Conditions: HIV Infections
Keywords: HIV nucleoside pharmacology drug-drug interaction Treatment Naive Drug resistance Drug pharmacokinetics
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 21
Healthy volunteers: no

Brief summary:
Once-daily nucleotide/nucleoside reverse transcriptase inhibitor (NtRTI/NRTI) combinations form the backbone of many regimens. Although efficacy data exists between tenofovir and the pyrimidine analogues (i.e. lamivudine and emtricitabine), recent clinical data suggests a potential interaction between tenofovir and purine analogs (i.e. abacavir and didanosine).

Specific Aim 1: To evaluate the impact of an acyclic nucleoside phosphonate, tenofovir (TDF), on the intracellular metabolism of a purine nucleoside analog, abacavir (ABC), as a determinant of the antiviral potency of this nucleotide/nucleoside reverse transcriptase inhibitor (NtRTI/NRTI) combination.

* Hypothesis #1: ABC and TDF dosed together will have reduced antiviral activity, as measured by early plasma HIV RNA decay kinetics, than the drugs given alone.
* Hypothesis #2: ABC dosed with TDF will have reduced intracellular concentrations, as measured by the ratio of carbovir triphosphate (active metabolite of ABC) to deoxyguanosine triphosphate (endogenous nucleotide), compared to ABC given alone.

Detailed description:
The primary objectives of this study are to compare the virologic potency and pharmacology of TDF and ABC alone and in combination. Since it is not feasible or ethical to give mono or dual-therapy with these agents for prolonged intervals, this project was designed to take advantage of a short term drug exposure. The study performs intensive lab monitoring with a cross-over design to compare short courses of monotherapy and dual-therapy. This is an open-labeled study of a dual NRTI/NtRTI combination, ABC + TDF, compared to ABC and TDF monotherapy administered for 7 days. A screening genotype will be done to confirm that there are no resistance-associated mutations at baseline. Each subject will then be randomized to a 7-day sequence of monotherapy (ABC or TDF), and four measurements for plasma HIV RNA will be done to calculate the slope of the phase one viral decay. Prior to initiation of nucleoside analogues, PBMCs will be collected to measure baseline expression of nucleoside transport enzymes via RT-PCR and Western blot analysis. On days 7 and 8, serial blood specimens will be collected for plasma and intracellular levels of TDF and ABC. The monotherapy sequence will be followed by a 35-day washout period.

After the washout (day 42), subjects will initiate the dual NRTI/NtRTI therapy sequence for an additional 7 days. During dual NRTI/NtRTI therapy, again, four measurements for HIV RNA will be done to calculate the slope of the phase one viral decay. On day 48 and 49, serial plasma and intracellular levels of ABC + TDF will be evaluated. On Day 49 a second HIV genotype will be performed in real time. On day 49, after the second 7-day sequence, all subjects will receive EFV in addition to the ABC + TDF combination for 14 days. Afterwards, a second sample of PBMCs will be collected to evaluate for a potential induction or suppression of nucleoside transport enzymes. Since the long-term efficacy of the TDF + ABC nucleoside backbone is not yet known, TDF will be discontinued (day 63) and 3TC will be substituted. Subjects will then continue on the HAART portion of the study for an additional 46 weeks of EFV + ABC + 3TC.

Arms:
arm 1: As part of this study visit, you participants will be assigned by chance to receive either TDF alone or ABC alone arm 2: As part of this study visit, you participants will be assigned by chance to receive either TDF alone or ABC alone

Interventions: intervention 1: Tenofovir intervention 2: Abacavir
Intervention descriptions: intervention 1: 300 mg once daily intervention 2: 600 mg once daily

Protocol document:
Prot_SAP_000.pdf: 
 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
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CCTG 584 
 
 
 
Viral Dynamics and Pharmacokinetics of TDF and ABC Monotherapy versus the 
Combination Therapy of TDF – ABC in HIV-Infected Treatment Naïve Patients 
 
 
Sponsored by: 
 
 
The University Wide AIDS Research Program (UARP) 
 
 
 
Pharmaceutical Support Provided by: 
 
 
GlaxoSmithKline Pharmaceuticals  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Co-Chair(s): 
 
 
 
Richard Haubrich, M.D. 
 
 
 
 
 
 
 
Doug Richman, M.D. 
Miguel Goicoechea, M.D.     
 


 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................. 4 
PROTOCOL TEAM ROSTER ........................................................................................... 6 
SCHEMA ............................................................................................................................ 8 
1.0 
STUDY OBJECTIVES ........................................................................................... 9 
1.1 
Primary Objectives.............................................................................................. 9 
1.2 
Secondary Objectives.......................................................................................... 9 
2.0 
INTRODUCTION ................................................................................................ 10 
2.1 
Background ....................................................................................................... 10 
2.2 
Rationale ........................................................................................................... 20 
3.0 
STUDY DESIGN.................................................................................................. 23 
4.0 
SELECTION AND ENROLLMENT OF SUBJECTS ......................................... 28 
4.1 
Inclusion Criteria .............................................................................................. 28 
4.2 
Exclusion Criteria ............................................................................................. 29 
4.3 
Study Enrollment Procedures ........................................................................... 30 
4.4 
Co-enrollment Guidelines ................................................................................. 30 
5.0 
STUDY TREATMENT ........................................................................................ 31 
5.1 
Regimens, Administration, and Duration ......................................................... 31 
5.2 
Product Formulation and Preparation ............................................................... 32 
5.3 
Product Supply, Distribution, and Pharmacy .................................................... 33 
5.4 
Concomitant Medications ................................................................................. 33 
5.5 
Adherence Assessment ..................................................................................... 38 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ......................................... 38 
6.1 
Schedule of Events ............................................................................................ 38 
6.2 
Definitions for Schedule of Events – Timing of Evaluations ........................... 42 
6.3 
Special Instructions and Definitions of Evaluations ......................................... 45 
6.4 
Off-Drug Requirements .................................................................................... 54 
7 
TOXICITY MANAGEMENT .............................................................................. 54 
7.1 
Criteria for subject management ....................................................................... 54 
7.2 
Commonly occurring adverse events ................................................................ 55 
8 
CRITERIA FOR TREATMENT DISCONTINUATION .................................... 64 
8.1 
Criteria for Treatment Discontinuation ............................................................. 65 
8.2 
Criteria for Discontinuation from the Study ..................................................... 65 
9.0 
STATISTICAL CONSIDERATIONS.................................................................. 65 
9.1 
General Design Issues ....................................................................................... 65 
9.2 
Endpoints .......................................................................................................... 66 
9.3 
Sample Size and Accural .................................................................................. 66 
9.4 
Monitoring ........................................................................................................ 67 
9.5 
Analysis............................................................................................................. 68 
10.0 
DATA COLLECTION AND MONITORING AND ADVERSE EXPERIENCE 
REPORTING .................................................................................................................... 69 
10.1 
Records to Be Kept ........................................................................................... 69 
10.2 
Role of Data Management ................................................................................ 69 
10.3 
Clinical Site Monitoring and Record Availability ............................................ 69 
10.4 
Serious Adverse Experience (SAE) Reporting ................................................. 70 


 
 
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11.0 
HUMAN SUBJECTS ........................................................................................... 70 
11.1 
Institutional Review Board (IRB) Review and Informed Consent ................... 70 
11.2 
Subject Confidentiality ..................................................................................... 70 
11.3 
Study Discontinuation ....................................................................................... 70 
12.0 
PUBLICATION OF RESEARCH FINDINGS .................................................... 71 
13.0 
BIOHAZARD CONTAINMENT ......................................................................... 71 
14.0 
REFERENCES ..................................................................................................... 71 
 


 
 
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LIST OF ABBREVIATIONS 
 
AE 
 
Adverse Event 
ALP 
 
Alkaline Phosphatase 
ALT 
 
Alanine Phosphatase 
AST 
 
Aspartate Phosphatase 
AUC  
Area Under the Curve 
BID 
 
Twice Daily 
BUN  
Blood Urea Nitrogen 
CBV  
Carbovir 
CCTG  
California Collaborative Treatment Group 
CD4 
 
CD4 lymphocytes 
CI 
 
Confidence Interval 
Cmax  
Maximum Plasma Concentration 
Cmin  
Minimum Plasma Concentration 
C24 
 
24 hour Plasma Concentration 
CRF 
 
Case Report Form 
CYP  
Cytochrome 
D.V. 
 
Dynamics Visit 
DAVG  
Time average difference 
HAART 
Highly Active Antiretroviral Therapy 
HBV  
Hepatitis B Virus 
Hct 
 
Hematocrit 
HIV-1  
Human Immunodeficiency Virus - 1 
Hgb 
 
Hemoglobin 
HSR  
Hypersensitivity Reaction 
IAS 
 
International AIDS Society 
IQR 
 
Interquartile Range 
ITT 
 
Intention To Treat 
iv 
 
Intravenous 
NRTI  
Nucleoside analogue Reverse Transcriptase Inhibitor 
 
 
ABC  
Abacavir 
 
 
3TC 
 
Lamivudine 
 
 
D4T 
 
Stavudine 
 
 
TDF 
 
Tenofovir 
 
 
ZDV  
Zidovudine 
NNRTI 
Non-Nucleoside analogue Reverse Transcriptase Inhibitor 
 
 
EFV 
 
Efaverenz 
PI 
 
Protease Inhibitor 
 
 
IDV 
 
Indinavir 
PK 
 
Pharmacokinetics 
PBMC  
Peripheral Blood Mononuclear Cells 
QD 
 
Once Daily 
RT-PCR 
Real Time – Polymerase Chain Reaction 
STI 
 
Structured Treatment Interruption  
SAE 
 
Severe Adverse Reaction 


 
 
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UA 
 
Urinalysis  
WBC  
White Blood Count 
 


 
 
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PROTOCOL TEAM ROSTER 
 
Co-chairs 
Richard Haubrich, M.D. 
Associate 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 
 
Douglas Richman, M.D. 
Professor of Pathology and Medicine 
University of California San Diego and 
San Diego VA Medical Center 
Room 329, Stein Clinical Sciences 
Building 
9500 Gilman Drive 
LaJolla, CA  92093-0679 
Phone:  (858) 552-7439 
Fax:   (858) 552-7445 
E-mail: drichman@ucsd.edu 
 
Miguel Goicoechea, M.D. 
Fellow, Infectious Diseases 
University of California, San Diego 
150 West Washington Street, 100 
San Diego, CA 92103 
Phone: (619) 543-8080 
E-mail: mgoicoechea@ucsd.edu  
 
Protocol Pharmacologist 
Stan Louie, Pharm.D., Ph.D. 
Associate Professor of Clinical 
Pharmacy 
USC, School of Pharmacy 
1985 Zonal Avenue 
Los Angesles, CA 90033 
Phone: (323) 442-3646 
Fax: (323) 442-1345 
Email: slouie@usc.edu 
 
Senior Statistician  
Hulin Wu, Ph.D. 
Head, Pharmacology/Dynamic 
   Modeling Section 
Frontier Science and Technology  
   Research Foundation. 
1244 Boylston Street, Suite 303 
Chestnut Hill, MA  02467 
Phone:  (617) 632-5738 
Fax:   (617) 632-2001 
E-mail: wu@sdac.harvard.edu 
 
SCV Investigator 
Carol Kemper, MD 
Assistant Professor of Medicine 
Stanford  University  
Associate Director, AIDS Health Services 
Santa Clara Valley Medical Center 
751 S. Bascom Avenue 
San Jose, CA 95128 
(408) 885-4311 
(408) 885-4306 FAX 
 
UCLA/Harbor Investigator 
Mallory Witt, MD 
Associate Professor of Medicine 
Harbor - UCLA 
1000 W. Carson Street 
PO BOX 2910 
Torrance, CA 90502-2910 
(310) 222-2365 
(310) 533-0447 FAX 
 
Eric S. 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 
Telephone:  (310) 222-2467 
Fax:  (310) 533-0447 
Email:  EDaar@LABioMed.org 
 
UCI Investigator 


 
 
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Jeremiah G. Tilles, MD 
Professor of Medicine 
University of California Irvine 
Department of Medicine 
Infectious Diseases Bldg. 53, Rt. 81 
101 City Drive South 
Orange, CA 92668 
(949) 824-5454 
(714) 456-7169 FAX 
email: jgtilles@uci.edu 
 
Li Lin, MD 
University of California Irvine 
Department of Medicine 
Infectious Diseases Bldg. 53, Rt. 81 
101 City Drive South 
Orange, CA 92668 
(714) 456-7169 FAX 
email: llin1@uci.edu 
 
Catherine Diamond, MD 
University of California Irvine 
Department of Medicine 
Infectious Diseases Bldg. 53, Rt. 81 
101 City Drive South 
Orange, CA 92668 
(714) 456-7612 
(714) 456-7169 FAX 
email: diamondc@uci.edu 
 
USC Investigators 
Robert Larsen, MD 
LAC+USC Medical Center 
2020 Zonal Avenue, Rm 632 
Los Angeles, CA 90033 
Phone : (323) 226-7150 
Fax : (323) 226-7150 
Email : rlarsen@usc.edu 
 
Alejandro Sanchez, MD 
LAC+USC Medical Center 
2020 Zonal Avenue, Rm 632 
Los Angeles, CA 90033 
Phone : (323) 226-7194 
Fax : (323) 226-7150 
Email : asanchez@usc.edu 
 
Industry Representatives 
Belinda Ha, Ph.D. 
Clinical Research Scientist 
GlaxoSmithKline 
5 Moore Drive 
Research Triangle Park, NC 27709 
Phone: (919) 483-8284 
Fax: (919) 483-8999 
 
Protocol Laboratories 
Stan Louie, Pharm.D., Ph.D. 
USC, School of Pharmacy 
1985 Zonal Avenue 
Los Angesles, CA 90033 
Phone: (323) 442-3646 
Fax: (323) 442-1345 
Email: slouie@usc.edu 
 
Stephen Spector, MD 
Chief, Pediatric ID Devision 
University of California San Diego 
Stein Clinical Sciences Building 
9500 Gilman Drive 
LaJolla, CA  92093-0679 
858-534-7170 
858-534-7411 Fax 
saspector@ucsd.edu 
 
Gilead Science 
333 Lakeside Drive 
Foster City, CA 94404 
650-574-3000 
 
Protocol Data Center 
Andrew Rigby, PA II 
CCTG Data and Biostatistical Unit 
150 West Washington, Suite 100 
San Diego, CA 92103-8208 
(619) 543-8080 
(619) 298-1379 FAX 
 
Edward L. Seefried, RN  
Protocol Coordinator/Monitor 
CCTG Data and Biostatistical Unit  
150 West Washington, Suite 100  
San Diego, CA 92103-8208 
(619) 543-8080   
(619) 298-1379 FAX 


 
 
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SCHEMA 
 
Viral Dynamics and Pharmacokinetics of TDF and ABC Monotherapy versus the 
Combination Therapy of TDF – ABC in HIV-Infected Treatment Naïve Patients 
 
Design: 
 
 
This is a comparative, open-labeled study of a dual NRTI regimen,  
TDF + ABC, compared to ABC and TDF monotherapy administered for 7 days.  
Each patient will be randomized to a 7-day sequence of either ABC or TDF once-
daily followed by a 35-day washout period. After completion of the monotherapy 
sequence all patients will then receive dual NRTI therapy of TDF + ABC for an 
additional 7 days. After completion of the dual NRTI sequence patients will enter 
the HAART treatment stage with the addition of EFV and continue on a once-
daily regimen of EFV + ABC + TDF for an additional 14 days. At day 63, TDF 
will be stopped and 3TC will be substituted. Patients will then continue on a once-
daily regimen of EFV + ABC + 3TC for an additional 46 weeks.  
 
