or 1-day equivalent of study 
medication will be replaced and followed on study but will not have 
proviral HIV DNA, extended flow cytometry or PBMC collected for 
storage.  
 
6.2.4 Evaluations and plan for subjects that complete the viral dynamics but not the 
remainder of the study 
 
a. Subjects who complete the viral dynamics portion of the study but 
then discontinue their antiretroviral regimen while on the follow-up 
portion of the study (weeks 2 to 48) will not be replaced and will be 
followed per protocol but will not have proviral HIV DNA, extended 
flow cytometry or PBMC collected for storage. 
 
b. Subjects that prematurely stop antiretroviral medications after the viral 
dynamics portion of the study and do not want to continue on study 
will not be replaced and a Premature Treatment Discontinuation vist 
(see Section 6.1) should occur within 4 weeks. 
 
6.2.5 Change in Antiretroviral Regimen 
 
Subjects who change their treatment regimen for any reason, should continue 
to be followed until the completion of the study. However, they will not have 
proviral HIV DNA, extended flow cytometry, PBMC collection for storage. 
 


 
 
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If the regimen change is due to toxicity, then the subject would be followed 
per criteria of a Change of Therapy Due to Toxicity visit (section 6.1). 
 
If the regimen change is due to virologic failure, then the subject would be 
evaluated per criteria for Virologic Failure visit (section 6.1). 
 
6.2.6 Virologic Failure 
 
Virologic failure will be defined as: 
 
• 
Week 4: 
Confirmed failure to achieve ≤50 copies/ml or, if >50 copies/ml, a 1 log10 
copies/ml reduction from the baseline level; 
 
• 
Week 12: 
Confirmed failure to achieve ≤50 copies/ml or, if >50 copies/ml, a 2 log10 
copies/ml reduction from baseline level;  
OR, if the Week 4 value is >50 copies/ml, confirmed rebound from the Week 
4 value by >0.5 log10 copies/ml; 
OR, if the Week 4 value is  ≤50 copies/ml, confirmed rebound to >50 
copies/ml  
 
• 
Week 24: Confirmed value >50 copies/ml. 
 
Confirmatory plasma HIV-1 RNA test must be performed within 4 weeks of 
the initial HIV-1 RNA sample with suspected virologic failure.  Subjects who 
meet criteria for confirmed virologic failure will undergo real-time genotypic 
resistance testing (testing not provided by study) and an alternative regimen 
will be chosen by the site investigator with recommendations of the protocol 
team. Follow-up intervals will continue per study protocol, but the site 
investigator may schedule additional non-study, safety visits as necessary. The 
patient will be followed off study medication but on study for the remainder 
of the 48 weeks of study.  
 
6.2.7 Post-Treatment Evaluations 
 
All randomized subjects who complete the study will complete the week 48 
End of Study Visit.  
 
6.2.8 Premature Treatment Discontinuation 
 
These evaluations are required at the subject’s final visit. 
 
6.2.9 Pregnancy  
 


 
 
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Women who become pregnant during the study will be required to 
permanently discontinue their study regimens and will not continue to be 
followed on study.  They should be advised to seek best available medical 
care for their pregnancy according to US PH Guidelines. 
 
6.3 Special Instructions and Definitions of Evaluations 
 
6.3.1 Documentation of HIV 
 
HIV-1 infection, as documented by any licensed screening antibody test, such 
as ELISA, and confirmed by a second antibody test, such as Western blot, at 
any time prior to study entry. HIV-1 culture, HIV-1 antigen, two plasma HIV-
1 RNA > 2,000 copies/mL.  HIV-1 infection can also be documented by two 
plasma HIV-1 RNA > 2,000 copies/mL. 
 
6.3.2 HIV Drug Resistance Testing 
 
All subjects must have resistance testing (genotype) obtained from any 
laboratory and made available for review by the protocol team and site 
investigator prior to randomization.  Obtaining resistance testing for patients 
with HIV infection is part of standard medical care according to current 
guidelines. If a historic resistance test is not available at the time of screening 
then resistance testing will need to be done at screening. However, the study 
will not provide the resistance assay. Resistance testing results should be 
scanned and uploaded to the on-line data collecting system 
(https://cfar.ucsd.edu/intranet).  
 
6.3.3 Medical and Laboratory History 
 
At screening, a medical history will be obtained and must be recorded in the 
source documents.  The medical history should include any previous HIV-
related diagnoses and AIDS-defining events.  
 
In addition, prior to obtaining screening laboratories, documentation of 
plasma HIV-1 RNA load > 5000 copies/mL and CD4+ T-cell counts > 50 
cells/mL must be recorded in the source documents.  
 
6.3.4 Medication History 
 
At screening, a medication history (only if within last 30 days prior to 
entry) with actual or estimated start and stop dates should be obtained and 
recorded in the source documents and the concomitant medication CRF, 
including:   
 


 
 
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All prescription medications.  Including medications taken for the treatment or 
prophylaxis of opportunistic infections. 
 
Non-prescription medications.  
 
Alternative therapies and/or dietary supplements.   
 