Duration: 
 
 
Total study duration is 59 weeks (including a 30 day screening period): Two 7-
day viral dynamic sequences separated by a 35 day washout period; followed by 2 
weeks of HAART treatment with EFV + ABC + TDF; followed by 46 weeks of 
HAART treatment with EFV + ABC + 3TC.  
 
Sample Size: 
 
20 subjects: 10 in TDF monotherapy arm, 10 in ABC monotherapy arm  
 
Study Population: 
 
HIV infected, treatment naïve (defined as no exposure to NRTI, NNRTI or PI 
therapy) patients.  Patients must be > 18 years old with CD4 cell counts above 
200 cells/mm3 and HIV RNA > 5000 copies/mL.  
 
Randomization and Stratification: 
 
Patients will be randomized to receive 7 days of either ABC monotherapy or TDF 
monotherapy prior to the dual NRTI regimen. The randomization will be stratified 
by baseline plasma HIV RNA < 100,000 or > 100,000 copies/ml.  
 
Regimen: 
 
The following short course regimens (dosing given for 7 days) will be compared 
by the two sequence design:  


 
 
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9
 
A. TDF 300 mg QD 
B. ABC 600 mg QD 
C. TDF 300 mg QD + ABC 600 mg QD 
 
A screening genotype will be done to confirm that there are no resistance-
associated mutations. The monotherapy sequence (regimen A or B) will continue 
for 7 days during which time 4 measurements for HIV RNA will be done to 
calculate the slope of the phase I viral decay. On day 1, PBMCs for baseline RT-
PCR of nucleoside transport enzymes will be collected. On days 7 and 8, serial 
blood specimens will be collected for PK data for plasma and intracellular levels 
of TDF and ABC.  A specimen of blood will be stored for future genotypic 
analysis if needed. This will be followed by a 35-day washout period after which 
patients will enter the dual NRTI therapy sequence (regimen C) for 7 days.  
During dual NRTI therapy, 4 measurements for HIV RNA will be done to 
calculate the slope of the phase I viral decay and on day 48 and 49, PK data on 
both plasma and intracellular levels of TDF + ABC will be collected, and a 
second genotype will be performed in real time. On day 49, after the second 7-day 
sequence, all patients will receive EFV in addition to the dual NRTI combination 
(regimen D) for 14 days. Afterwards, on day 63, a second sample of PBMC’s for 
RT-PCR of nucleoside transport enzymes will be collected. On the same day, 
TDF will be discontinued and 3TC will be substituted. Patients will then continue 
for an additional 46 weeks of HAART (regimen E). 
 
D: EFV 600 mg QD + ABC 600 mg QD + TDF 300 mg QD 
E: EFV 600 mg QD + ABC 600 mg QD + 3TC 300 mg QD  
 
1.0 
STUDY OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 To evaluate the relative potencies of two monotherapy regimens 
(TDF alone or ABC alone) compared to a dual NRTI regimen of 
TDF + ABC as assessed by the short-term virologic response 
(slope of the phase I viral decay and change in HIV RNA at day 7).  
 
1.1.2 To compare the plasma and intracellular PK data of the two 
monotherapy regimens to the dual NRTI regimen.  
 
1.2 
Secondary Objectives 
 
1.2.1 To evaluate the change in cellular regulatory enzymes involved 
with nucleoside analogue transport across cell membranes as 
assessed by RT-PCR of specific mRNA transcripts after 21 days of 
TDF+ABC exposure.  
 


 
 
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1.2.2 To determine if NRTI-associated mutations emerge after 7 days of 
ABC or TDF monotherapy or after 7 days of dual NRTI therapy 
with ABC + TDF. 
 
1.2.3 To compare the relative viral potency of TDF monotherapy versus 
ABC monotherapy. 
 
1.2.4 To evaluate the long-term viral response to EFV + ABC + 3TC 
after two 7-day sequences of mono/dual-therapy. 
 
1.2.5 To evaluate the relative toxicities of the two monotherapy 
treatment regimens.   
 
2.0 
INTRODUCTION 
 
2.1 
Background 
 
Dual nucleoside analogues form the backbone of most potent antiretroviral 
regimens. Although many possible combinations are used there are 
relatively few clinical trials that have evaluated the relative potency of 
these dual NRTI regimens. Recently, several studies have suggested 
increased rates of early virologic failure when the combination of 
abacavir, tenofovir and lamivudine were used [1-3]. This is in contrast to 
other settings in which a four NRTI combination was used without 
evidence of increased rates of early virologic failure (eg. Trizivir® + 
tenofovir) [4].  
 
The primary goals of this study are to evaluate: (1) the antiviral potency, 
as assessed by sort-term viral dynamics, of the dual NRTI combination of 
TDF – ABC relative to monotherapy of each NRTI and (2) the 
intracellular pharmacokinetics of ABC and TDF in monotherapy 
compared with dual-therapy in antiretroviral naïve subjects.  
 
Tenofovir Disoproxil Fumarate (Viread®, TDF) 
 
Tenofovir, PMPA, (9-[(R)-2-(phosphonomethoxy) propyl] adenine 
monohydrate) is an acyclic nucleotide analogue with activity in vitro 
against retroviruses, including HIV-1 and HIV-2.  Tenofovir is 
metabolized intracellularly to tenofovir diphosphate (PMPApp), which is a 
competitive inhibitor of HIV-1 reverse transcriptase (RT) that terminates 
the growing DNA chain. 
  
 Tenofovir has limited oral bioavailability.  TDF is a prodrug of tenofovir 
with good oral bioavailability in animals and humans and is rapidly 
converted to tenofovir following absorption. 
  


 
 
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An HIV-1 variant with a K65R mutation and a three-fold decrease in 
susceptibility to tenofovir was selected in vitro by serial passage.  
Tenofovir shows potent anti-HIV activity against a variety of drug-
resistant viruses.  Viruses containing the M184V mutation showed a 
slightly increased sensitivity to tenofovir in vitro [5]. ZDV-resistant, 3TC-
resistant, and multi-nucleoside drug-resistant viruses (expressing the 
hallmark Q151M mutation and others) remain susceptible to tenofovir in  
vitro. 
  
GS-907:  This phase III, 48-week study enrolled 552 treatment-
experienced subjects who had HIV-1 RNA levels of 400-10,000 
copies/mL and were receiving stable antiretroviral therapy for at least 8 
weeks prior to entering the study[6].  Subjects were randomized (2:1) to 
receive 300 mg of TDF (one pill once daily) or placebo in addition to their 
existing antiretroviral therapy.  After 24 weeks of blinded, placebo-
controlled dosing, subjects assigned to TDF or placebo were allowed to 
receive TDF for the remainder of the 48-week study period.  At baseline, 
subjects had a mean HIV-1 RNA level of 3.36 log10 copies/mL, a mean 
CD4+ cell count of 427 cells/mm3, and a mean previous treatment 
duration of 5.4 years.  About half of all study participants (n = 253) were 
randomly assigned to a virology substudy of this clinical trial.  Baseline 
genotypic analysis of HIV isolates from these subjects revealed that 94% 
had evidence of NRTI resistance mutations, 58% had PI resistance 
mutations, and 48% had NNRTI resistance mutations. 
  
Twenty-four-week data showed that TDF was associated with a 
statistically significant HIV-1 RNA decrease in mean average post-
baseline change over 24 weeks (DAVG24) of -0.61 log10 copies/mL 
compared with -0.03 log10 copies/mL in the placebo group (p < 0.0001).  
Additionally, 45% (155/346) of subjects treated with TDF achieved HIV-1 
RNA reductions to < 400 copies/mL at 24 weeks compared with 13% 
(23/172) in the placebo group (p < 0.0001).  The DAVG24 for CD4+ cells 
was an increase of 12.6 cells/mm3 in the TDF group compared with a 
decrease of 10.6 cells/mm3 in the placebo group (p = 0.0008). 
  
Through the 24-week, placebo-controlled portion of the trial, the incidence 
of Grade > 3 laboratory abnormalities and clinical adverse events was 
similar between the placebo and TDF arms.  Drug discontinuation at 24 
weeks was 6% in both arms of the study. 
 
Study 903 was a randomized, double-blind, active-controlled clinical trial 
conducted at 81 sites in the United States, Europe, and South America.  
The trial was designed to compare the efficacy and safety of a treatment 
regimen of TDF, 3TC, and EFV with a regimen of d4T, 3TC, and EFV in 
600 antiretroviral-naïve subjects with HIV infection.  In the interim 
analysis of the ITT population, for which missing data are counted as 


 
 
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failures, an identical 87% of subjects in the TDF arm (n = 299) and the 
d4T arm (n = 301) achieved suppression of HIV-1 RNA to < 400 
copies/mL at 48 weeks of treatment (95% confidence intervals [CI]: -6%, 
+5%) [7].  Additionally, subjects in both treatment groups experienced 
significant increases in CD4+ cell count.  At 48 weeks, combination 
treatment including TDF was associated with a mean increase from 
baseline of 169 cells/mm3, and treatment including d4T was associated 
with a mean increase from baseline of 167 cells/mm3.  In each treatment 
group, therapy was generally well tolerated and the study discontinuation 
rate was 9%.  The incidence of Grades 3 and 4 AEs in the TDF-containing 
study arm was 19% compared with 17% in the d4T-containing study arm.  
The incidence of Grades 3 and 4 laboratory abnormalities in the TDF arm 
was 28% compared with 31% in the d4T arm.  There were no differences 
by arm in changes in creatinine or hypophosphatemia. 
  
For further information, please consult the most recent Viread package 
insert. 
 
Abacavir (Ziagen®, ABC) 
 
 
ABC is a potent and generally well-tolerated nucleoside analogue which 
offers the convenience of once or twice daily dosing. ABC is a 2N-
deoxyguanosine analogue, with activity against HIV-1. ABC is activated 
intracellularly to the triphosphate derivative of the carbocyclic guanine 
analogue 1144U88 (1R,4S)-9-(4-[hydroxymethyl])-2-cyclopentene-1-yl 
guanine, which is a potent in vitro inhibitor of HIV-1 reverse transcriptase 
with a Ki=20 nM.  
 
High-level resistance to ABC is not rapidly selected in vitro, and multiple 
mutations are required to confer a 10-fold reduction in sensitivity. 
Mutations in the HIV-1 reverse transcriptase that correlate with ABC 
resistance include M184V, L65R, L74V, and Y115F.  
 
Efficacy 
 
The CNAB3014 study was a comparison of open-label ABC/3TC/ZDV 
with IDV/3TC/ZDV in 342 antiretroviral naïve adults for 48 weeks [8]. At 
randomization, subjects were stratified based on screening HIV-1 RNA: 
5000-100,000 (63%) or >100,000 (37%) copies/mL. Median HIV-1 RNA 
was 4.78 log10 and 4.82 log10 and median CD4 count was 331 and 299 
cells/μL for the ABC/3TC/ZDV and IDV/3TC/ZDV groups, respectively. 
HIV-1 RNA was measured at the sites using the <400 copies/mL assay 
and by a central laboratory using the <50 copies/mL assay. Study 
medication adherence was assessed via patient self-report. Based on an 
ITT (missing=failure) analysis at 48 weeks, 66% of subjects on 
ABC/3TC/ZDV had HIV RNA levels <400 copies/mL, as compared to 


 
 
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13 
50% on IDV/3TC/ZDV (p=0.002). In the subset of subjects with baseline 
HIV RNA <100,000 copies/mL, the results were 70% and 49%, 
respectively, while in the subset with baseline >100,000, the results were 
60% and 51%, respectively. Using the <50 copies/mL assay, 60% of 
subjects on ABC/3TC/ZDV compared with 50% on IDV/3TC/ZDV were 
below the threshold (ITT, missing=failure). In the <100,000 copies/mL 
stratum, the values were 67% and 53%, respectively, while in the 
>100,000 copies/mL stratum, the values were 48% and 46%, respectively. 
Over the 48 weeks, the time to treatment failure was significantly longer 
in the ABC group (p=0.001). Median CD4+ cell count increases were 148 
and 152 cells/mm3 in the ABC and IDV groups, respectively. Seven 
percent of subjects on ABC/3TC/ZDV experienced Grade 3/4 AEs, 
compared with 14% on IDV/3TC/ZDV; 6% of those on ABC experienced 
an HSR. At week 48, 46% of subjects on ABC/3TC/ZDV and 23% on 
IDV/3TC/ZDV reported taking all antiretroviral doses over the last 4 
weeks. 
 
Abacavir Once Daily Dosing 
 
Study CNA 10905 provided the pharmacokinetic data of abacavir and 
intracellular carbovir triphosphate in a group (n= 20) of HIV-infected 
patients that had been on a stable abacavir 300mg BID regimen for at least 
6 weeks or more [9]. Subjects were admitted to an inpatient setting where 
PK measurements were performed following a single a.m. dose. The 
evening dose was held and re-started the following day.  Although the 
geometric mean intracellular carbovir triphosphate levels demonstrated 
little variation over time, there was a fair amount of individual variability; 
with Cmax levels of 29.7 fmol/mil cells versus Ctau levels of 16.6 versus C24 
levels of 14.9 fmol/mil cells.  The t1/2 of intracellular carbovir triphosphate 
was approximately 21 hours.   
 
The CNA 30021 study was a double-blinded comparison in which 784 
treatment-naïve patients were randomized to receive once daily ABC 
dosing with ABC QD/3TC/EFV (n=384) or standard ABC BID dosing 
with ABC BID/3TC/EFV (n=386) for 48 weeks [10].  Baseline subjects 
were similar between groups with median HIV RNA levels of 4.9 log10 
and CD4+ counts of 264 cells/mm3 in the once-daily dosing arm and 
median HIV RNA levels of 4.9 log10 and CD4+ counts of 262 cells/mm3 
in the BID ABC dosing arm.  The primary endpoint of virologic 
suppression < 50 copies/mL at 48 weeks was reached by 66% in the ABC 
once daily dosing group and 68% in the ABC BID dosing group. When 
stratified for baseline HIV RNA levels (> 100K c/mL or < 100K c/mL) the 
two groups continued to be similar.  Median CD4+ count increases were 
188 and 200 cells/mm3 in the ABC BID and ABC once daily group, 
respectively.  This study establishes the non-inferiority of ABC once daily 
compared to ABC BID in combination with 3TC QD and EFV. 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
14 
 
Safety 
 
More than 200,000 HIV-infected patients have been treated with abacavir, 
either in clinical trials or clinical practice. ABC is generally well tolerated. 
Most clinical AEs are mild to moderate in severity and generally self-
limiting. The most frequently reported clinical AEs across phase III 
studies were nausea/vomiting, headache, malaise or fatigue, and diarrhea. 
Elevated triglycerides and anorexia have also been reported. Clinical AEs 
and clinical laboratory abnormalities common to some nucleoside 
antiretroviral agents (i.e., pancreatitis, peripheral neuropathy, anemia, and 
neutropenia) have not been commonly seen with ABC therapy. No 
differences in the safety profile of ABC based on gender, race, or age are 
apparent; however, safety in selected populations (i.e., moderate to severe 
hepatic impairment) has not been evaluated.  
 
Abacavir and Lamivudine Fixed Dose Combination 
 
Epzicom is the The Fixed Dose Combinations (FDC) of abacavir and 
lamivudine that was FDA approved in August 2004. Each tablet contains 
600 mg of abacavir as abacavir sulfate and 300 mg of lamivudine.  
 
Effect of Food on Absorption of EPZICOM:  
EPZICOM may be administered with or without food. Administration 
with a high-fat meal in a single-dose bioavailability study resulted in no 
change in AUC last, AUC∞ and Cmax for lamivudine. Food did not alter 
the extent of systemic exposure to abacavir (AUC∞), but the rate of 
absorption (Cmax) was decreased approximately 24% compared to fasted 
conditions (n = 25). These results are similar to those from previous 
studies of the effect of food on abacavir and lamivudine tablets 
administered separately. 
 
Impaired Hepatic Function: EPZICOM:  
Abacavir is contraindicated in patients with moderate to severe hepatic  
impairment and dose reduction is required in patients with mild hepatic 
impairment. Because EPZICOM is a fixed-dose combination and cannot 
be dose adjusted, EPZICOM is contraindicated for patients with hepatic 
impairment. 
 
Dose Adjustment: Because it is a fixed-dose tablet, EPZICOM should not 
be prescribed for patients requiring dosage adjustment such as those with 
creatinine clearance <50 mL/min, those with hepatic impairment, or those 
experiencing dose-limiting adverse events.  


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
15 
 
Hypersensitivity Reaction 
 
In clinical studies, approximately 3%-5% of patients receiving ABC 
develop an HSR that in rare cases has proved fatal [11]. The abacavir 
hypersensitivity reaction is characterized by the appearance of symptoms 
indicating multi-organ involvement. The majority of patients have fever 
and/or rash as part of the syndrome, however reactions have occurred 
without rash or fever. Symptoms can occur at any time during treatment 
with abacavir, but usually appear within the first six weeks of initiation of 
treatment (median time to onset 11 days). The symptoms worsen with 
continued therapy and can be life threatening. These symptoms usually 
resolve shortly after discontinuation of abacavir. Frequently observed 
signs and symptoms include fever, rash, malaise or fatigue, 
gastrointestinal symptoms such as nausea, vomiting, diarrhoea, or 
abdominal pain and respiratory symptoms such as dyspnea, sore throat, or 
cough. Other signs and symptoms include myalgia, arthralgia, oedema, 
pharyngitis, headache, paresthesia or myolysis. Physical findings may 
include rash (usually maculopapular or urticarial), lymphadenopathy or 
mucous membrane lesions (conjunctivitis, mouth ulceration). Abnormal 
chest x-ray findings may also be present (predominantly infiltrates, which 
can be localised). Laboratory abnormalities may include elevated liver 
function tests (such as hepatic transaminases), increased creatine 
phosphokinase or creatinine levels, and lymphopenia. Anaphylaxis, 
hypotension, liver failure, renal failure, adult respiratory distress syndrome 
or respiratory failure may occur.  
 
Some patients with hypersensitivity were initially thought to have 
respiratory disease (pneumonia, bronchitis, pharyngitis), a flu-like illness, 
gastroenteritis or reactions to other medications. This delay in diagnosis of 
hypersensitivity has resulted in abacavir being continued or re-introduced, 
leading to a more severe hypersensitivity reaction or death.  Therefore, the 
diagnosis of hypersensitivity reaction should be carefully considered for 
patients presenting with symptoms of these diseases. If hypersensitivity 
reaction can not be ruled out, no medicinal product containing abacavir 
(Ziagen, Trizivir or the abacavir/lamivudine fixed dose combination) 
should be restarted. 
 
Patients who develop a hypersensitivity reaction must discontinue 
abacavir and must never be rechallenged with any medicinal product 
that contains abacavir (Ziagen, Trizivir or the abacavir/lamivudine 
fixed dose combination).  Restarting any abacavir-containing product 
following a hypersensitivity reaction results in a prompt return of 
symptoms within hours. This recurrence of the hypersensitivity 
reaction may be more severe than on initial presentation, and may 
include life-threatening hypotension and death. 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
16 
 
Symptoms usually start to resolve soon (within 24 hours) after stopping 
therapy. Symptomatic support, such as intravenous fluids for those who 
develop hypotension, is advised. There are no clinical data demonstrating 
the benefit of antihistamines or corticosteroids in the management of 
hypersensitivity. Nevertheless, symptomatic and/or supportive treatment 
may be reasonable. 
 
Treatment Interruptions with Abacavir and Risk of HSR  
 
There have been infrequent reports of hypersensitivity reactions following 
reintroduction of abacavir, where the interruption was preceded by a 
single key symptom of hypersensitivity (rash, fever, malaise/fatigue, 
gastrointestinal or a respiratory symptom).On very rare occasions 
hypersensitivity reactions have been reported in patients who have re-
started therapy, and who had no preceding symptoms of a hypersensitivity 
reaction [12, 13]. Retrospective analyses have attempted to assess the 
safety of abacavir re-introduction after transient treatment interruptions in 
patients with no previous evidence of hypersensitivity reaction. In a 
cohort of 20 patients with a total of 25 treatment interruptions for a 
median of 13 days (IQR 6-41), none developed symptoms suggestive of 
re-challenge HSR [14]. GlaxoSmithKline conducted an analysis of 1442 
cases of HSR, of which only seven reports were suggestive of re-
challenge HSR in the setting of no previous HSR symptoms. None of 
these cases were fatal and only two had rapidly, progressive symptoms 
[12].  Thompson et al. [15], evaluated re-challenge HSR reactions during 
structured treatment interruption (STI). A study of 195 ARV-naïve 
patients were followed for 24 weeks, of which 70% had an STI of 2 days 
or more; none of these patients had evidence of HSR. Although 4 subjects 
did have symptoms suggestive of HSR in this study, review of MEMS 
caps data, did not suggest that patients had an unplanned STI. Although 
HSR to abacavir may occur after STI, it is unlikely that treatment 
interruption increases the risk of HSR to abacavir. 
 
Drug Interactions 
 
In vitro studies utilizing human liver microsomes demonstrated that ABC 
did not inhibit cytochrome P450 isoforms (2C9, 2D6, 3A4). Based on 
these data, it is unlikely that clinically significant drug interactions will 
occur between ABC and drugs metabolized through these pathways. 
 
Please refer to the Ziagen® package insert for complete prescribing 
information. 
 
Tenofovir – Abacavir Combination  
 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
17 
In a pilot study by Farthing C, et al. [2] showed increased rates of early 
virologic failure with the combination of abacavir, tenofovir and 
lamivudine.   Twenty patients naïve to antiretrovirals were enrolled, of 
which 17 were available for analysis. At baseline, mean plasma HIV-1 
RNA was 82,381 copies/ml [range: 7650-213,486] and mean CD4 count 
of 273 cells/mm3 [range: 59-598].  The study was prematurely interrupted 
when 9/17 (52%) patients experienced viral rebound in spite of adherence 
rates of > 95% by pill count. Limited genotypic analysis showed M184V 
mutation in two patients and both M184V + K65R mutations is one 
patient (6 samples are pending).  
 
A larger phase III trial, ESS30,009 [1], demonstrated similar failure rates 
in the abacavir, tenofovir and lamivudine arm (n=102).  Patients were 
considered to be non-responder/failing if there was less than 2.0 log10 drop 
in plasma HIV RNA and viral load >50 copies/ml at week 8 or a greater 
than 1.0 log10 increase in plasma HIV RNA from nadir by week 8.  
Similarly, this study was also prematurely interrupted when 50/102 (49%) 
subjects met at least one of these criteria. Genotypic analysis of 11/12 
patients at week 12 showed all had an un-mixed population of mutation 
M184V with six of those patients also having either a mixed population of 
K65R/K or a homogeneous population of K65R in addition to the M184V 
mutation.   
 
Lamivudine (Epivir®, 3TC)    
 
3TC is an approved, potent nucleoside reverse transcriptase inhibitor that 
is widely used for treating subjects with HIV infection.  Although 3TC is 
an effective NRTI, virus with a resistance mutation at codon 184 rapidly 
emerges within 2 weeks of monotherapy and is also seen with dual-
nucleoside regimens. 
 
3TC is phosphorylated to its active 5’-triphosphate metabolite (3TC-TP).  
3TC-TP inhibits HIV-1 reverse transcriptase by terminating viral DNA 
chains and also directly inhibits the RNA- and DNA-dependent DNA 
polymerase activities of reverse transcriptase.  In all acute virus-cell 
infections (including monocytes and fresh, human peripheral blood 
lymphocytes) tested with 3TC, anti-HIV-1 activity was demonstrated.   
 
Once daily-dosing of 3TC 
 
The originally recommended dose of 3TC was 150 mg BID.  However, the 
PK profile of 3TC suggests that it may be successfully dosed on a once 
daily basis and it has now been approved by the FDA for this once daily 
dosing regimen.  The observed mean elimination half-life in HIV-infected 
subjects ranged from 5 to 7 hours.  However, 3TC 5’-triphosphate has an 
intracellular half-life of 10.5 to 15.5 hours in HIV-infected and uninfected 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
18 
human peripheral blood lymphocytes.  The intracellular anabolic pathway 
for 3TC has a saturable formation step from the diphosphate to the active 
triphosphate.  This allows pooling of 3TC-DP, which is the immediate 
precursor of 3TC-TP.  Thus, 3TC-TP can still be formed when plasma 
concentrations are low long after dosing.  The active moiety, 3TC-TP, is 
slowly eliminated from cells with an intracellular half-life of 11 to 13 
hours in HIV-1 infected cells in vitro. 
 
These findings have been supported by clinical data.  A PK study of 3TC 
phosphorylation in peripheral blood mononuclear cells (PBMCs) from 
HIV-infected subjects found the 3TC-TP intracellular half-life to be 
approximately 15-16 hours, irrespective of dose, either 150 mg BID or 
300 mg BID [16].  Another study demonstrated the PK equivalence of 
3TC 300 QD to 3TC 150 mg BID in healthy volunteers with respect to 
plasma AUC24,ss, Cave,ss, and intracellular AUC24,ss, Cmax,ss, and Cave,ss [17].  
Thus, the relatively long plasma and intracellular half-lives, pooling of the 
immediate precursor (3TC-DP) of the active moiety (3TC-TP), and the PK 
equivalence of both dosing schedules support the ongoing investigation of 
3TC 300 mg once daily as a component of a multiple drug dosing 
regimen. 
 
In addition to PK data, several clinical studies support the further 
evaluation of once-daily 3TC administration.  Preliminary 24 week data 
from one clinical study suggest the combination of QD 3TC + nevirapine 
+ ddI administered to both naïve and experienced subjects provides potent 
immunological and antiviral effects and warrants further evaluation [18].  
In ICC-604, an open-label, pilot study evaluating QD 3TC + adefovir + 
ddI + efavirenz in subjects naïve to all four drugs (N = 11), 100% and 
90% of subjects achieved <400 and <50 copies/mL plasma HIV-1 RNA at 
24 weeks by intent-to-treat (ITT) analyses. 
 
Two clinical studies have compared 3TC BID with 3TC QD.  In 
EPV40001, 159 ART-naïve adults were randomized to one of three 3TC + 
ZDV + abacavir regimens (all given BID, 3TC given QD, or ABC given 
QD).  At 48 weeks, both 3TC and ABC given QD demonstrated virologic 
equivalence compared with the respective twice daily regimens.  All 
regimens were safe and well tolerated [19].  COLA4005 compared 
switching to 3TC once daily versus continuing 3TC BID in virologically 
suppressed adult subjects on a stable regimen of  either 3TC + d4T + 
indinavir or 3TC + d4T + nelfinavir.  At week 24, the proportion of 
subjects with HIV-1 RNA <50 copies/mL was similar in the subjects who 
switched to 3TC QD and in those who remained on 3TC BID (95% vs., 
90%; p = 0.679, ITT M = F) [20]. 
 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
19 
Based on in vitro and supportive clinical data, the once daily 
administration of 3TC should pose no safety or efficacy issues and will 
add to the compact nature of study regimens. 
 
Safety 
 
3TC is an extremely well tolerated nucleoside analogue.  Side effects 
include anemia, neutropenia, increased in liver function enzymes, 
peripheral neuropathy, rash, nausea, vomiting, diarrhea, headache, 
insomnia, malaise, fatigue, dizziness, and allergic reactions.  Rare side 
effects include psychosis, mania, and thrombocytopenia. 
 
Exacerbations of HBV-related hepatitis have been detected in HIV-HBV 
coinfected subjects that discontinued 3TC-containing antiretroviral 
regimens.  Most episodes were self-limited, however fatalities have been 
reported. Coinfected subjects should be monitored for exacerbation of 
their hepatitis if 3TC is permanently discontinued. 
 
For more information concerning 3TC, refer to the most recent package 
insert. 
 
Efavirenz (Sustiva®, EFV)        
  
 
Efficacy 
 
EFV is a potent NNRTI that is widely used in combination with other 
antiretrovirals for the treatment of HIV-1 infection.  Studies support its use 
for initial therapy as well as for salvage therapy. 
 
A phase III study (DMP 266-006) compared the safety and efficacy of 
ZDV (300 mg BID) + 3TC (150 mg BID) + EFV (600 mg QD), EFV + 
indinavir (IDV) (800 mg Q8h), and ZDV + 3TC + IDV.  IDV was 
administered in a fasted state [21].  A total of 1266 subjects who were 
EFV, NNRTI-, PI-, and 3TC-naïve at study entry were enrolled.  The 
mean baseline CD4+ cell count was 341/mm3, and the mean baseline HIV-
1 RNA level was 4.78 log10 copies/mL.  At 48 weeks, the proportion of 
subjects with HIV-1 RNA levels < 400 (< 50) copies/mL was 68% (62%) 
for the EFV/NRTI group, 55% (49%) for the EFV/IDV group, and 49% 
(43%) for the IDV/NRTI group.  No differences in CD4+ cell count 
changes were noted among the groups.  During long-term follow-up, the 
proportion of subjects with HIV-1 RNA < 50 copies/mL at 72 weeks was 
58% for the EFV/NRTI group, 42% for the EFV/IDV group, and 36% for 
the IDV/NRTI group. 
 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
20 
In another study (DMP 266-049), subjects who had HIV-1 RNA levels < 
50 copies/mL while receiving a regimen containing a PI and two NRTIs 
were randomized to continue their PI/NRTI regimen or switch to EFV 
(600 mg QD) + the same two NRTIs.  Overall, 266 subjects were in the 
EFV group and 120 were in the PI group.  Mean CD4+ cell count at 
baseline was 578 cells/mm3 for the EFV group and 566 cells/mm3 for the 
PI group.  At 24 weeks, the proportion with HIV-1 RNA levels < 50 
copies/mL was 89% for the EFV group and 81% for the PI group.  
Confirmed viral rebound (HIV-1 RNA > 50 copies/mL) rates were 3% for 
the EFV group and 10.2% for the PI group (p = 0.011).  No differences in 
CD4+ cell counts were noted between the two groups.  No differences in 
nonfasting lipid levels or AST/ALT were noted between the two groups.  
Subjects receiving EFV noted the following Grade ≥ 2 adverse 
experiences:  abnormal dreams (7%), rash (5%), dizziness (4%), insomnia 
(3%), impaired concentration (3%), and increased triglycerides (3%). 
 
Safety  
 
The most significant adverse events observed in subjects receiving EFV 
were nervous system symptoms, psychiatric symptoms, and rash (see 
efavirenz package insert).  Fifty-three percent of subjects noted central 
nervous system (CNS) complaints.  Nervous system symptoms usually 
begin during the first 1 or 2 days of therapy and generally resolve after the 
first 2 to 4 weeks.  Dosing at bedtime improves the tolerability of these 
symptoms and is recommended during the first weeks of therapy and in 
subjects who continue to experience these symptoms.  
 
Serious psychiatric adverse experiences have been reported including 
severe depression, suicidal ideation or attempts, aggressive behavior, 
paranoid reactions, and manic reactions.  Rash is usually mild to moderate 
and occurs within the first 2 weeks of initiating therapy.  In most subjects, 
rash resolves with continuing EFV therapy within 1 month.  EFV can be 
reinitiated in subjects interrupting therapy because of rash. 
 