Allergies to any medications and their formulations must be documented. 
 
6.3.5 Concomitant Medications 
 
During study visits (See section 6.1 for specific dates) all concomitant 
medications taken since the last visit will be recorded in the source 
documentation and entered into the concomitant medication log CRF. 
 
6.3.6 Study Treatment Modifications 
 
All modifications to study drug(s) including initial doses, patient-initiated 
and/or protocol-mandated interruptions, modifications, and permanent 
discontinuation of HIV antiretrovirals need be recorded on the CRFs at each 
visit. 
 
6.3.7 Clinical Assessments 
 
Complete Physical Exam 
 
A complete physical examination will be performed at entry. Documentation 
must include a complete review of systems. 
 
Targeted Physical Exam 
 
A targeted physical examination will be based on any signs or symptoms 
previously identified that the subject has experienced within 30 days of entry 
or since the last visit.  This examination will be performed at weeks 4, 8, 12, 
16, 24, 36 and 48 of therapy and in instances of virologic failure/toxicity or 
premature treatment discontinuation if they should occur. 
 
Height and Weight 
 
Height and weight should be measured at study entry. 
 
Signs and Symptoms 
 
All signs, symptoms, deaths, and toxicities must be documented in the 
subject’s record.  At entry, record all signs/symptoms experienced within 30 
days of entry on the CRFs.  For all other visits and at the time of confirmation 


 
 
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of virologic failure, record all Grade > 2 signs and symptoms, HIV-related and 
AIDS-defining events and deaths on the CRFs that have occurred since the 
last visit. Any signs or symptoms that lead to a change in treatment, regardless 
of Grade, must be recorded on the CRF.  The source document must include 
date of onset and date of resolution, but the CRF will only record prevalence 
of a given adverse event since the previous study visit. 
 
Refer to the Division of AIDS Table for Grading Adult Adverse Experiences, 
which can be found on the CCTG website: www.cctg.ucsd.edu  
 
Diagnoses 
 
The following should be recorded on the CRFs:  HIV-related diagnoses, 
malignancies, AIDS-defining events and death.  Any other diagnosis that is, in 
the opinion of the site investigator, associated with study medications, should 
be recorded on the adverse event CRF.  The source document must include 
date of diagnosis and date of resolution. 
 
Karnofsky Performance Status 
 
A Karnofsky performance status must be completed within 30 days before 
study entry. 
 
Vital Signs 
 
Temperature, pulse, and blood pressure collected at all visits and kept as a part 
of the source document. 
 
6.3.8 Laboratory Evaluations 
 
For all visits record all Grade ≥ 2 laboratory values on the CRFs throughout 
the course of the study. All values, regardless of toxicity, of specific 
laboratories will also be recorded on the laboratory CRF; including: wbc, 
neutrophil count, hemoglobin, platelets, blood urea nitrogen, creatinine, 
glucose, AST/ALT, alkaline phosphatase, total bilirubin, total cholesterol, low 
density lipoprotein, high density lipoprotein and triglycerides. 
 
Any laboratory toxicities that lead to a change in treatment, regardless of 
Grade, must be recorded on the adverse event CRF.  
 
Refer to the Division of AIDS Table for Grading Adult Adverse Experiences, 
which can be found on the CCTG website: www.cctg.ucsd.edu 
 
Hematology:  
 


 
 
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Hemoglobin, hematocrit, white blood cell count (WBC), differential WBC, 
absolute neutrophil count (ANC), and platelet count will be performed in real 
time at the site’s local laboratory. 
 
Blood volume: 3 mL 
 
Liver & Kidney Function Tests 
 
Total bilirubin, AST (SGOT), ALT (SGPT), and alkaline phosphatase, BUN, 
creatinine and electrolytes (sodium, potassium, chloride, and bicarbonate) will 
be performed in real time at the site’s local laboratory. 
 
Estimated creatinine clearance should be calculated each time a creatinine 
level is determined. To estimate creatinine clearance, use the following 
method of Cockcroft and Gault: 
 
For men: [(140 - age in years) x (body weight in kg)] ÷ (serum creatinine in 
mg/dL x 72). 
 
For women: use the same calculation as for men, then multiply the result by 
0.85.  
 
A calculator is available at the Data Management Center Web site at 
https://www.fstrf.org/ACTG/. 
 
Blood volume: 7 mL 
 
Fasting Lipid Profile 
 
Total cholesterol, low density lipoprotein (LDL), high density lipoprotein 
(HDL) and triglycerides will be performed in real time at the site’s local 
laboratory. 
 
Blood volume: 7 mL 
 
Pregnancy Test 
 
For women with reproductive potential: Urine β-HCG (urine test must have a 
sensitivity of < 50 mIU/mL) should be done at the site’s local laboratory 
during screening, at study entry and whenever clinically suspected. 
 