Malformations have been observed in fetuses from EFV-treated monkeys 
that received doses resulting in plasma drug concentrations similar to 
those in humans given 600 mg/day.  Therefore, pregnancy should be 
avoided in women receiving EFV and barrier contraception should always 
be used in combination with other methods of contraception (e.g., oral or 
other hormonal contraceptives).   
 
It is recommended that EFV be taken on an empty stomach, preferably at 
bedtime.  For more information concerning Sustiva®  refer to the most 
recent package insert.  
 
2.2 
Rationale 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
21 
 
In light of the recent clinical data suggesting increased rates of early 
virologic failure in the setting of an abacavir + tenofovir combination, 
further studies are needed to evaluate potential mechanisms for this 
clinical observation. Individually the relative potency of tenofovir and 
abacavir are among the more potent in this class.  There are several 
reasons to evaluate the dual NRTI combination of TDF and ABC alone 
and in combination:  
 
1. TDF combined with ABC is a potentially potent regimen that has not 
been fully evaluated. Recent data suggest increased rates of virologic 
failure when given with lamivudine alone. However, this failure rate 
was not observed when given with zidovudine in addition to 
lamivudine. 
 
2. The relative potency of the dual NRTI (TDF + ABC) combination can 
be evaluated by short term phase I viral decay kinetics relative to the 
decay rates of each NRTI given alone. 
 
3. Plasma and intracellular concentrations of the dual NRTI combination 
(TDF + ABC) can be evaluated and compared to pharmacokinetic data 
when the NRTI is given as monotherapy. 
 
4. Induction or suppression of certain transport enzymes that control 
influx and efflux of nucleoside analogues can be evaluated by 
measuring baseline and steady state mRNA expression in PBMCs via 
RT-PCR.  
 
Possible explanations for the increased rates of virologic failures when the 
TDF + ABC + 3TC combination was used include: (1) a 
pharmacodynamic phenomena in which drug-drug antagonism results; 
decreasing relative NRTI potency, (2) a pharmacokinetic interaction 
resulting in reduced intracellular or plasma levels, or finally (3) a low viral 
genetic barrier to resistance results from the combination of this particular 
nucleoside combination.   
 
First, the evaluation of the relative antiviral potency of individual 
nucleosides or dual combinations is complicated by the inability to 
administer these regimens for long durations due to the risk of 
development of resistance. Antiretroviral potencies of drugs and drug 
doses has been evaluated in studies of first phase decay rates and 
magnitude of HIV RNA reductions in studies of 2 weeks or less [22].  One 
supposition of these studies is that the phase one decay rate is a predictor 
of antiviral potency of a regimen and that differences between the decay 
rates of different regimens might translate into differences in longer term 
virologic suppression. Analysis of phase I HIV RNA decay kinetics in 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
22 
studies of 2 weeks or less has been used as a predictor of antiviral potency 
of perspective NRTI regimens. It is unclear whether the gain in precision 
of the measurement (by doing multiple HIV RNA measures over the 1- 2 
week interval) of virologic potency truly justifies the cost and 
inconvenience of calculating the slopes.  Thus, if some simpler method 
could give the same information as the slope, then that measure could be 
used instead of the slope. Wu et al have shown a high correlation between 
the change in HIV RNA at week 1 and the slope of the phase I decay [23-
25].  
 
The short duration of NRTI mono or dual therapy also allows for the 
prompt addition of drugs to comprise a fully acceptable combination 
regimen before significant risk of drug resistance develops.  Brief courses 
of monotherapy for several antiretroviral drugs, including TDF and ABC, 
have been given and found to be safe without the emergence of premature 
resistance:  In a viral dynamics study of TDF monotherapy in 10 
antiretroviral-naïve patients no evidence of nucleoside mutations were 
detected after 21 days of treatment [26].  An escalating-dose study of TDF 
monotherapy for 28 days in 38 antiretroviral patients also did not show 
emergence of new nucleoside mutations from baseline [27].  Abacavir 
monotherapy has been given in several studies for short durations with 
subsequent good clinical responses upon addition of a fully potent regimen 
[28]. Miller et al. evaluated antiviral potency and genotypic and 
phenotypic susceptibility of abacavir monotherapy followed by the 
addition of zidovudine and lamivudine [29]. Sixty antiretroviral-naïve 
patients were randomized to receive 100, 300 or 600mg abacavir twice 
daily. With the exception of one patient at week 8 who developed the 
K65R mutation, no subjects developed new RT mutations prior to week 
12. However at week 12, 26/38 subjects were still on abacavir 
monotherapy and had genotypic data: 18 out of 26 subjects had new RT 
mutations. These data indicate that short courses of TDF and/or ABC 
monotherapy should be safe and unlikely to result in new on-
treatment RT mutations.  
 
The pharmacokinetic interaction of ABC + TDF will be evaluated by 
comparing steady-state intracellular and plasma concentrations of each 
nucleoside alone and then again when dosed in combination. Although 
preliminary data has not suggested a significant intracellular interaction: 
The Tonus Study [3], a pilot study of once daily ABC/TDF/3TC, plasma 
concentrations were evaluated at month 1: 32/37 patients had adequate 
Cmin concentrations for all three nucleosides. In a random subset of 14 
patients intracellular nucleoside concentrations were also measured and 
failed to show a major interaction. In a study by Hawkins et al [30], CBV-
TP and TDF-DP were evaluated in a cohort of 13 subjects with viral 
suppression and on a stable regimen of ABC/TDF/3TC.  After substitution 
of either TDF or ABC with another nucleoside, intracellular 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
23 
concentrations were measured of the companion nucleoside. No change in 
intracellular concentrations was noted for either TDF-DP or CBV-TP. 
This study is limited, however, because all patients had successfully 
suppressed their plasma HIV RNA on the triple nucleoside regimen. Thus, 
if altered pharmacokinetics only occurs in patients with failure on this 
triple nucleoside regimen, then this study would not be able to detect this 
difference as no patients were failing at enrollment. CCTG 584 will better 
evaluate a potential PK interaction by: (1) evaluating monotherapy and 
combination therapy separately, (2) comparing concentrations of 
intracellular triphosphate levels and (3) by evaluating the induction or 
suppression of certain cellular enzymes critical for cellular nucleoside 
transportation. 
 
Finally, the third possibility of a low genetic barrier to resistance leading 
to increased rates of virologic resistance will be evaluated by serial 
genotypic evaluations. Specimens for genotypic analysis will be collected 
and run in real-time at baseline and after NRTI dual-therapy with ABC + 
TDF. If significant mutations are detected, then day 7, post-monotherapy, 
samples will be analyzed and mutations can be discerned as either 
preexisting or de novo. If more than one patient develops any new NRTI 
or NNRTI-associated resistance mutations as defined by the updated IAS-
USA mutation list, the study will hold enrollment and study progression 
for those subjects in Sequence I and present the data to an independent 
review committee for evaluation. Based upon the independent 
committee’s recommendations the study may either continue, continue 
with study design modification or be discontinued. Multiple specimens for 
stored plasma will be collected during the mono- and dual-therapy 
sequences for possible future genotypic analysis of low frequency mutant 
variants not detected on standard pooled genotypes.   
 
3.0 
STUDY DESIGN 
 
   
This is a comparative, open-labeled study of a dual NRTI regimen,  
TDF + ABC, compared to ABC and TDF monotherapy administered for 7 
days.  Each patient will be randomized to a 7-day sequence of either ABC 
or TDF once-daily followed by a 35-day washout period. After completion 
of the monotherapy sequence and washout period all patients will then 
receive dual NRTI therapy with TDF + ABC for an additional 7 days. 
After completion of the dual NRTI sequence patients will enter the 
HAART treatment stage with the addition of EFV and continue on a once-
daily regimen of EFV + ABC + TDF for an additional 14 days. At day 63, 
TDF will be stopped and 3TC will be substituted. Patients will then 
continue on a once-daily regimen of EFV + ABC + 3TC for an additional 
46 weeks. 
 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
24 
The following short course regimens (dosing given for 7 days) will be 
compared by the two sequence design:  
 
A. TDF 300 mg PO QD 
B. ABC 600 mg PO QD 
C. TDF 300 mg PO QD + ABC 600 mg PO QD  
 
A screening genotype will be done to confirm that there are no resistance-
associated mutations. The monotherapy sequence (regimen A or B) will 
continue for 7 days during which time 4 measurements for HIV RNA will 
be done to calculate the slope of the phase I viral decay. On day 1, PBMCs 
for baseline RT-PCR of nucleoside transport enzymes will be collected. 
On days 7 and 8, serial blood specimens will be collected for PK data for 
plasma and intracellular levels of TDF and ABC.  A specimen of blood 
will be stored for future genotypic analysis if needed. This will be 
followed by a 35-day washout period after which patients will enter the 
dual NRTI therapy sequence (regimen C) for 7 days.  During dual NRTI 
therapy, 4 measurements for HIV RNA will be done to calculate the slope 
of the phase I viral decay and on day 48 and 49, PK data on both plasma 
and intracellular levels of TDF + ABC will be collected and a second 
genotype will be performed in real time. On day 49, after the second 7-day 
sequence, all patients will receive EFV in addition to the dual NRTI 
combination (regimen D) for 14 days. Afterwards, on day 63, a second 
sample of PBMC’s for RT-PCR of nucleoside metabolic enzymes will be 
collected. On the same day, TDF will be discontinued and 3TC will be 
substituted. Patients will then continue for and additional 46 weeks of 
HAART (regimen E). 
 
D: EFV 600 mg QD + ABC 600 mg QD + TDF 300 mg QD 
E: EFV 600 mg QD + ABC 600 mg QD + 3TC 300 mg QD 
 
A total of 20 patients will be randomized to receive the two sequences of 
therapy. The sequences will be given in the following fashion (note: D.V. 
means viral Dynamic Visit): 
 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
25 
 
 
Screening
(30 Day)  
HIV RNA 
Genotype 
HIV RNA  
Day 1  
D.V. 1 
D.V. 2 
D.V. 3 
Day 8  
Sparse PK  
Day 7  
Day 8  
Washout
(Day 9 – Day 42)  
TDF (Arm A)
ABC (Arm B)  
HIV RNA 
Day 1  
D.V. 1 
D.V. 2 
D.V. 3 
Day 8  
Sparse PK
Day 7  
Day 8  
Sequence I  
Stop Drug  
Day 37
Labs (including HIV RNA)
HIV RNA 
 
D ay 42 
D.V. 1 
D.V. 2 
D.V. 3 
Day 49
 
Sparse PK
Day 48
Day 49
HAART (Day 49 - Day 63)
Start EFV+ABC+TDF (Arm D)  
(give in evening) 
Day 63
Stop TDF & Start 3TC  
 
HAART – 46 weeks
EFV + 3TC + ABC (Arm E)
Sequence I I  
Start Drug
ABC + TDF (Arm C)  
collect PBMC’s  
Start Drug & 
Collect PBMCs 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
26 
 
A total of 20 patients will be randomized in a 1:1 fashion in the first 
sequence to receive 7 days of monotherapy with TDF or ABC alone. After 
the washout period all patients will receive 7 days of TDF + ABC dual 
therapy in the second sequence.  If both the study site and the patient are 
willing and able to attend a Saturday visit then it would be preferable to 
initiate Sequence 1 and/or Sequence 2 on a Wednesday or Thursday. This 
will allow for doses of study medication prior to PK assessment to be 
witnessed doses. Otherwise patients would need to initiate Sequence 1 and 
Sequence 2 on a Tuesday. This would allow for all visits to occur during 
the work week, obviating the need for weekend visits, with sparse PK 
collection occurring on Monday-Tuesday of the following week after 
initiation of study drug.  Since 100% medication adherence is necessary 
for an accurate PK assessment, patients will be asked to allow phone calls 
from study personal to remind them to take study medication on days that 
do not require a study visit. During Sequence 1 and Sequence 2 all 
medication should be taken with food as a single morning dose.  
During the HAART portion of the study medications should also be 
taken with food, but as a single evening dose.   
 
Samples for sparse TDF and ABC plasma and intracellular levels will be 
collected on days 7-8 and days 48-49. During Sequence 1: the first 
intracellular (PBMC) and plasma PK sample will be collected (time 0) and 
then a witnessed dose of medication will be given, and subsequent 
intracellular and plasma samples will be collected at 3-hr and 6-hr post 
dose.  Additional, low-volume blood samples for plasma PK will be 
collected after the witnessed dose at 30 minutes, 1 hour and 2 hour post 
witnessed dose. No additional doses of TDF or ABC monotherapy will be 
given after day 7. The following day the patient will return for a fourth 
specimen that will represent the 24-hr post-dose. During Sequence 2: the 
first intracellular (PBMC) and plasma PK sample will be collected (time 
0) and then a witnessed dose of medication will be given, and subsequent 
intracellular (PBMC) and plasma samples will be collected at 3-hr and 6-
hr post dose. Additional, low-volume blood samples for plasma PK will be 
collected after the witnessed dose at 30 minutes, 1 hour and 2 hour post 
witnessed dose. On the following day, day 49, the a.m. dose will be held 
and the 24-hr post dose PK level will be collected. That same evening the 
patient will begin the HAART portion of the study with the addition of 
EFV to continue on a once-daily regimen for EFV + ABC + TDF for the 
next 14 days. For the remainder of the study, patients will be encouraged 
to continue p.m. dosing.  
 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
27 
 
 
PBMCs will also be collected to evaluate potential interactions of 
nucleoside analogues and host cell transport enzymes responsible for 
cellular influx and efflux of nucleoside analogues. A baseline sample will 
be collected on day 1 followed by a second collection on day 63. On day 
63, TDF will be stopped and 3TC will be substituted. The patients will 
then continue for an additional 46 weeks of HAART with once-daily EFV 
+ ABC + 3TC.   
 
If a patient develops a treatment-limiting toxicity during Sequence 1 or 
Sequence 2 of the study that results in a need to change or stop therapy 
then that patient will be removed from study and replaced with another 
study subject.  Likewise if a patient misses more than one visit during the 
viral dynamic measurements he/she will be removed from the study and 
will be replaced. Additionally, given the risks of prolonged mono and 
dual-therapy, patients will not be allowed to take more than 7 days of 
study drug during Sequence 1 and 2. Therefore, a patient will not be able 
to continue on the study if he/she is not able to complete both PK visits as 
scheduled.   
 
Patients will have HIV RNA levels drawn on day 37.  An HIV genotype 
will be drawn and run in real time at day 49, but will not be available until 
shortly after the patient begins the HAART.  If the genotype reveals any 
evidence of drug resistance, the regimen can be modified by the 
investigator (in consultation with the protocol chairs) to provide the best 
possible therapy.  Any discovery of resistance mutations at day 49 will 
also prompt retrospective evaluation of stored plasma from day 7 to 
determine if the resistance was present prior to the start of the second 
sequence.  The protocol team will monitor the day 48 genotypes in real 
time and data listings will be provided every 3 months. If more than one 
patient develops any new NRTI or NNRTI-associated resistance mutations 
as defined by the updated IAS-USA mutation list, the study will suspend 
enrollment and subjects in Sequence 1 will not progress to Sequence 2. 
Data will be presented to an independent review committee for evaluation. 
 
Wash-out 
Day 7 
Day 8 
Day 48 
Day 49 
PBMC & Plasma for PK (20 mL) 
Time 0   Dose                   3-hr       6-hr  
   24-hr 
PBMC & Plasma for PK (40 mL) 
Time 0   Dose                  3-hr         6-hr 
   24-hr 
             30 min  1-hr  2hr 
Plasma for PK (3 mL) 
             30 min  1-hr  2hr 
Plasma for PK (3 mL) 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
28 
Based upon the independent committee’s recommendations the study may 
either continue, continue with study design modification or be 
discontinued.  
 