5 ml urine 
 
6.3.9 Immunologic Studies 
 
Nadir CD4+ T-cell count 


 
 
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The subject’s prior nadir CD4+ T-cell count (absolute value and date) should 
be documented during screening and, when possible, a copy of the nadir 
CD4+ T-cell count report should be included in the source document. If this 
documentation is not available, then subject recollection will suffice. For 
subjects who do not know the exact nadir value and for whom there is no 
source documentation, then recall of the categorical nadir (e.g., <50, <100, 
<200 cells/mm3) will suffice. 
 
CD4/CD8 
 
All CD4/CD8 count and percentages must be performed at the site’s local 
laboratory prior to study entry. Pre-entry and entry measurements must be 
obtained at two separate time points at least 48 hours apart.  The mean of the 
pre-entry and entry measurements will be used as the baseline value. See 
section 6.1 for specific collection dates.  
 
Because of the diurnal variation in CD4+ and CD8+ T-cell counts; all 
determinations should be obtained consistently in either the morning or the 
afternoon throughout the study, if possible. 
 
Blood volume: 5 mL 
 
Extended Flow Cytometry Markers 
 
Extended flow markers for activation, maturation, apoptosis and regulatory 
function will be evaluated on CD4+/CD8+ T-cells. Samples will be collected 
at entry and on weeks 4 and 24.  These analyses will be done on fresh samples 
in real-time. Specimens will need to be shipped ambient, overnight and in 
real-time to the UCSD central laboratory.  
 
Blood volume: 10 mL 
 
6.3.10Virologic Studies 
 
Proviral HIV-1 DNA 
 
Whole blood for proviral HIV-1 DNA quantitation should be collected at Pre-
Entry and during the Viral Dynamic Sequence [Day 0, 2, 7 and 14 (except 
Day 10)] and at weeks 4, 24 and 48. Specimens should be shipped 
immediately after collection to the central lab (UCSD). 
 
Blood volume: 10 mL 
 
Plasma HIV-1 RNA 


 
 
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Pre-entry HIV-1 RNA must be collected and stored prior to study entry then 
shipped in batch on Day 14 to the central lab (UCSD). Pre-entry and entry 
measurements must be obtained at two separate time points at least 48 hours 
apart.  The mean of the pre-entry and entry measurements will be used as the 
baseline value. See section 6.1 for specific collection dates.  
 
Plasma HIV-1 RNA during the Viral Dynamic Sequence should be collected 
at every study visit (Day 0, 2, 7, 10 and 14) and stored until shipped in batch 
to the central lab (UCSD) after completion of the viral decay dynamics (Day 
14). Afterwards, during the follow-up phase of the study, the HIV RNA load 
should be determined at the site’s local laboratory at weeks 4, 8, 12, 16, 24, 
36 and 48. 
 
 
Genotype Resistance Assay 
 
If a historic genotype resistance test is not available at screen, a baseline 
genotype test should be done at screening (this test will not be provided by the 
study). In addition, samples for genotypic analysis obtained at the time of 
virologic failure should be done in real time a the local laboratory for subject 
management by the site’s investigator (this test will not be provided by the 
study). All resistance testing results should be scanned and uploaded on the 
on-line data collection system for review by the protocol team 
(https://cfar.ucsd.edu/intranet). 
 
Stored Plasma 
 
Stored Plasma will be collected at screening, study entry, all visits of the viral 
dynamics sequence and during weeks 4, 8, 12, 24 and 48.  
 
 
* Specimens obtained during pre-entry, entry and viral dynamics will be 
stored at the site’s local laboratory and batched shipped to the central 
laboratory (UCSD) after completion of the viral dynamics sequence. 
  
** Specimens obtained at weeks 4, 8, 12, 24 and 48 will be stored at the site’s 
local laboratory and batched shipped to the central laboratory (UCSD) after 
completion of week 48 or upon premature discontinuation from study. 
 
Blood volume for combined HIV RNA and stored plasma: 15 mL  
Blood volume for HIV RNA: 5 mL  
 
6.3.11 PBMCs for storage 
 


 
 
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Blood for PBMCs will be collected in and shipped ambient, overnight and 
in real-time to the central laboratory (UCSD) at entry and weeks 4, 24 and 
48.  
 
Blood volume: 10 mL 
 
6.3.12 Adherence Questionnaires 
 
Medication diaries will be conducted by study personal during the viral 
dynamics sequence. Dosing dates and exact times of study medications will 
need to be recorded. Afterwards, on the follow-up portion of the study, 
adherence questionnaires (standard ACTG style questionnaires) will be 
conducted on weeks 4, 8, 12, 16, 24, 36 and 48 of therapy and in instances of 
virologic failure and/or premature treatment discontinuation. 
 
6.4 Off-Drug Requirements 
Additional safety monitoring and reporting of serious adverse experiences (SAEs) 
continues to be required upon completion or discontinuation of study treatment 
regardless of whether a protocol follow-up period is scheduled to occur. Adverse 
experiences occurring during the immediate 8-week period after the last dose of 
study treatment which meet SAE reporting requirements must be reported to the 
CCTG Data Center. Additionally, after 8 weeks OFF study treatment, there are 
four types of events that must be reported to the CCTG Data Center if the 
relationship to the study drug is assessed by the site physician as definitely, 
possibly, or unable to judge: DEATHS, NEW ONSET CANCERS, CONGENITAL 
ANOMALIES, AND PERMANENT DISABILITIES. 
 
 
7.0 TOXICITY MANAGEMENT  
 
Only toxicities related to study medications (LPV/r, RAL, TDF, 3TC and EFV) will 
be considered in the toxicity management section. The management of these 
medication related toxicities should be undertaken by the local investigators, with 
guidance available from the protocol team, protocol pharmacist and pharmaceutical 
sponsor, to insure the optimal safety and efficacy for the individual subject. 
 
Toxicity resulting from any non-study medications (other than study medications as 
listed above) should be managed per standard of care. The grading system is located 
in the Division of AIDS Table for Grading Adult Adverse Experiences, which can 
be found on the Division of AIDS Regulatory Compliance Center Web Site:  
http://rcc.tech-res-intl.com. 
  
 
NOTE: The study Co-chairs and the study protocol team need to be notified by e-
mail regarding any toxicities that result in a change in regimen.  In case an EFV 
containing regimen needs to be discontinued, consideration should be given to 


 
 
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discontinue EFV prior to stopping the other components of the antiretroviral 
regimen. Simultaneous discontinuation of an EFV containing regimen leads to de 
facto EFV mono-therapy due to difference of half lives between EFV and other 
ARV drugs.  
 
 
7.1 Grade 1 or 2 
 
Subjects who develop a Grade 1 or 2 adverse event or toxicity may continue study 
drugs without alteration of the dosage, except for Grade > 2 creatinine elevation in 
subjects receiving TDF (component of Atripla).  Those subjects experiencing 
Grades 1 or 2 adverse events which results in discontinuation of, or substitution, for 
any of the study drugs should be reported to the protocol team.  
 
7.2 Grade 3 
 
Management of Grade 3 toxicities should be discussed with the protocol team via 
email. Please refer to the subsequent sections for management of specific events.  
 
Subjects who develop a Grade 3 adverse event or toxicity judged to be study drug-
related should have all medications held or have the toxicity causative study drug 
switched to an alternative drug.  In the event that the regimen is held, that subject 
should be re-evaluated weekly until the adverse event returns to Grade ≤ 2, at which 
time the study drugs may be reintroduced at the discretion of the investigator or 
according to standard practice.  Subjects experiencing Grade 3 adverse events 
requiring permanent discontinuation of any study drug should be followed weekly 
until resolution of the adverse event.  The treatment regimen should be modified at 
the discretion of the site investigator and subjects should be encouraged to remain 
in the study.  Exemptions include asymptomatic elevations of CPK, cholesterol or 
triglycerides. For these laboratories, medication may be continued at the discretion 
of the site investigator and laboratories repeated within 2 weeks.    If the toxicity or 
laboratory elevation is thought not to be due to study medication, the study 
medication may be continued with follow-up at the discretion of the primary 
provider. 
 
7.3 Grade 4 
 
Management of Grade 4 toxicities should be discussed with the protocol team via 
email. 
 
Subjects who develop a Grade 4 adverse event or toxicity judged to be study drug 
related will have the presumed causative study drug(s) permanently discontinued 
and another drug will be substituted. Subjects experiencing Grade 4 adverse events 
should be followed weekly until resolution of the adverse event.  At that time, they 
will resume study visits and evaluations according to the Schedule of Events. A 
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include: asymptomatic elevations of cholesterol or triglycerides that can be 
managed with diet and/or lipid lowering therapy or CPK, if the CPK elevation is not 
felt to be related to study medications. For these laboratories, medication may be 
continued with follow-up at the discretion of the site investigator.  If the toxicity or 
laboratory elevation is thought not to be due to study medication, the study 
medication may be continued and laboratories repeated within 2 weeks. If it is not 
possible for the investigator to discern the causative agent, then all study 
medications must be discontinued. 
 
7.4 Rash 
 
Rash may be caused by therapies in any of the major antiretroviral classes or by 
other therapies commonly used as concurrent medications, such as cotrimoxazole. 
As it is not possible to provide an exhaustive list of products that may cause rash in 
this protocol, please consult the product information leaflets for other products for 
information relating to rash.   
 
Rash and any associated symptoms should be reported as adverse events and 
appropriate toxicity ratings should be used to grade the events.   
 
If the etiology of the rash can be definitively diagnosed as being due to a specific 
medical event or a concomitant medicinal product, routine management should be 
performed and documentation of the diagnosis provided.  
 
For Grade 2 rash antihistamines, topical corticosteroids, or a brief course of 
systemic corticosteroids, at the discretion of the site investigator, may be prescribed 
and subjects may continue all study medications. The subject should be advised to 
contact the physician immediately if there is any worsening of the rash.  EFV (as 
part of Atripla®) may be temporarily discontinued along with all other study 
medications, at the site investigator’s discretion, until the cutaneous toxicity returns 
to Grade <1, at which time therapy should be reinstituted at full dose. The subject 
should be closely monitored for recurrence of the rash. The protocol team should be 
consulted. 
 