Since the study’s principle endpoints will be reached at day 63, patients 
will be offered the option of stopping HAART if their screening and 
baseline CD4 count as greater than 350 cells/mm3 and plasma HIV RNA 
was less than 55,000 copies/mL. Otherwise HAART therapy will continue 
for an additional 46 weeks (48 weeks after completion of the second 
sequence).  Monitoring will include HIV RNA, CD4 cell counts, routine 
chemistry and hematology and CCTG adherence questionnaires. 
 
Patients who develop a treatment-limiting toxicity during the HAART 
portion of the study thought to be related to one of the NRTIs, can have 
one or both of their NRTIs modified at the discretion of the site 
investigator in consultation with the protocol team (alternate therapy will 
not be provided by study).  Patients who develop a treatment-limiting 
adverse event related to EFV can receive the best available therapy as 
recommended by the site investigator (the protocol team should also be 
consulted).  Patients that develop virologic failure will receive a genotype 
resistance assay (if the HIV RNA is > 1000 copies/mL) and can receive 
the best available therapy as recommended by the site clinician.  Follow 
up will continue for 48 weeks from start of HAART for the patients with 
virologic or toxicity failures. 
 
4.0 
SELECTION AND ENROLLMENT OF SUBJECTS 
 
4.1 
Inclusion Criteria 
 
4.1.1 HIV-1 infection, as documented by any licensed ELISA test kit and 
confirmed by Western blot at any time prior to study entry. HIV-1 culture, 
HIV-1 antigen, plasma HIV-1 RNA, or a second antibody test by a method 
other than ELISA is acceptable as an alternative confirmatory test.  
 
4.1.2 Antiretroviral naïve defined as no prior therapy. 
 
4.1.3 CD4+ cell count > than 200 cells/ mm3 determined by site clinical 
laboratory within 90 days of screening.  
 
4.1.4 HIV-1 RNA level > 5000 copies/mL obtained by site clinical laboratory 
within 90 days of screening. 
 
4.1.5 Laboratory values obtained by screening laboratories within 30 days of 
entry: 
 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
29 
• Absolute neutrophil count (ANC) ≥ 750/mm3. 
 
• Hemoglobin ≥ 8.0 g/dL. 
 
• Platelet count ≥ 50,000/mm3. 
 
• Calculated creatinine clearance (CrCl) > 50 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)  
 
• AST (SGOT), ALT (SGPT), and alkaline phosphatase ≤ 5 x ULN. 
 
• Total bilirubin ≤ 2.5 x ULN. 
 
4.1.6 Negative serum or urine pregnancy test within 30 days of study entry. 
 
4.1.7 Karnofsky performance score ≥ 70.  
 
4.1.8 Men and women age ≥ 18 years. 
 
4.1.9 Ability and willingness of subject or legal guardian/representative to give 
written informed consent. 
 
4.1.10 If the subject has evidence of recent HIV-1 infection (defined as 
acquisition in the past 24 months), a resistance assay (either genotype or 
phenotype from any laboratory) must be obtained and made available for 
review by the protocol team prior to the screening genotype assay.  (The 
protocol will not provide the resistance assay.)  The protocol team will 
make the decision on whether significant resistance is present that might 
make randomization into the study a potential risk for the subject. 
 
4.2 
Exclusion Criteria 
 
4.2.1  Any NRTI or NNRTI-associated resistance mutations as defined by the 
updated IAS-USA mutation list. 
4.2.2 Pregnancy and breast-feeding. 
4.2.3 Active drug or alcohol use or dependence that, in the opinion of the 
investigator, would interfere with adherence to study requirements. 
 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
30 
4.2.4 Urgent need to initiate antiretroviral therapy, as determined by the 
patient’s primary provider. 
 
4.2.5 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 14 days prior to study entry. 
 
4.2.6 Use of any immunomodulator, HIV vaccine, or investigational therapy 
within 30 days of study entry 
 
4.2.7 Use of human growth hormone within 30 days prior to study entry.   
 
4.2.8 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 faxed to the 
UCSD [(619) 298-1379].  
 
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. 
 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
31 
 
5.0 
STUDY TREATMENT 
 
5.1 
Regimens, Administration, and Duration 
 
 
5.1.1 Regimens 
 
At entry subjects will be randomized to one of two arms with each arm 
enrolling no more than 10 subjects each. This first 7-day course of mono 
NRTI comprises Sequence 1:  
 
Sequence 1:  Day 1 - Day 7 
 
Arm A: 
TDF 300 mg q day (given as an a.m. dose – with 
food) 
 
Arm B: 
ABC 600 mg q day (given as an a.m. dose – with 
food) 
 
After completion of Sequence 1 and a 35-day washout period, subjects 
will receive a 7 day course of dual NRTI therapy that comprises Sequence  
2: 
 
Sequence 2: Day 42 – 48 
 
Arm C: 
 
TDF 300 mg q day + ABC 600 mg q day  
(given as an a.m. dose – with food) 
 
After completion of Sequence 2, subjects will enter the HAART portion of  
the study by the addition of EFV to the dual NRTI regimen of Sequence 2. 
 
HAART: Day 49 through Day 63 (first two weeks of HAART) 
 
Arm D: 
 
TDF 300 mg q day + ABC 600 mg q day + 
EFV 600 mg q day (given as a p.m. dose – with 
food) 
 
On day 63, TDF will be stopped and 3TC will be substituted for the 
remainder of the 48 week HAART portion of the study. 
 
HAART: Day 63 through week 48 (46 weeks) 
 
Arm E: 
[3TC 300 mg q day + ABC 600 mg q day] fixed dose 
combination + EFV 600 mg q day (given as a p.m. dose – 
with food) 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
32 
 
 
5.1.2 Administration 
 
NOTE: All antiretrovirals should be administered at the same time. 
During Sequence 1 and Sequence 2, study medications should be 
administered as a single a.m. dose.  On days occurring during a study 
visit the dose should be witnessed and recorded in a CRF. On days not 
occurring on a study visit, the dose should be recorded via telephone 
adherence from study staff (if such calls permitted by patient). 
Thereafter, during the HAART portion, it is preferable but not required, 
that study medications should be taken as a single p.m. dose with food.  
 
5.1.2.1 
EFV will be administered as a single 600 mg capsule PO q 
day with food 
 
5.1.2.2 
TDF will be administered as a single 300 mg tablet PO q 
day with food. 
 
5.1.2.3 
ABC will be administered as two 300 mg tablets PO q day 
with food. 
 
5.1.2.4 
3TC will be administered in combination with ABC as a 
fixed dose combination tablet with each tablet containing 
300 mg of lamivudine and 600 mg of abacavir. 
 
5.1.3 Duration 
 
5.1.3.1  
Sequence 1: Each subject will receive 7 days of therapy. 
 
5.1.3.2 
Sequence 2: Each subject will receive 7 days of therapy. 
 
5.1.3.3  
HAART: Each subject will receive 48 weeks of therapy. 
  
5.2 
Product Formulation and Preparation  
 
5.2.1 Efavirenz (Sustiva®, EFV):  200 or 600 mg capsules. Store at room 
temperature; 15º - 30º C (59º – 86º F).  
 
5.2.2 Tenofovir (Viread®, TDF):  300 mg tablets should be stored and 
dispensed in the original container.  Each bottle contains a silica gel 
desiccant canister to protect the product from humidity and should remain 
in the original container.  Store at 25°C (77°F), excursions permitted to 
15°-30°C (59°-86°F). 
 
 
5.2.3 Abacavir (Ziagen®, ABC): 300 mg tablets. Store 20°-25° C (68°-77°F). 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
33 
 
5.2.4 Abacavir and Lamivudine fixed dose combination (Epzicom®) is 
available as tablets. Each tablet contains 600 mg of abacavir as abacavir 
sulfate and 300 mg of lamivudine. Store at 25°C (77°F); excursions 
permitted to 15° to 30°C (59° to 86°F). 
 
5.3 
Product Supply, Distribution, and Pharmacy 
 
5.3.1 Study Product Acquisition 
 
Study medications will be provided by GSK. EFV 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 study 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 
 
5.4.2 Prohibited Medications 
 
  
5.4.2.1    All investigational drugs. 
 
5.4.2.2    Any antiretroviral drug, except study medications 
 
 
5.4.2.3       All HIV vaccines 
 
5.4.2.4       Any immunomodulators 
 
5.4.2.5    Systemic cytotoxic chemotherapy 
 
5.4.2.6    All of the following systemic drugs: 
 
 
 
Agent by Class 
Agents 
 
 
Alternative/Complementary 
St. John’s wort (Hypericum perforatum) 
 
 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
34 
Agent by Class 
Agents 
 
 
Antiarrhythmics 
Flecainide (Tambocor) 
 
Propafenone (Rythmol) 
 
 
Antihistamines 
Astemizole (Hismanal) 
 
Terfenadine (Seldane) 
 
 
Anti-infectives 
Rifampin (Rifadin, Rimactane , 
Rifamate, Rifater) 
 
 
GI Motility 
Cisapride (Propulsid) 
 
 
HMG Co Reductase 
Inhibitors  
Lovastatin (Mevacor) 
 
  Simvastatin (Zocor ®) 
 
 
Hormonal Agents 
  Dexamethasone 
 
Human growth hormone 
 
 
Psychiatric Medications 
Pimozide (Orap) 
 
 
Sedative/hypnotics 
Midazolam (Versed) is allowed as a 
single dose given under monitored 
conditions for procedures  
 
Triazolam (Halcion) 
 
 
Other 
Dihydroergotamine (Migranal and 
others) 
 
Ergonovine  
 
Ergotamine (Ergostat, Ergomar, and 
others) 
 
Methylergonovine (Methergine) 
 
5.4.2.6    All herbal products should be avoided because of the unknown 
drug interactions between herbal products and the antiretroviral drugs used 
in this study. 
 
5.4.3 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 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
35 
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. 
 
5.4.3.1    Systemic medications that interact at CYP3A as substrates, 
inhibitors, or inducers of the enzyme must be used with caution.  
These include but are not limited to: 
  
Agent by Class 
 
Precautionary Concomitant 
Medications 
 
Alternative/complementary 
 
Milk Thistle 
 
 
 
Analgesics  
 
Opioids, including:  
 
    Codeine 
 
    Methadone 
 
    Meperidine 
 
    Morphine 
 
Pentazocine (Talwin™) 
 
 
 
Anesthetics 
 
Propofol (Diprivan™) 
 
 
 
Anti-arrhythmics 
Amiodarone (Cordarone) 
 
Bepridil (Vascor) 
 
Disopyramide (Norpace™) 
 
Encainide (Enkaid™) 
 
Lidocaine (Xylocaine™) 
 
Mexiletine (Mexitil™) 
 
Quinidine (Quinidex) 
 
 
 
Anti-convulsants 
 
Carbamazepine (Tegretol™) 
 
Lamotrigine (Lamictal™) 
 
Phenobarbital (Luminal™) 
 
Phenytoin (Dilantin™) 
 
Valproic acid (Depakene™) 
 
 
 
Anti-histamines 
 
Chlorpheniramine (Chlor-Trimetron™ 
and others) 
 
Diphenhydramine (Benadryl™ and 
others) 
 
 
Anti-infectives 
Acyclovir (Zovirax™) 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
36 
 
Agent by Class 
 
Precautionary Concomitant 
Medications 
 
Aminoglycosides 
 
Amphotericin B (Amphocin™, 
    Fungizone™) 
 
Cidofovir (Vistide™) 
 
 
 
Clarithromycin (Biaxin™) 
 
Dapsone 
 
Erythromycin (E-mycin™ and others) 
 
Fluconazole (Diflucan™) 
 
Ganciclovir (Cytovene™) 
 
Isoniazid  
 
Systemic Itraconazole (Sporonox®) 
 
Systemic Ketoconazole (Nizoral®) 
 
Ribavirin (Virazole™) 
 
Rifabutin (Mycobutin®) 
 
 
 
 
Vancomycin (Vancocin™,  
 Vancoled™) 
 
 
Voriconazole (Vfend) 
 
 
 
Beta blockers (selected 
agents listed, caution should 
be exercised for the entire 
class) 
 
Atenolol (Tenormin™) 
 
Metoprolol (Lopressor™, Toprol™) 
 
Propranolol (Inderal™, Inderide™, 
and others) 
 
 
 
Calcium channel blockers 
(selected agents listed, 
caution should be exercised 
for the entire class) 
Amlodipine (Norvasc ®) 
 
Diltiazem (Cardizem® and others) 
 
Felodipine (Plendil) 
 
Isradipine (DynaCirc®) 
 
Lacidipine (Lacipil) 
 
Nicardipine (Cardene®) 
 
Nifedipine (Adalat and Procardia®) 
 
Nimodipine (Nimotop®) 
 
Nisoldipine (Sular®) 
 
Nitrendipine (Nitrendipine) 
 
Verapamil (Calan and Isoptin®) 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
37 
 
Agent by Class 
 
Precautionary Concomitant 
Medications 
 
 
 
Hormonal agents 
Estrogens and Progesterones 
 
Glucocorticoids 
 
Hypoglycemics 
Pioglitazone (Actos) 
 
 
H 
HMG Co Reductase 
Inhibitors 
Atorvastatin (Lipitor®) 
 
Fluvastin (Lescol®) 
 
 
 
Psychiatric medications 
Bupropion (Wellbutrin®, Zyban®) 
 
Chlorpromazine (Thorazine) 
 
Clozapine (Clozaril®) 
 
Fluoxetine (Prozac and others) 
 
Nefazodone (Serzone®) 
 
Paroxetine (Paxil) 
 
Risperidone (Risperdal®) 
 
Venlafexine (Effexor®) 
 
 
 
Tricyclic Antidepressants 
(including but not limited to) 
Amitriptyline (Elavil and others) 
 
Desipramine (Norpramin and 
others) 
 
Imipramine (Tofranil and others) 
 
Nortriptyline (Pamelor and others) 
 
 
 
Sedative/Hypnotics 
 
All benzodiazepines 
 
Alprazolam (Xanax™) 
 
Clorazepate (Tranxene™) 
 
Diazepam (Valium™) 
 
Estazolam (ProSom™) 
 
Flurazepam (Dalmane™) 
 
Oxazepam (Serax™) 
 
Temazepam (Restoril™) 
 
Busprione (Buspar™) 
 
Zaleplon (Sonata™) 
 
Zolpidem (Ambien™) 
 
 
 
Other agents 
 
Chlorzoxazone (Parafon Forte™) 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
38 
 
Agent by Class 
 
Precautionary Concomitant 
Medications 
 
Cimetidine (Tagamet™) 
 
Naloxone (Narcan™) 
 
Piroxicam 
 
Promethazine (Mepergan™, 
   Phenergan™) 
 
Sildenafil (Viagra®) - see note below 
 
Warfarin (Coumadin™) 
 
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 
 
5.3.4.3 Co-administration of Nephrotoxic Agents 
Co-administration of agents with nephrotoxic potential (e.g., 
amphotericin B, aminoglycosides, cidofovir, acyclovir, 
ganciclovir, vancomycin) or that are renally excreted (e.g., 
probenicid) may increase serum drug concentrations of TDF and/or 
increase the concentrations of the other renal-excreted agents.  
Additional monitoring may be indicated if subjects are placed on 
these agents while on TDF.  
5.3.4.2 Co-administration of Prednisone 
 
Prednisone < 10 mg (or equivalent) is permitted as a stable or 
tapering dose. 
 
 
5.5 
Adherence Assessment 
 
Throughout the study, the documentation of adherence to study drugs is essential. 
During each visit an adherence diary will be completed by study personal and 
reviewed with subjects and adherence assessed and clinical importance of strict 
adherence reinforced. During weekend visits that do not require a study visit, if 
permitted by patients, subjects should be contacted by phone (at least one attempt) 
and dose recorded in adherence diary. An adherence questionnaire will be 
completed during the HAART portion of the study at weeks 8, 24 and 48. 
 