If the rash is considered to be most likely due to concomitant illness or medication, 
standard management, including discontinuation of the likely causative agent, 
should be undertaken. If no other causative factor is found after clinical evaluation, 
the subject should be treated symptomatically until the rash resolves.  
 
For Grade 3 rash thought to be related to the study medications, subjects should 
either discontinue all drugs or consider switching from the likely causative agent. 
 
For Grade 4 rash subjects should discontinue all study medications. The Protocol 
team should be consulted. 
 
NOTE: In the event that Grade 2, 3, or 4 rash fails to resolve, increases in severity, 


 
 
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is associated with systemic (fever, malaise, nausea) or allergic (e.g., urticaria) 
symptoms, or is associated with exfoliative dermatitis or mucous membrane 
involvement or erythema, multiforme or suspected Stevens-Johnson syndrome or 
necrosis requiring surgery, all study medications should be temporarily 
discontinued until symptom resolution. Some or all study medications may then be 
reintroduced. 
 
7.5 Skin hyperpigmentation 
 
Development of skin hyperpigmentation, if assessed as being related to FTC, can be 
followed without modification of therapy, at the discretion of the site investigator.  
 
7.6 Nausea and Vomiting  
 
Nausea and vomiting may be treated symptomatically with oral antiemetics or 
antiemetic suppositories. For Grade >3 nausea or vomiting thought to be secondary 
to study drugs that fails to improve on antiemetics to Grade <2, all study drugs may 
be held until Grade <2. If Grade >3 nausea or vomiting recurs with reinstitution of 
study drugs or persists beyond 14 days despite symptomatic  management, then 
other antiviral agents may be substituted. 
 
7.7 Diarrhea 
 
For Grade <2 diarrhea the study treatment should continue without interruption.  
Subjects with diarrhea of any toxicity grade may be treated symptomatically with 
permitted antimotility agents.  For Grade 3 or 4 diarrhea that is unresponsive to 
antimotility agents and for which an alternative etiology (e.g., infectious diarrhea) is 
not established, all study medications should be interrupted until resolution of 
diarrhea to Grade ≤ 2 or baseline and then study treatment can be resumed at the 
discretion or the site investigator.  If Grade ≥ 3 diarrhea recurs upon the resumption 
of study medications, all study medications should be interrupted and the protocol 
team should be notified for alternative antiretroviral therapy. 
 
7.8 Hyperglycemia 
 
Fasting hyperglycemia of > 110 to 125 mg/dL is considered evidence of impaired 
glucose tolerance.  A fasting blood glucose level above 126 mg/dL is highly 
suggestive of diabetes mellitus.  Subjects with previously undiagnosed fasting 
hyperglycemia may continue study medications at the discretion of the investigator, 
but should be discussed with the protocol team via email.  A confirmatory fasting 
glucose must be obtained within 4 weeks and prior to the institution of medical 
therapy.  Hyperglycemia may be treated with oral hypoglycemic agents or insulin 
according to standard guidelines. 
 
7.9 AST/ALT Elevations 
 


 
 
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All study medications may be continued for asymptomatic Grade <3 AST/ALT 
elevations at the discretion of the site investigator after discussion with the protocol 
team.  Careful assessments should be done to rule out the use of alcohol, non-study 
medication-related drug toxicity, or viral hepatitis as the cause of the Grade 3 
elevation.  The possibility of lactic acidosis syndrome should also be explored. 
 
For symptomatic Grade 3 and all Grade 4 elevations of AST or ALT, all study 
drugs should be stopped and the protocol team consulted,  Repeat laboratories 
should be performed and all study medications held until the toxicity returns to 
Grade < 2.  If symptomatic Grade 3 or any Grade 4 elevation in AST or ALT recurs 
upon reinitiation of therapy, treatment should be stopped and alternative ARV 
therapy considered in consultation with the protocol team. 
 
7.10 Lipase elevation 
 
Pancreatitis will be reported as either clinical (i.e., symptomatic) or chemical (i.e., 
persistent elevation in enzymes without any symptoms).  
 
For asymptomatic lipase elevation Grade > 3, lipase should be repeated within 2 
weeks and triglyceride levels should be checked. For Grade > 3 asymptomatic 
lipase elevation on repeat testing, the implicated drug(s) should be stopped at the 
discretion of the site investigator and in consultation with the protocol team. When 
lipase returns to Grad < 2, the implicated drug(s) may be restarted or may be 
replaced if a substitution can be identified, at the discretion of the site investigator. 
Routine evaluation of lipase are not required by the study.  
 
Symptomatic pancreatitis is not commonly associated with study-provided drugs. If 
clinical pancreatitis is suspected, please refer to the ACTG Definition of 
Pancreatitis, located at  
http://aactg.s-3.com/members/download/other/pancdefv2.doc.  
The protocol team should be informed.   
 
7.11 Creatinine Elevations 
 
Discontinue TDF if confirmed creatinine clearance becomes < 50 mL/min.   
Subjects should be followed as medically indicated until the creatinine returns to 
Grade < 2. The protocol team should be notified within 48 hours of any permanent 
therapy discontinuations. 
 
7.12 Hypertriglycredemia / Hypercholesterolemia 
 
Subjects who experience asymptomatic triglyceride or cholesterol elevations may 
continue to receive study drugs. Only triglyceride levels obtained in a fasting state 
should be evaluated for toxicity management. For Grade >3, confirmatory fasting 
triglyceride should be obtained within 4 weeks and must be obtained prior to the 
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Subjects with asymptomatic triglyceride or cholesterol elevation should be 
counseled on dietary modification. Oral antihyperlipidemic agents should be 
considered at the discretion of the site investigator (and documented on the 
concomitant drug CRF). Guidelines for the treatment of hyperlipidemia are 
available on the ACTG web site  
(http://aactg.s-3.com/members/download/other/metabolic/Chol.rtg).  
 
Resin binding agents, such as cholestyramine and colestipol, should be avoided as 
they may interfere with absorption of LPV/r as well as the absorption of other drugs 
and fat-soluble vitamins.       
 
7.13 CNS Symptoms with EFV 
 
Subjects should be informed that these symptoms are likely to improve with 
continued ARV therapy. Dosing at bedtime improves the tolerability of these 
symptoms and is recommended. Subjects receiving EFV should be alerted to the 
potential for additive CNS effects when EFV is used concomitantly with alcohol or 
psychoactive drugs.  In addition, taking EFV with food may increase blood levels 
and CNS symptoms.  In the event of treatment-limiting (in the opinion of the site 
investigator) CNS AEs attributable to EFV, the protocol team should be informed 
and EFV should be discontinued and alternative regimens discussed.  
 
7.14  Pregnancy 
 
Women who become pregnant on study must continue all study medications 
immediately and must prematurely discontinue the study. The protocol team should 
be notified. In addition, pregnancy outcome data will be collected and recorded in 
her source document and on the CRF.  
 
Sites are strongly discouraged to register any pregnancy that occurs on study with 
The Antiretroviral Pregnancy Registry as soon as the site become aware of it. More 
information is available at www.apregistry.com. Phone: 800-259-4263; Fax; 800-
800-1052.   
 
8.0 
CRITERIA FOR TREATMENT DISCONTINUATION 
 
8.1 Criteria for Treatment Discontinuation 
• Drug-related toxicity (see section 7, Toxicity Management). 
• Requirement for prohibited concomitant medications (see section 5.4.2) 
 
8.2 Criteria for Discontinuation from the Study 
• Pregnancy or breast-feeding. 


 
 
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• Active drug or alcohol use or dependence that, in the opinion of the investigator, 
would interfere with adherence to study requirements. 
• Failure by the subject to attend three consecutive clinic visits during the follow-
up portion may result in discontinuation. 
• Request by the subject to withdraw. 
• Request of the primary care provider if s/he thinks the study is no longer in the 
best interest of the subject. 
• Clinical reasons believed life threatening by the physician, even if not addressed 
in the toxicity management of the protocol. 
• Subject judged by the investigator to be at significant risk of failing to comply 
with the provisions of the protocol as to cause harm to self or seriously interfere 
with the validity of the study results. 
• At the discretion of the CCTG, FDA, investigator, or pharmaceutical sponsors. 
 
9.0 STATISTICAL CONSIDERATIONS 
 
9.1 General Design Issues 
 
This is a 1:1 randomized, open-label, pilot study of RAL+ LPV/r vs. Atripla® in 
HIV-1-infected, treatment-naïve subjects for 48 weeks. During the initial 2-week 
period, subjects will undergo intensive monitoring of viral decay dynamics 
(baseline, days 2, 7, 10, 14) and immune T-cell subset changes (baseline and week 
4).  From weeks 4 to 48, subjects will be monitored for treatment efficacy (CD4+ 
cell counts, and plasma HIV-1 RNA levels) and safety/ tolerability (hematology, 
chemistry, fasting lipids and symptom questionnaire).  
 
 
9.2 Endpoints 
 
Primary:   
 
The viral decay rate of the phase 1 decay in HIV RNA. 
 
Secondary: 
 
1. The proportion of participants with plasma HIV RNA < 50 copies/mL at week 
48. 
 
2. The proportion of participants with treatment failure at week 48.  
 
3. Time to treatment failure. 
 
4.   The change in CD4+ T-cell absolute count and percentage from baseline week 
48. 
 


 
 
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5. The change in CD4+ T-cell absolute count and percentage during phase 1 
(baseline to week 12) and phase 2 (weeks 12 to 48) immune recovery.  
 
6. The proportion of CD4+/CD8+ T-cell immune activation, maturation, 
regulatory and apoptosis markers at baseline and weeks 4 and 24. 
 
7.   Fasting lipid profiles (total cholesterol, high-density cholesterol, calculated LDL 
cholesterol, triglycerides) at baseline weeks 12, 24 and 48. 
 