6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Events 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
39 
Evaluation 
 
On-Study Evaluations 
Sequence 1 
monotherapy 
 
Sequence 2 
Dual therapy 
 
HAART 
TDF 
switch to 
3TC 
Screening 
Entry 
viral dynamic visits: 
3 visits between days 
2-6 (+1 day) 
PK 
 
± 1 
week 
Start 
 
viral dynamic visits: 
3 visits between days 
 43-47 (+1day) 
PK 
PK 
+ 3days 
Within 30 
days of 
entry 
1 
visit 
1 
visit 
2 
visit 
3 
 
7 
 
8 
Washout 
9-36 
 
37 
 
42 
visit 
1 
visit 
2 
visit 
3 
48 
49 
63 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Medication History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Documentation of HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessment / AE 
(include ABC HSR CRF at day 37 
for subject restarting ABC) 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
 
X 
 
 
Height, Weight 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EFV prescription given 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Targeted Physical Exam 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Start Drug  
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
Observed Dose 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
Last dose for Sequence 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
Complete Adherence Diary  
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
40 
Schedule of Events – Sequence 1 and Sequence 2 
Evaluation 
 
On-Study Evaluations 
Sequence 1 
 
Sequence 2 
 
HAART 
TDF 
switch to 
3TC 
Screening 
Entry 
viral dynamic visits: 
3 visits between days 
2-6 (+1 day) 
PK 
 
± 1 
week 
start 
viral dynamic visits: 
3 visits between days 
43 -47 (+1 day) 
PK 
PK 
+ 3 days 
Within 30 
days of 
entry 
1 
visit 
1 
visit 
2 
visit 
3 
 
7 
 
8 
Washout 
day 9-36 
 
37 
 
42 
visit 
1 
visit 
2 
visit 
3 
48 
49 
63 
Hematology (local lab) 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Chemistry / LFT (local lab) 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Urinalysis (local lab) 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Immunology: CD4+/CD8+ 
(local lab) 
X 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
Pregnancy Testing  (local lab) 
X 
X 
Whenever pregnancy is suspected 
Virology : (UCSD lab) 
Plasma HIV-1 RNA PCR  
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
HIV Genotype (UCSD lab)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Stored Plasma  
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
Sparse PK sampling (PBMC 
and Plasma)  
 
 
 
 
 
X 
X 
 
 
 
 
 
 
X 
X 
 
PBMC’s for cellular enzymes 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Shipment to UCSD  
(HIV RNA and genotype)  
X  
 
 
 
 
 
X  
 
 
 
 
 
 
 
X 
 
Shipment to USC               (All 
plasma levels, ABC PBMCs, RT-PCR) 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Shipment to Gilead 
(TDF  PBMCs – not plasma) 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
41 
Schedule of Events – HAART portion 
 
 
 
 
Evaluation 
On study Evaluations 
 
Weeks from start of HAART (+/- 1 week) 
(Weeks post sequence 2 – day 49) 
Virologic 
Failure 
Regimen 
Change due to 
Toxicity 
Premature 
Treatment 
Discontinuation 
HAART 
week 4 
HAART 
week 8 
HAART 
week 16 
HAART 
week24 
HAART 
week 36 
HAART 
week 48 
 
 
 
Clinical Assessment / AE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Targeted Physical Exam 
X 
 
 
 
 
X 
X 
X 
X 
Hematology / WBC (local lab) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry / LFT (local lab) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis  (local lab) 
X 
 
 
 
 
X 
X 
X 
X 
Immunology: CD4+/CD8+ (local lab) 
X 
X 
 
X 
X 
X 
X 
X 
X 
Plasma HIV-1 RNA PCR (UCSD lab) 
 
 
 
X 
 
X 
X 
X 
X 
Plasma HIV-1 RNA PCR  (local lab) 
X 
X 
X 
 
X 
 
 
 
 
HIV Genotype (UCSD lab) 
 
 
 
 
 
 
X 
 
 
Stored Plasma 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adherence Questionnaire  
 
X 
 
X 
 
X 
X 
X 
X 
Shipment to UCSD             (HIV RNA) 
 
 
 
X 
 
X 
X 
X 
X 
 
 


 
 
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42 
 
6.2 
Definitions for Schedule of Events – Timing of Evaluations 
 
6.2.1 Prerandomization 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 
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 faxed to the UCSD [(619) 298-
1379]. 
 
Pre-Screening Site Clinical Labs 
 
Plasma HIV RNA and CD4 clinical labs must be available prior to 
screening and have been obtained no more than 90 days prior to 
screening.  
 
Screening  
 
Study screening laboratories must be determined within 30 days of 
study entry (Day 1). Screening and entry evaluations must be 
separated by at least 48 hours.  
 
                                    Laboratory Results - Screening 
 
All laboratory testing, save the HIV RNA and genotype, will be 
coordinated through the sites local laboratory and results will be 
tracked by the CCTG Data Center.  The plasma HIV RNA and the 
genotype will be done centrally and results will be sent back to the 
sites within the 30 day screening period. 
 
Once the screening laboratories have been done the patient will be 
evaluated for study eligibility if all other entry criteria are satisfied.  
The patient can then be randomized.  
 
The total blood volume for screening labs is 35 mL. 
 


 
 
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Protocol version 1.2 
 
 
September 1, 2004 
 
43 
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.  
 
Randomization 
 
Upon receipt of the screening laboratory eligibility, the 
randomization CRF should be completed and faxed to the CCTG 
Data and Biostatistical Unit at (619-298-1379).  This 
randomization CRF will include PID, patient initials, screening 
laboratory eligibility sign off, genotype eligibility sign off and 
study site.  
 
The randomization will be done by the Data and Biostatistical Unit 
and will be faxed to the site within 2 working days of receipt of a 
correctly completed randomization CRF. Eligible participants will 
be randomized to one of two mono NRTI therapy arms (TDF alone 
or ABC alone) for the first sequence.  
 
Entry 
 
The entry evaluation should be scheduled within 30 days of the 
screening visit.  The randomization should be completed and the 7-
day supply of treatment for the first sequence should be available. 
The first dose of study medication should be given and witnessed 
by the study coordinator after drawing the baseline laboratories.  
A 7-day adherence diary should be completed by study personal 
for all doses of medication during the 7 day sequence. 
 
6.2.2 On-Study Evaluations         
 
Evaluations should occur after randomization. Ideally, start dates 
for Sequence 1 (day 1) and Sequence 2 (day 42) should occur on 
either a Wednesday or Thursday if the patient and site are willing 
and/or able to have Saturday visits – otherwise on Tuesday. 
Afterwards 3 viral dynamic visits should occur between days 2 – 6 
and days 43-47, respectively, with a visit window of + 1 day. 
Should the start date begin on a Wednesday or Thursday, then the 
PK visits should occur on days Tuesday-Wednesday or 
Wednesday-Thursday, respectively. If the start date occurred on a 
Tuesday then the PK visits would occur the following Monday-
Tuesday. Thereafter, while on HAART therapy, study evaluations 
will occur on day 63 (week 2 from day 49) and weeks 4, 8, 16, 24, 
36 and 48 or as needed. In instances of virologic failure and/or 
premature treatment discontinuation evaluations would also need 
to occur. 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
44 
 
Total blood volume for laboratory evaluations from days 1 – 49 
will be approximately 448 mL.  
 
On day 37, prior to Sequence 2, those patients that were 
randomized to ABC monotherapy during Sequence I should be 
evaluated for evidence of potential ABC hypersensitivity at any 
time since study initiation. If a patient has evidence of ABC 
hypersensitivity symptoms all study medication should be held and 
the protocol team notified. 
 
6.2.3 Evaluations for randomized or registered subjects who do not start 
study treatment: 
 
No follow-up evaluations will be required for subjects that are not 
randomized and/or do not start study treatment.   
 
6.2.4 Treatment Discontinuation Evaluations 
 
1. Subjects on either Sequence 1 or Sequence 2 portion of the 
study, who discontinue treatment regimen before the end of 
Sequence 2 will be removed from the study. 
2. Subjects that miss more than one scheduled visit during the 
viral dynamics portion will need to be removed from the study. 
3. Subjects that miss either of the PK visit days (there is no visit 
window period for PK visits) will need to be removed from the 
study. 
Subjects should have a Premature Treatment Discontinuation visit 
(see section 6.1) within 14 days after stopping their antiretrovirals. 
 
 
Subjects on the HAART therapy portion of the study, who 
discontinue their study regimens at day 63 or before the end of the 
study will not be followed until study completion. They will return 
for a Premature Termination Visit.  
 
6.2.5 Change in Antiretrovial Regimen 
 
Subjects on the HAART therapy portion of the study, who change 
their treatment regimen before the end of the study and who 
choose to be followed on the study, will come in for a visit for 
therapy change and the new regimen should be initiated within 72 
hours. 
 
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). 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
45 
 
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 during HAART portion of study 
 
Virologic failure will be decided on a case by case basis by the 
local site’s study investigator in collaboration with the protocol 
team. Suggested criteria include: a < 2.0 log drop in plasma HIV 
RNA by week 8 from day 49 and/or a > 0.5 log increase from 
nadir. For subjects who reach a plasma HIV-1 RNA failure, a 
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 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 HAART.  
 
6.2.7 Post-Treatment Evaluations 
 
All randomized subjects who complete the study will complete the 
week 48 End of Study Visit.  
 
6.2.7 Premature Treatment Discontinuation 
 
These evaluations are required at the subject’s final visit. 
 
6.2.8 Pregnancy  
 
Women who become pregnant during the study will be required to 
permanently discontinue their study regimens.  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 
 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
46 
Include antigen, antibody, or other recognized methods of 
documenting HIV infection from subject’s source documentation.  
 
If the subject has evidence of recent HIV infection, defined by 
infection within 24 months, a resistance assay (either genotype or 
phenotype) from any laboratory must be obtained and made 
available for review by the protocol team prior to screening.  
Obtaining resistance testing for patients with suspected recent HIV 
infection is part of standard medical care according to current 
guidelines. (The protocol will not provide the resistance assay.) 
The protocol team will make the decision on whether significant 
resistance is present that might make entry into the study a 
potential risk for the subject. If the patient is allowed to enter the 
study, another genotypic analysis will be provided by the study. 
Note: this resistance assay is different than the one obtained at 
screening which is provided by the study. 
 
Recent HIV Infection 
 
The following are possible laboratory and clinical symptoms that 
should prompt consideration of recent or acute HIV infection:  
(This is not intended to be a complete list, but should help the 
investigator consider recent HIV infection) 
 
 
                   
Negative HIV ELISA (or other screening test) within the past 24 
months. 
 
 
Positive ELISA or other screening test with negative or 
indeterminate (≤ 2 bands) Western blot in the past 24 months. 
 
 
Detuned HIV ELISA with an OD reading < 0.75 with a positive 
standard HIV ELISA in the past 6 months 
 
 
A history consistent with acute retroviral syndrome (HIV 
seroconversion illness) in the past 24 months and no previous HIV 
ELISA in the past 24 months (in a subject who has not had a 
previous HIV test).  Seroconversion symptoms, in the absence of 
other defined etiology, include the following: 
 
- Fever  
 
 
- Weight loss 
- Sore throat  
 
- Myalgia 
- Fatigue 
 
 
- Rash 
- Headache 
 
 
-Diarrhea 
- Nausea 
 
 
-Vomiting 
 
6.3.2 Medical History 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
47 
 
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.  
 
6.3.3 Medication History 
 
At screening, a medication history will be obtained and must be 
recorded in the source documents, including: 
 
Complete history of any prescription medications taken for the 
treatment or prophylaxis of opportunistic infections, including 
actual or estimated start and stop dates in the past 30 days.  This 
will be recorded in the concomitant medication form. 
 
All prescription medications in addition to those noted taken 
within 30 days of entry, including actual or estimated start and stop 
dates. 
 
Nonprescription medications taken within 30 days of entry.  
Include actual or estimated start and stop dates.  
 
Alternative therapies and/or dietary supplements taken within 30 
days of entry or since the last clinic visit.  Include actual or 
estimated start and stop dates. 
 
Allergies to any medications and their formulations must be 
documented. 
 
6.3.4 Concomitant Medications 
 
The following medications should be recorded on the case report 
forms (CRFs): 
 
Exclusionary medications (Section 5.4.2) 
 
Precautionary Medications (Section 5.4.3)  
 
Please refer to the most recent study medication’s package insert or 
investigator’s brochure to access additional current information on 
prohibited and precautionary medications. 
 
At the following study visits all concomitant medications taken 
since the last visit will be recorded in the source documentation 
and entered into the concomitant medication CRF (log): screening, 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
48 
entry to sequence 1, entry to sequence 2 and at each study visit 
during the HAART treatment period. A copy of the concomitant 
medication log should be faxed to the CCTG Data Center at the 
end of study. The following medications and/or class of 
medications should be included on the CRFs: all prescription 
medications. 
 
During the study, all modifications to study drugs including 
subject-initiated and/or protocol-mandated interruptions, 
modifications, and permanent discontinuation of treatment will be 
recorded on the CRFs at each visit.  Subject-initiated and protocol-
mandated interruptions include both inadvertent and deliberate 
interruptions of study drug(s) dose(s) for a period of > 1 day. 
 
6.3.5 Study Treatment Modifications 
 
All modifications to study drug(s) including initial doses, patient-
initiated and/or protocol-mandated interruptions, modifications, 
and permanent discontinuation of treatment will be recorded on the 
CRFs at each visit. 
 
6.3.6 Nadir CD4+ 
 
The subject’s prior nadir CD4+ cell count (absolute value and date) 
should be documented during screening and, when possible, a copy 
of the nadir CD4+ 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. 
 
6.3.7 Clinical Assessments 
 
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 entry, at completion of sequence 2, at weeks 4 
and 48 of HAART therapy and in instances of virologic failure or 
premature treatment discontinuation if they should occur. 
Documentation must include any HIV-related, toxicity-related, or 
AIDS-defining events. 
 
Height and Weight 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
49 
 
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 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. CRFs should be completed within 48 hours of a 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, HIV-related 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 other visits, record all Grade ≥ 2 laboratory toxicities on the 
CRFs throughout the course of the study. All values, regardless of 
toxicity, of specific laboratories will also be recorded on the 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
50 
laboratory CRF; including: wbc, neutrophil count, hemoglobin, 
platelets, phosphorous, blood urea nitrogen, creatinine, glucose, 
AST/ALT, alkaline phosphatase, total bilirubin. 
 
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:  
 
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, electrolytes (sodium, potassium, 
chloride, and bicarbonate), calcium, and phosphate will be 
performed in real time at the site’s local laboratory. 
 
 
 
 
Blood volume: 7 mL 
 
 
 
 
Urinalysis Test 
 
Specific gravity, pH, protein and blood will be performed in real 
time at the site’s local laboratory. 
 
5 ml urine 
 
Pregnancy Test 
 
For women with reproductive potential: Urine β-HCG (urine test 
must have a sensitivity of 25-50 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 
 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
51 
CD4/CD8 
 
Obtain absolute CD4/CD8 count and percentages within 30 days of 
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.  
 
CD4+ and CD8+ cell counts and percentage evaluations should be 
performed at the same local laboratory for baseline calculation and 
throughout the course of the study. 
 
Because of the diurnal variation in CD4+ and CD8+ cell counts; all 
determinations should be obtained consistently in either the 
morning or the afternoon throughout the study, if possible. 
 
Blood volume: 5 mL 
 
6.3.10 Virologic Studies 
 
Plasma HIV-1 RNA 
 
Screening HIV-1 RNA must be performed at a central lab within 
30 days prior to study entry.  
 