8. Grades > 2 laboratory abnormalities and signs and symptoms. 
 
9. Time to treatment discontinuation due to toxicity. 
 
9.3 Sample Size  
 
Primary objective: To compare the antiviral potency as measured by phase 1 plasma 
viral decay rates between RLT + LPV and EFV + TDF + FTC.  
 
In A5160, a viral dynamics sub-study of A5142, the first-phase viral decay rate (d1) 
for EFV + 2 NRTI regimen (n=25 subjects) was 0.638 days-1 (IQR: 0.577, 0.703) 
and 0.530 days-1 (IQR: 0.414, 0.662) for LPV + 2 NRTI (n=22 subjects) 
combinations.  EFV-containing combinations had a significantly faster decay rate 
that LPV/r-based regimens (difference of 0.108 days-1; P=0.03). Although similar 
intensive phase 1 viral decay data are not yet available, plasma HIV RNA levels 
were 70% lower at day 14 of treatment in RLT + TDF/3TC vs. EFV + TDF/3TC 
treated patients (Murray J, et al., Abstract TUAB103). Therefore, we hypothesize 
that the RLT + LPV/r combination will have a greater phase 1 viral decay rate 
compared to EFV + TDF + FTC. 
 
The study is powered to compare the phase 1 viral decay rate between the 
EFV+TCD+FTC and RLT+LPV/r groups using a two-sided, two-sample t-test with 
alpha=0.05. Assuming the phase 1 viral decay rate for EFV+TCD+FTC (d1) is 
0.638, we calculated power for the following situations. 
 
Table 1. Power to declare difference in phase 1 decay rate d1, for various 
differences and standard deviations with n=25 per group. 
 
Difference 
between arms in 
d1 
SD, decay 
rate 
Power 
0.1 
0.1 
93% 
0.1 
0.12 
82% 
0.12 
0.15 
79% 
 
Assuming the SD of the viral decay rate is 0.12, the study has 82% power to detect 
a 0.1 difference in the decay rates between the EFV+TCD+FTC and RLT+LPV/r 


 
 
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with n=25 subjects per group (alpha=0.05). 
 
9.4 Methods of Analysis 
 
9.4.1 Analysis of Primary Objectives 
 
Repeated HIV RNA measured at different time points (baseline, days 2, 7, 10, 14) 
will be treated as the outcome variable in a linear mixed-effects model. The primary 
fixed effects will include time, treatment group, treatment group-by-time 
interaction; random effects will include both intercept and slope allowing each 
subject to have individual baseline viral load and viral decay rate. The treatment 
group-by- time interaction term in the model will indicate the difference in viral 
decay rates between the two treatment groups. Baseline covariate adjustment will 
be included if necessary. 
 
9.4.2 Analysis of Secondary Objectives 
 
Secondary analyses will include descriptive statistics and tests of significance 
between the two treatment arms.  All significance tests will be two-sided and no 
adjustment for multiple comparisons will be made.  If necessary due to assumption 
failures, appropriate non-parametric statistical tests will be applied. 
 
1a. Differences in the proportion of participants on each arm with plasma HIV RNA 
< 50 copies/mL at week 48 will be compared via Fisher’s exact test (intention to 
treat analysis with data imputation for missing data). 
 
1b. Differences in the proportion of participants on each arm with plasma HIV 
RNA < 50 copies/mL at week 48 will be compared via Fisher’s exact test (no data 
imputation for missing data). 
 
2. Differences in the proportion of participants on each arm with treatment failure 
(defined as non-completer, protocol-defined virologic failure, treatment 
discontinuation, or change in treatment regimen) at week 48 will be compared via 
Fisher’s exact test. 
 
3. Differences in time to treatment failure (defined as non-completer, protocol-
defined virologic failure, treatment discontinuation, or change in treatment regimen) 
will be compared via Kaplan-Meier curves and the log-rank test. 
 
4. Differences in the change in CD4+ T-cell absolute count and percentage from 
baseline to week 48 will be compared via a two-sample Student t-test. 
 
5a. Differences in the change in CD4+ T-cell absolute count and percentage from 
baseline to week 12 (Phase 1) and week 12 to week 48 (Phase 2) will be compared 
via separate two-sample Student t-tests. 
 


 
 
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5b. Association between viral decay kinetics and Phase 1 CD4 recovery will be 
determined via Pearson’s correlation analysis.  
 
6a. Differences in the proportion of CD4+/CD8+ T-cell immune activation, 
maturation, regulatory and apoptosis markers at baseline and weeks 4 and 24 will 
be separately compared cross-sectionally via Fisher’s exact test. 
 
6b. Association between change in early immune subsets and phase 2 CD4 recovery 
will be assessed via Pearson’s correlation analysis 
 
7. Differences in fasting lipid profiles (total cholesterol, high-density cholesterol, 
calculated LDL cholesterol, triglycerides) at baseline weeks 12, 24 and 48 will be 
compared cross-sectionally via two-sample Student t-tests. 
 
 
8. Differences in proportions of grades > 2 laboratory abnormalities and signs and 
symptoms will be compared via Fisher’s exact test. 
 
9. Differences in time to treatment discontinuation because of toxicity/intolerance 
will be compared via Kaplan-Meier curves and the log-rank test. 
 