CD4 and HIV RNA eligibility will be determined by laboratories 
obtained from patient’s provider as part of standard of care within 
90 days of screening (prior to screening).  The calculated baseline 
value (used for analysis) will be the mean of the pre-entry and 
entry determinations, which must have been obtained at least 48 
hours apart.   
 
Plasma HIV-1 RNA should be collected at every study visit, 
except day 7 and day 48, during Sequence 1 and 2 and during 
scheduled visits of HAART therapy. HIV RNA samples for 
screening, Sequence 1, Sequence 2 and weeks 24 and 48 of 
HAART will be performed at a central laboratory – all other HIV 
RNA testing during the HAART portion of the study will be done 
at the site’s local laboratory. 
 
Genotype Resistance Assay 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
52 
 
Samples for genotypic analysis of plasma HIV-1 RNA obtained at 
screening and day 7.  The screening sample will be run in real-
time, while day 7 sample will be stored for possible future 
analyses.   
 
An HIV genotype will be performed in real time at day 49, but will 
not be available until after patient begins EFV. Any identification 
of new resistance mutations will prompt a retrospective evaluation 
of stored plasma from day 7. And any evidence of virologic failure 
will also prompt a genotype evaluation. 
 
Samples for genotypic analysis obtained at the time of virologic 
failure will be tested in real time for subject management by a 
central laboratory.   
 
Stored Plasma 
 
 
Stored Plasma will be collected at study entry and during every 
visit during Sequence I and II (except days 7 and 48) and HAART 
therapy and in cases of virologic failure and/or premature 
treatment discontinuation for future studies. Specimens will be 
batched and stored in the central CCTG specimen repository. 
 
Blood volume: 20 mL – for screening  
Blood volume: 15 mL – for all other virology collections 
 
 
6.3.11 Pharmacokinetic Studies 
 
Sequence 1 (monotherapy) 
 
At day 7 of Sequence 1 a sparsely populated pharmacokinetic 
profile will be collected from all patients. This includes a pre-dose 
intracellular (PBMC) and plasma trough level (time 0) of TDF or 
ABC monotherapy followed by a witnessed dose of study 
medication and two additional intracellular (PBMC) and plasma 
samples collected 3 and 6 hours post witnessed dose. Additional 
plasma-only samples should be collected at 30 minutes, 1-hr and 2-
hr post dose. After each sample is collected PBMC and plasma 
separation should be done immediately after collection and stored 
for shipping the next day. 
 
At day 8 of Sequence 1, a 24-hour post dose intracellular (PBMC) 
and plasma sample should be collected before any dose of study 
medication is given. All 7 samples from the sparse PK (time 0, 30-


 
 
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Protocol version 1.2 
 
 
September 1, 2004 
 
53 
min, 1-hr, 2-hr, 3-hr, 6-hr and 24-hr post dose) should be sent 
overnight to the appropriate off-site lab for analysis. If the patient 
is on the ABC arm then both PBMCs and plasma specimens 
should be sent to USC (one shipment). If the patient is on the TDF 
arm then the PBMCs should be sent to Gilead AND the plasma 
should be sent to USC (two separate shipments). 
 
Blood volume (PBMC-plasma): 20 mL – each draw 
Blood volume (plasma only): 3 mL – each draw 
Blood volume: 89 mL- over 2 days 
 
Sequence 2 (dual-therapy) 
 
At day 48 of Sequence 2, a sparsely populated pharmacokinetic 
profile will be collected from all patients. This includes a pre-dose 
intracellular (PBMC) and plasma trough levels (time 0) of TDF + 
ABC dual-therapy followed by a witnessed dose of study 
medication and two additional intracellular (PBMC) and plasma 
samples collected 3 and 6 hours post witnessed dose. Additional 
plasma-only samples should be collected at 30 minutes, 1-hr and 2-
hr post dose. After each sample is collected PBMC and plasma 
separation should be done according to PBMC processing protocol 
after collection and stored for shipping the next day. 
 
At day 49 of Sequence 2 a 24-hour post dose intracellular (PBMC) 
and plasma sample should be collected and processed. All 7 
samples from the sparse PK (time 0, 30-min, 1-hr, 2-hr, 3-hr, 6-hr 
and 24-hr post dose) should be sent overnight to appropriate off-
site lab for analysis. Since the patient is on dual therapy and the 
each drug is measured in separate labs each PBMC samples should 
be split at each time-point with half of the samples shipped to 
Gilead and half shipped to USC (two separate shipments). ALL 
plasma samples should be sent to USC. Since samples have to be 
split we will need to collect double the blood for the intracellular 
(PBMC) PK: 
 
Blood volume (PBMC-plasma): 40 mL – each draw 
Blood volume (plasma only): 3 mL – each draw 
Blood volume: 169 mL- over 2 days 
 
 
 
 
6.3.12 PBMCs for RT-PCR 
 
At day 1 and day 63 a PBMC sample for RT-PCR of nucleoside 
analogue transport enzymes (enzymes for efflux, influx) will be 
collected. The day 1 specimen should be stored and sent with day 8 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
54 
PK specimens to USC. Day 63 specimen should be sent to USC 
after collection and processing. 
 
Blood volume: 20 mL 
 
6.3.17 Adherence Questionnaires 
 
Adherence questionnaires will be conducted by study personal 
during sequence 1 and 2. Adherence questionnaires will also be 
conducted on weeks 8, 24, and 48 of HAART 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 
TOXICITY MANAGEMENT 
 
Specific management of toxicity will be discussed only to those medications 
thought to be related to any of the study-provided medications (include: TDF, 
ABC, 3TC and EFV). 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.  
 
7.1 Criteria for subject management 
 
The toxicities expected to be attributed to one or more study medications may have 
one or more of the following dosing modifications: 
 
a.   all study drugs may be held; 


 
 
CCTG 584 
 
 
Protocol version 1.2 
 
 
September 1, 2004 
 
55 
b. if during the Sequence 1 or Sequence 2 of the study a toxicity thought to be 
related to one of the NRTI’s occurs that results in the need to switch or 
discontinue study medications, then that subject would be removed from study; 
c. if after the Sequence 2 of the study a toxicity thought to be related to one of the 
NRTI’s occurs, the regimen may be switched to an alternative NRTI; 
d. if after Sequence 2 of the study a toxicity thought to be related to EFV occurs, 
then best available therapy as recommended by the site investigator may be 
offered and the patient may continue on the study. 
 
NOTE:  The protocol endpoint must be notified by e-mail of all toxicities that 
result in a change (temporary hold or discontinuation) in regimen. 
Patients that develop limiting toxicities after Sequence 2 thought to be 
related to study medications should continue to receive follow up for 48 
weeks. 
 
7.2 
Commonly occurring adverse events 
 
7.2.1 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 creatine in subjects receiving TDF (See section 7.2.14).  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.  
 
However, in the event that a subject develops a Grade 1 or 2 reaction 
considered to be drug-related to either NRTI’s during Sequence 1 or 
Sequence 2 of the study, then this subject should be removed from the 
study only if this results in a need to discontinue or substitute any of the 
study drugs. Otherwise study subject may continue in study.   
 
7.2.2 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 to an NRTI should have all medications held or have 
their NRTI regimen switched for an alternative NRTI regimen. 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 and laboratories repeated within 2 weeks. 


 
 
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Protocol version 1.2 
 
 
September 1, 2004 
 
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Likewise if the Grade 3 adverse event is thought to be related to EFV then 
an alternative therapy may be offered at the discretion of the site 
investigator.  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. 
 
However, in the event that a subject develops a symptomatic Grade 3 
reaction considered to be study drug-related to either the NRTI’s during 
Sequence 1 or Sequence 2 of the study, then this subject should be removed 
from study.  
 
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.   
 
7.2.3 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. 
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 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.  A 
new regimen may be chosen at the discretion of the local investigator.  
Subjects experiencing Grade 4 adverse events requiring permanent 
discontinuation of study drug therapy 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. 
 
However, in the event that a subject develops a symptomatic Grade 4 
reaction considered to be study drug-related to either the NRTI’s during 
Sequence 1 or Sequence 2 of the study, then this subject should be 
removed from study. 
 
7.2.4 Rash 
 


 
 
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57 
Subjects receiving ABC who develop rash of any grade should be 
evaluated for the possibility of an HSR or a serious skin reaction such as 
Stevens Johnson Syndrome, Toxic Epidermal Necrolysis or Erythema 
Multiforme and managed appropriately as outlined below. 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.   
The 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.    
 
 
Grade 1 or 2 
 
Study treatment should continue without interruption (assuming no 
evidence of ABC hypersensitivity reaction is present). Subjects with a 
Grade 1 or 2 rash may be treated symptomatically with permitted 
antipyretic, antihistamine, and/or non-steroidal anti-inflammatory 
medications, but should be monitored closely by the local investigator.  
 
Grade 3 or 4 
 
A rash of Grade 3 or 4 necessitates that all study medications should be 
held for any Grade 3 or 4 rash unless the rash is determined to be 
unrelated to study medications. Upon resolution to Grade < 1, the site 
investigator should discuss alternative regimens with the protocol chairs. 
 
7.2.5 Hypersensitivity Reaction (HSR) with ABC 
 
All suspected cases of ABC HSR should be considered serious adverse 
experiences. The diagnosis of hypersensitivity to ABC remains a clinical 
diagnosis. There is no pathogenomonic clinical sign or laboratory finding 
that renders the diagnosis.  
 
 Fatal HSRs have been associated with ABC therapy. ABC therapy 
SHOULD NOT be restarted following an HSR, because more severe 
symptoms will occur within hours and may include life-threatening 
hypotension and death. Subjects who develop signs or symptoms of 
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suspected and should seek medical evaluation immediately, preferably on 
the same day that symptoms are reported.  
 
 
 
Management of HSR 
  
All subjects that receive ABC will be given a wallet-sized card of common 
ABC HSR symptoms. 
    
   Patients developing signs or symptoms of hypersensitivity MUST  
contact their doctor immediately for advice. If a hypersensitivity 
reaction is diagnosed the abacavir-containing product MUST be 
discontinued immediately. The patient should be asked to return all 
unused supplies of the abacavir-containing product for disposal to prevent 
an accidental re-challenge. 
 
An abacavir containing medicinal product (Ziagen, Trizivir or the 
abacavir/lamivudine fixed dose combination, Epzicom), MUST 
NEVER be administered following a hypersensitivity reaction, as 
more severe symptoms will recur within hours and may include 
life-threatening hypotension and death.  
 
To avoid a delay in diagnosis and minimise the risk of a life-threatening 
hypersensitivity reaction, the abacavir-containing product should be 
permanently discontinued if hypersensitivity cannot be ruled out, even 
when other diagnoses are possible (respiratory diseases, flu-like illness, 
gastroenteritis or reactions to other medications).  
Symptomatic support for abacavir hypersensitivity may be indicated. This 
should include, for example, administration of intravenous fluids to 
patients who develop hypotension. Antihistamines or corticosteroids have 
been used in cases of abacavir hypersensitivity, however there are no 
clinical data demonstrating the benefit of these in the management of the 
reaction.  
Laboratory and other investigations which may be useful in the evaluation 
and treatment of abacavir hypersensitivity include, but may not be limited 
to, measurement of ALT, AST, creatine phosphokinase, serum creatinine 
and white blood cell differential count and chest x-ray, if respiratory 
symptoms are present. 
 
 If a subject reports symptoms suggestive of hypersensitivity, s/he should be 
instructed not to take any additional doses and should be evaluated at the 
clinic. The evaluation should consist of a careful history and physical 
examination. Laboratory studies should be obtained as clinically indicated. 
There is no diagnostic test available to confirm the clinical diagnosis. If 
upon evaluation the subject does have a presentation consistent with 


 
 
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hypersensitivity, therapy with ABC must be permanently discontinued and 
the protocol team informed.  
 
 
 
 
 
Discontinuation and Reintroduction of ABC Therapy 
  
 
Subjects who discontinue ABC for any reason should be queried regarding 
signs and symptoms of HSR. This should be done at the beginning of 
Sequence 2 (day 37) for those patients randomized to ABC during 
Sequence 1. An ABC HSR checklist will be completed on day 37 and 
whenever symptoms of ABC HSR are suspected. Patients will be given a 
wallet-sized ABC HSR symptom card to carry when they receive ABC 
medication.  
 
If therapy with abacavir has been discontinued and restarting therapy is 
under consideration, the reason for discontinuation should be evaluated to 
ensure that the patient did not have symptoms of a hypersensitivity 
reaction. If hypersensitivity reaction cannot be ruled out, no medicinal 
product containing abacavir (Ziagen, Trizivir or the 
abacavir/lamivudine fixed dose combination) should be restarted. 
 
There have been infrequent reports of hypersensitivity reaction following 
reintroduction of an abacavir-containing product where the interruption 
was preceded by a single key symptom of hypersensitivity (rash, fever, 
malaise/fatigue, gastrointestinal symptoms or a respiratory symptom).  If a 
decision is made to restart any abacavir-containing product in these 
patients, this should be done only under direct medical supervision.  
On very rare occasions hypersensitivity reactions have been reported in 
patients who have re-started therapy, and who had no preceding symptoms 
of a hypersensitivity reaction. If a decision is made to re-start an abacavir-
containing product, this must be done only if medical care can be accessed 
readily by the patient or others. 
 
If symptoms consistent with HSR are not identified, reintroduction of 
ABC can be undertaken with caution. This will be done for all patients 
randomized to ABC on Sequence 1 who then start Sequence 2. Patients 
will be seen 4 out of 7 days after starting ABC in Sequence 2. 
Reintroduction of the drug must occur in a setting where the subject can 
readily access medical care. 
 
After Sequence 2, the physician may deem that reintroduction of ABC is 
medically advantageous or necessary in a subject who had a documented 
intercurrent medical illness, which included one or more symptoms that 
could have also represented an ABC HSR. The primary responsibility for 
the decision to restart ABC in this setting rests with the site principal 
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of the possibility of rapid onset HSR. Reintroduction in these 
circumstances must be done under close medical supervision. 
 
 
 
 
Essential patient information 
Investigators must ensure that patients are fully informed regarding the 
following information on the hypersensitivity reaction: 
 
- 
Patients must be made aware of the possibility of a hypersensitivity 
reaction to abacavir that may result in a life threatening reaction or death. 
- 
Patients developing signs or symptoms possibly linked with a 
hypersensitivity reaction MUST CONTACT their doctor 
IMMEDIATELY. 
- 
Patients who are hypersensitive to abacavir should be reminded that they 
must never take any abacavir containing medicinal product (Ziagen, 
Trizivir or the abacavir/lamivudine fixed dose combination) again. 
- 
In order to avoid restarting the abacavir-containing product, patients who 
have experienced a hypersensitivity reaction should be asked to return the 
remaining tablets or oral solution to the pharmacy. 
- 
Patients who have stopped an abacavir-containing product for any reason, 
and particularly due to possible adverse reactions or illness, must be 
advised to contact their doctor before restarting. 
- 
Each patient should be reminded to read the Package Leaflet included in 
the pack. 
- 
Patients should be reminded of the importance of removing the Alert Card 
(wallet size card) and keeping it with them at all times. 
 
Reporting of Hypersensitivity Reactions 
All cases of potential abacavir hypersensitivity should be reported as Serious 
Adverse Events (SAE). 
 