9.5  Monitoring 
 
It is the responsibility of the Principal Investigator and the CCTG protocol team to 
interpret the viral response and toxicity data and make any decisions needed to 
protect patients from undue risk. Safety and tolerability of the study medications 
will be monitored by means of adverse event reports (AER) and bimonthly toxicity 
reports presenting laboratory and clinical data. Safety data will be tabulated by 
study arm and reviewed by the statisticians but study arm assignment will be 
blinded to protocol team and site investigator’s unless safety issues require an un-
blinding. These reports will be discussed by the protocol team on monthly 
conference calls. Accrual and toxicity summaries will be provided to the Protocol 
Chairs and CCTG Investigators by the Data Manager and Biostatistician. 
 
The study will undergo an internal review by the protocol chairs and study team 
when either twelve subjects in the RAL+LPV/r arm have enrolled or after one year 
has elapsed from when the first subject was enrolled, whichever comes first. The 
study would be reviewed by an independent Study Monitoring Committee if 
protocol chairs deemed necessary or if greater than 30% of subjects in the 
RAL+LPV/r arm (and at least 12 subjects enrolled in this arm) experience virologic 
failure. The independent review committee will be composed of at least 3 people 
(including one statistician) outside the protocol team. The committee will make 
specific recommendations about changes to the study protocol. 
 
10.0 
DATA COLLECTION AND MONITORING AND ADVERSE EXPERIENCE 
REPORTING 
 


 
 
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10.1 Records to Be Kept 
Case report forms (CRF) will be provided for each subject. Subjects must not be 
identified by name on any CRFs. Subjects will be identified by the patient 
identification number (PID) provided by the CCTG Data and Biostatistical Unit 
upon registration. 
 
10.2 Role of Data Management  
10.2.1 Instructions concerning the recording of study data on CRFs will be  
 provided by the CCTG Data and Biostatistical Unit.  
 
10.2.2 It is the responsibility of the CCTG Data and Biostatistical Unit to assure the 
quality of computerized data for this study.   
 
10.3 Clinical Site Monitoring and Record Availability 
10.3.1 Site monitors provided by the CCTG will visit participating clinical research 
sites to review the individual subject records, including consent forms, 
CRFs, supporting data, laboratory specimen records, and medical records 
(physicians’ progress notes, nurses’ notes, individuals’ hospital charts), to 
ensure protection of study subjects, compliance with the protocol, and 
accuracy and completeness of records. The monitors also will inspect sites’ 
regulatory files to ensure that regulatory requirements are being followed 
and sites’ pharmacies to review product storage and management. 
 
10.3.2 The investigator will make study documents (e.g., consent forms, drug 
distribution forms, CRFs) and pertinent hospital or clinic records readily 
available for inspection by the local IRB, the site monitors, the Food and 
Drug Administration (FDA), the pharmaceutical sponsor(s), or the sponsor’s 
designee for confirmation of the study data.  
 
10.4 Serious Adverse Experience (SAE) Reporting 
Serious adverse experiences must be documented on the Serious Adverse 
Experience (SAE) Reporting Form and submitted to the CCTG Data and 
Biostatistical Unit. 
 
11.0 HUMAN SUBJECTS 
 
11.1 Institutional Review Board (IRB) Review and Informed Consent 
This protocol and the informed consent document and any subsequent 
modifications will be reviewed and approved by the IRB or ethics committee 
responsible for oversight of the study. A signed consent form will be obtained from 


 
 
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54 
the subject. The consent form will describe the purpose of the study, the procedures 
to be followed, and the risks and benefits of participation. A copy of the consent 
form will be given to the subject. 
 
11.2 Subject Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records that leave the 
site will be identified by coded number only to maintain subject confidentiality. All 
records will be kept locked. All computer entry and networking programs will be 
done with coded numbers only. Clinical information will not be released without 
written permission of the subject, except as necessary for monitoring by IRB, the 
FDA, the OHRP, the pharmaceutical supporter(s), or the supporter’s designee. 
 
11.3 Study Discontinuation 
The study may be discontinued at any time by the IRB, the pharmaceutical 
supporter(s), the FDA, or other government agencies as part of their duties to ensure 
that research subjects are protected.  
 
 
12.0 PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by CCTG policies. Any 
presentation, abstract, or manuscript will be made available for review by the 
pharmaceutical supporters prior to submission. 
 
 
13.0 BIOHAZARD CONTAINMENT 
 
As the transmission of HIV and other blood-borne pathogens can occur through 
contact with contaminated needles, blood, and blood products, appropriate blood 
and secretion precautions will be employed by all personnel in the drawing of blood 
and shipping and handling of all specimens for this study, as currently 
recommended by the Centers for Disease Control and Prevention and the National 
Institutes of Health. 
 
All infectious specimens will be transported using packaging mandated in the 
Federal Code of Regulations, CDC 42 CFR Part 72. Please also refer to individual 
carrier guidelines, e.g., FedEx, Airborne, for specific instructions. 
 
14.0 
REFERENCES 
 
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