Stevens Johnson Syndrome, Toxic Epidermal Necrolysis or Erythema 
Multiforme 
 
Serious skin reactions such as Stevens Johnson Syndrome, Toxic Epidermal 
Necrolysis or Erythema Multiforme have been reported very rarely in 
patients taking abacavir-containing products. These patients generally do not 
have the cluster of additional symptoms (e.g., gastrointestinal and 
respiratory) that characterize the abacavir hypersensitivity reaction, but they 
do have features typical of these serious skin reactions.  
If a serious skin reaction develops, the abacavir-containing product should be 
discontinued, and the patient should not be rechallanged with any abacavir-


 
 
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containing medicinal product (Ziagen, Trizivir or the abacavir/lamivudine 
fixed dose combination).  
As many products other than abacavir also cause these serious skin reactions, 
all other medicinal products that the patient is receiving should also be 
reviewed and discontinued as appropriate. 
 
 
 
 
7.2.6 Nausea and Vomiting  
 
Grade 1 or 2 
 
Study treatment should continue without interruption.  Subjects with 
Grade 1 and 2 nausea or vomiting may be treated symptomatically with 
permitted oral antiemetic therapies or antiemetic suppositories.  Subjects 
should be instructed to take medications with food.   
 
Grade 3 or 4 
 
Subjects with Grade 3 or 4 study-related nausea and vomiting should 
interrupt all study drugs until the toxicity grade returns to Grade < 2 or to 
baseline and be treated symptomatically.  If Grade ≥ 3 nausea and 
vomiting recurs upon the resumption of study medications despite 
symptomatic treatment, these should again be interrupted and the protocol 
team notified for possible alternative antiretroviral agents. 
 
7.2.7 Diarrhea 
 
Grade 1 or 2 
 
Study treatment should continue without interruption.  Subjects with 
diarrhea of any toxicity grade may be treated symptomatically with 
permitted antimotility agents. 
 
Grade 3 or 4 
 
For 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.  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. 
 
7.2.8 Hyperglycemia 
 


 
 
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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 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. 
 
7.2.9 AST/ALT Elevations 
 
Grade 1 or 2 
 
Study medications may be continued. 
 
Grade 3  
 
Study medications may be continued for 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. 
 
Grade 4 
 
All study medications should be held for AST or ALT Grade 4 elevations 
until the toxicity returns to Grade < 2.  If the Grade 4 elevation in AST or 
ALT recurs, alternative ARV therapy should be considered in consultation 
with the protocol team. 
 
7.2.10 Lactic Acidosis 
 
Symptomatic Hyperlactatemia 
 
If symptoms develop suggestive of hyperlactatemia, the site should 
perform a lactate level. 
 
Symptomatic hyperlactatemia will be defined as new, otherwise 
unexplained and persistent occurrence for > 2 weeks of one or more of the 
following: 
 
• nausea and vomiting 
• abdominal pain or gastric discomfort 
• abdominal distention 
• increased LFTs 


 
 
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• unexplained fatigue 
• dyspnea 
 
PLUS a confirmed lactate level > 2 x ULN. 
 
If the lactate value is > 2 x ULN, obtain a confirmatory lactate value as 
soon as possible, preferably within 1 week.  Antiretroviral therapy should 
be interrupted immediately if the confirmatory value remains > 2 x ULN 
or if the site is unable to obtain a confirmatory value within 1 week.  
Determine lactate levels every 4 weeks until the lactate value returns to 
normal, at which time a new antiretroviral regimen may be constructed in 
consultation with the protocol team. 
 
Management of symptomatic lactate value ≤ 2 x ULN will precede at the 
discretion of the local investigator.  However, any modification of a 
subject’s antiretroviral regimen should be made in consultation with the 
protocol team.  Since some of the symptoms of hyperlactatemia are vague 
and may be present in many subjects (e.g., fatigue), repeated lactate 
determinations are advised. 
 
NOTE: See the AACTG Web site for guidelines for the collection of 
lactate specimens:  
 
(http://aactg.s-
3.com/members/download/other/Metabolic/LacAcid.doc). 
 
Asymptomatic Hyperlactatemia 
 
If the lactate value is > 2 x ULN, a confirmatory lactate value must be 
obtained as soon as possible, preferably within 1 week.  Subjects should 
be evaluated for any of the symptoms or findings listed above in 
Symptomatic Hyperlactatemia.  Study medications must be discontinued 
for all subjects with a confirmed lactate value of > 4 x ULN, whether or 
not the subject has any symptoms listed above.  Lactate levels should be 
obtained every 4 weeks until the level returns to < 2 x ULN, at which time 
a new antiretroviral regimen may be initiated in consultation with the 
protocol team. 
 
If a lactate level of Grade > 2 to 4 x ULN is confirmed and the subject 
remains asymptomatic, the subject should be followed with repeat lactate 
levels every 4 weeks.  Serial monitoring may be discontinued if two or 
more lactate measurements are ≤ 2 x ULN and the subject remains 
asymptomatic. 
 
 
7.2.11 Creatinine Elevations 
 


 
 
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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. 
 
7.2.12 Anemia/Neutropenia 
 
Subjects with Grade 3 or 4 anemia or neutropenia attributed to any of the 
NRTI’s should have all study treatment interrupted until the abnormality 
returns to Grade ≤ 2.  Therapy may be resumed after the anemia or 
neutropenia has returned to Grade ≤ 2 using the same dual-NRTI regimen.  
Recurrent Grade 3 or 4 anemia or neutropenia attributed to any of the 
NRTI’s after should prompt a change in dual-NRTI regimen in 
consultation with the protocol team.   
 
Subjects with anemia or neutropenia may be treated with blood transfusion 
and/or erythropoietin (Epogen, Procrit) or G-CSF (Neupogen®) at the 
discretion of the site investigator. 
 
7.2.13 CK Elevations 
 
Asymptomatic elevations in CK or elevations due to exercise should be 
repeated (within 2-4 weeks) to assure that they are transient or due to 
exercise and will not require a change in study treatment.  Elevations in 
CK > 20 X ULN should be repeated after the subject has abstained from 
exercise for > 24 hours.  For persistent CK elevations >20 x ULN should 
prompt a change in dual-NRTI regimen and the protocol team should be 
notified. 
 
7.2.14 Hypophosphatemia (for TDF) 
 
For Grades 1 and 2 hypophosphatemia, the phosphate should be repeated 
within 2 weeks and TDF may be continued.  For Grades 3 and 4 
hypophosphatemia, the phosphate should be repeated within 1 week.  
Supplemental phosphate should be given and other causes of low 
phosphate should be investigated.  Persistent hypophosphatemia (Grade 3 
or 4) should lead to permanent discontinuation of TDF and notification of 
the protocol team.  
 
 
8 CRITERIA FOR TREATMENT DISCONTINUATION 
 


 
 
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8.1 
Criteria for Treatment Discontinuation 
 
• Drug-related toxicity (see section 7, Toxicity Management). 
• Active drug or alcohol use or dependence that, in the opinion of the 
investigator, would interfere with adherence to study requirements. 
• Requirement for prohibited concomitant medications (see section 5.4.2) 
• Pregnancy or breast-feeding. 
 
8.2 
Criteria for Discontinuation from the Study 
 
• Failure to complete Sequence 1 or 2 whether due to toxicity, poor adherence 
or need to stop drug. 
• If the subject misses more than 1 visit during the viral dynamics portion of 
Sequence I and II 
• Failure to complete both PK visits in Sequence I and II as scheduled 
• Failure by the subject to attend three consecutive clinic visits during the 
HAART 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 randomized comparative, open-labeled study of potency and 
pharmacokinetics of two antiretroviral agents, TDF and ABC. Eligible patients 
will be randomized into two monotherapy arms (TDF and ABC) for a short (one 
week) viral dynamics and pharmacokinetics evaluation to determine their 
potency. After a one-month washout period, all patients will start a dual-therapy 
of ABC+TDF. Viral dynamics and pharmacokinetics of the dual-therapy will be 
evaluated during the first week of the treatment. EFV will be added to the 
regimen after one week of the dual-therapy administered. Two weeks later, 


 
 
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3TC will be used to replace TDF in this HAART regimen, and continue this 
treatment up to 46 weeks. 
 
9.2 
Endpoints 
 
9.2.1 Primary Endpoint 
 
1. Slope of Phase I HIV RNA dynamics and plasma HIV RNA change 
from baseline to Day 7. 
 
 2. Plasma TDF and ABC concentrations; intracellular CBV-TP and TDF-
DP concentrations. 
 
9.2.2 Secondary Endpoints 
 
 1. Plasma HIV RNA < 50 copies/mL at week 24 and 48 
 
2. Change in CD4 count from baseline at week 24 and 48 
 
3. New reverse transcriptase mutations assessed by genotype (IAS-USA 
mutation list) at day 48. 
 
4. Change in expression of nucleoside transport expression as assessed by 
specific mRNA transcript expression. 
 
5. Treatment related toxicity between regimens. 
 
9.3 
Sample Size and Accural 
 
Our sample size is determined based on one of the primary endpoints, the 
viral dynamic endpoint. Notermans et al. [31] presented the phase 1 decay 
rates for two groups: Group A (ritonavir, AZT, 3TC): d1 (slope of the 
phase 1 decay) mean=0.56, standard deviation =0.17 (CV=30%) and 
Group B (ritonavir given alone for 21 days, added AZT and 3TC on Day 
21): d1 mean=0.46, standard deviation =0.13 (CV=28%). More recent data 
for phase 1 decay for TDF monotherapy yielded a mean value of 0.4 and 
standard deviation of 0.1 (5), i.e. CV=25%.  
 
If we accept a type I error alpha=0.05 and a minimum of 80% power, the 
following table gives the sample sizes per arm required to detect the 
percentage differences of two sample means using a two-sided, two-
sample test under the normality and between-group equal variance 
assumptions: 
 
Sample Size Per Arm (N1=N2) 
=============================== 


 
 
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CV 
Difference (%) in Means 
20% 
30% 
40% 
25% 
25 
11 
7 
30% 
36 
16 
9 
35% 
49 
22 
13 
 
With a sample size of 10 subjects per arm, we can detect a 30% difference 
in Phase I viral decay rates with a power of 80% and significance level of 
0.05 if the CV=25%; and a 40% difference if the CV=30%. Since we 
expect a smaller within-subject variation in viral decay rates, we may be 
able to detect a smaller difference in viral decay rates between the 
monotherapy and dual-therapy. 
 
Additionally, sample size determinations were done for pharmacokinetic 
parameters. Assuming an intra-patient coefficient of variation (CV) of 
20%, a sample size of 10 should be able to detect a 30% difference in 
intracellular concentrations between mono and dual NRTI therapy 
sequences. If the intra-patient CV is higher, only larger differences 
between mono or dual therapy would be detectable.  
 
9.4 
Monitoring 
 
The safety and tolerability of the study medications will be monitored by 
means of adverse event reports (AER) and biweekly toxicity reports 
presenting laboratory and clinical data. It is required that these data be 
entered into the database within 48 hours of the time at which the results 
of the laboratory tests or clinical examinations become available. These 
reports will be discussed by the protocol team on biweekly or monthly 
conference calls. Since Phase I studies are not routinely reviewed by the 
Data and Safety Monitoring Board, it is the responsibility of the Principal 
Investigator and the CCTG protocol team to interpret the toxicity data and 
make any decisions needed to protect patients from undue risk. Accrual 
and toxicity summaries will be provided to the Protocol Chairs and CCTG 
Investigators by the Data Manager and Biostatistician. 
 
The protocol team will review all screening genotypes in order to assure 
eligibility prior to randomization. The day 49 genotype will be run in real 
time and reviewed by the protocol team as soon as it is available. If more 
than one patient develops a new (i.e. not present on screening genotype) 
genotypic mutation in reverse transcriptase at day 48, an independent 
interim review committee will be established to review the study results to 
date. The interim 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.  
 


 
 
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9.5 
Analysis 
 
9.5.1 Primary Objective Analysis 
 
1)  Viral decay rates will be estimated using the least squared methods and 
mixed-effects model approach. The comparisons of viral decay rates 
between mono and dual NRTI treatment groups will be performed based 
on the estimated viral decay rates (derived variable approach)using 
Wilcoxon rank tests [23, 32, 33]. 
 
2)  The plasma pharmacokinetic parameters (AUC, Cmin, Cmax, T1/2, 
etc.) will be calculated using non-compartmental method (trapezoidal 
rule), and two arms will be compared using the nonparametric Wilcoxon 
rank sum test. 
 
Plasma concentrations of TDF and ABC alone and in combination with 
each other will be fit to compartmental pharmacokinetic models using a 
non-parametric population-modeling program (NPEM2, USC*PACK 
software, Laboratory of Applied Pharmacokinetics, University of Southern 
California). Intracellular levels will be assessed in relationship to viral 
plasma kinetics. 
 
Plasma TDF and ABC concentrations will be weighted according to the 
inverse of the assay error variance. Model discrimination will be 
determined based on Akaike information criteria and log-likelihood 
values.  
 
Subjects will be randomized to either TDF or ABC PO route for 7 days, 
which involves a fixed number of subjects. A sample size of 20 subjects 
(10 ABC and 10 TDF monotherapy and 20 ABC+TDF dualtherapy in 
HIV-positive patients). A 15% difference in plasma concentration will be 
considered to be clinically significant. Unpaired t-test or Mann-Whitney 
rank sum test, whenever appropriate, will be utilized for the comparison of 
demographic characteristics as well as PK parameters between the two 
studied groups. Selection of parametric or nonparametric will be 
determined after completion of tests for normality.   
 
9.5.2 Secondary Objective Analysis 
 
1)  The number of subjects whose plasma HIV RNA < 50 copies/mL at 
weeks 24 and 48 will be descriptively summarized and reported. 
 
2)  The change in CD4 count from baseline at weeks 24 and 48 will be 
summarized tabulated. 
 


 
 
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3)  The new reverse transcriptase mutations assessed by genotype (IAS-
USA mutation list) at day 48 will be summarized by Arms A and B. A 
comparison between the two arms will be conducted using the exact 
Fisher test. 
 
4)  The change in expression of nucleoside transport expression as 
assessed by specific mRNA transcript expression will be summarized by 
Arms A and B. A comparison between the two arms will be conducted 
using Wilcoxon rank test. 
 
5)  The treatment related toxicities will be summarized by Arms A and B. 
A comparison between the two arms will be conducted using the exact 
Fisher test. 
 
10.0 
DATA COLLECTION AND MONITORING AND ADVERSE EXPERIENCE 
REPORTING 
 
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 
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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 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.  


 
 
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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 
 
 
1. J G. Early Virologic Failure Rates with combination of Lamivudine, Abacavir and 
Tenofovir in Therapy Naive Patients: GSK 30009. In: 43rd Annual ICAAC. Chicago, IL, 
2003 
2. Farthing C KHaYV. Early virologic failure in a pilot study evaluating the efficacy of 
abacavir, lamivudine and tenofovir in the treatment naive HIV-infected patients. In: The 
2nd IAS Conference on HIV Pathogenesis and Treatment. Paris, France, 2003 
3. Landman R ea. Low genetic barrier to resistance is a possible cause of early virologic 
failures in once-daily regimen of abacavir, lamivudine and tenofovir: The Tonus Study. 
In: 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA, 
2004 
4. Elion R ea. COL40263: Resistance and efficacy of once-daily trzivir and tenofovir DF 
in antiretroviral naive subjects: Abstract 53. In: 11th Conference on Retroviruses and 
Opportunistic Infections. San Francisco, CA, 2004 
5. Miller MD MN, Schooley R, et al. Baseline and week 48 final phenotypic analysis of 
HIV-1 from patients adding tenofovir DF therapy to background ART [Abstract 441]. In: 
8th Conference on Retroviruses and Opportunistic Infections. Chicago, IL, 2001 
6. Squires K, Pozniak AL, Pierone G, Jr., et al. Tenofovir disoproxil fumarate in 
nucleoside-resistant HIV-1 infection: a randomized trial. Ann Intern Med 2003;139:313-
20 


 
 
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