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Stavudine or zidovudine in three-drug combination therapy for initial treatment of HIV infection in antiretroviral-naïve individuals

  1. Alicen Spaulding1,*,
  2. George W Rutherford2,
  3. Nandi Siegfried3

Editorial Group: Cochrane HIV/AIDS Group

Published Online: 4 AUG 2010

Assessed as up-to-date: 8 JUL 2009

DOI: 10.1002/14651858.CD008651


How to Cite

Spaulding A, Rutherford GW, Siegfried N. Stavudine or zidovudine in three-drug combination therapy for initial treatment of HIV infection in antiretroviral-naïve individuals. Cochrane Database of Systematic Reviews 2010, Issue 8. Art. No.: CD008651. DOI: 10.1002/14651858.CD008651.

Author Information

  1. 1

    University of Minnesota, Division of Epidemiology and Community Health, Minneapolis, Minnesota, USA

  2. 2

    University of California, San Francisco, Global Health Sciences, San Francisco, California, USA

  3. 3

    University of Cape Town, Department of Public Health and Primary Health Care, Cape Town, South Africa

*Alicen Spaulding, Division of Epidemiology and Community Health, University of Minnesota, 1300 S. Second Street, Suite 300, Minneapolis, Minnesota, 55454-1015, USA. alicenspaulding@yahoo.com.

Publication History

  1. Publication Status: Stable (no update expected for reasons given in 'What's new')
  2. Published Online: 4 AUG 2010

SEARCH

 

Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms

 
Summary of findings for the main comparison. d4T compared to AZT for initial treatment of HIV infection in antiretroviral-naive individuals

d4T compared to AZT for initial treatment of HIV infection in antiretroviral-naive individuals

Patient or population: patients with initial treatment of HIV infection in antiretroviral-naive individuals
Settings: Multiple locations
Intervention: d4T
Comparison: AZT

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

AZTd4T

Mortality
Follow-up: median 48 weeks
5 per 10007 per 1000
(2 to 27)
RR 1.36
(0.34 to 5.42)
1179
(6 studies)
⊕⊝⊝⊝
very low1,2,3,4

Clinical progression
Follow-up: median 48 weeks
22 per 100017 per 1000
(6 to 47)
RR 0.78
(0.28 to 2.13)
719
(7 studies)
⊕⊕⊝⊝
low1,2,4

Severe adverse events
Follow-up: median 48 weeks
202 per 1000236 per 1000
(196 to 283)
RR 1.17
(0.97 to 1.4)
1363
(9 studies)
⊕⊕⊝⊝
low1,2,4

Virologic response
Follow-up: median 48 weeks
424 per 1000437 per 1000
(373 to 505)
RR 1.03
(0.88 to 1.19)
2157
(12 studies)
⊕⊕⊝⊝
low1,2,4

Adherence/tolerability/retention
Follow-up: median 48 weeks
586 per 1000551 per 1000
(492 to 615)
RR 0.94
(0.84 to 1.05)
2157
(12 studies)
⊕⊕⊝⊝
low1,2,4,5

Immunologic response
Follow-up: median 48 weeks
The mean Immunologic response in the intervention groups was
9.61 higher
(17.62 lower to 36.84 higher)
1537
(10 studies)
⊕⊕⊝⊝
low1,2,4

Drug resistance110 per 100073 per 1000
(28 to 190)
RR 0.66
(0.25 to 1.73)
174
(1 study)
⊕⊝⊝⊝
very low1,2,3,6

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 8 out of 9 RCT studies were open-label studies, and some studies had large rates of loss to follow-up, but studies were not downgraded based on these facts.
2 5 out of 9 RCT studies looked at indirect comparisons of drug regimens.
3 Number of events <300 and/or confidence intervals include potential harm and benefit.
4 7 out of 9 RCT studies were industry funded, although some were funded simultaneously by competitors.
5 This outcome was coded as the proportion who finished the trial out of those who were initially assigned the treatment.
6 Only 1 RCT study (Kumar) reported on drug resistance, suggesting selective reporting.

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms

Globally, there were 33 million people living with HIV in 2007, the majority of whom resided in sub-Saharan Africa (UNAIDS 2009). Since its introduction in 1996, highly active antiretroviral therapy (ART) has markedly reduced the morbidity and mortality of patients with HIV/AIDS (Palella 1998, Holtgrave 2005), and significant public and private resources have been devoted over the last 5 years to rapid scale-up efforts in low- and middle-income countries to provide access to first-line ART (UNAIDS 2009; Bendavid 2009). It is estimated that approximately 5 million (low estimates) to 10 million people (high estimates) from low- and middle-income countries will need ART by 2010 (UNAIDS/WHO 2006). The World Health Organization (WHO), in collaboration with the Joint United Nations Programme on HIV/AIDS (UNAIDS), publishes guidelines on the use of ART in adults, adolescents and children, which currently recommend standard initial treatment of two nucleoside reverse transcriptase inhibitors (NRTI) and a non-nucleoside reverse transcriptase inhibitor (NNRTI) (Gilks 2006; WHO 2006b). Guidelines were first published in 2002 (WHO 2002) and updated in 2006 (WHO 2006b) and guidelines provided on scale up in 2003 (WHO 2003). Additionally, ART guidelines have been published separately for pregnant and lactating women, infants and children (WHO 2004; WHO 2006a WHO 2006b) and for general care and treatment of adolescents and adults with HIV infection (WHO 2006d; WHO 2008). However, given the rapidly emerging scientific understanding of HIV treatment and care and the dynamic scale-up efforts in resource-limited settings, WHO guidelines are updated routinely every few years. To the greatest extent possible, these guidelines are based on evidence of efficacy and effectiveness. Systematic reviews serve as the basis for compiling and assessing the evidence upon which these recommendations are updated. The current review represents a collaborative effort between the Cochrane Collaborative Review Group on HIV Infection and AIDS, the University of California, San Francisco (UCSF), the School of Public Health of the University of Minnesota, the U.S. Centers for Disease Control and Prevention (CDC), the South African Medical Research Council and WHO to address questions through systematic reviews regarding the optimum first-line ART regimen in patients living with HIV in low- and middle-income countries and was used by WHO in developing its 2009 ART treatment guidelines for adults and adolescents (WHO 2009).

OBJECTIVES

 

Description of the condition

Choosing the optimal first-line ART regimen for people living with HIV in low- and middle-income countries, is critical since HIV infection, if left untreated, will almost invariably progress to clinical AIDS and death.

 

Description of the intervention

The use of stavudine (d4T) or zidovudine (AZT) in three-drug combination therapy with one nucleoside reverse transcriptase inhibitor (NRTI) and one non-nucleoside reverse transcriptase inhibitor (NNRTI) or with two other NRTIs or with one NRTI and one protease inhibitor (PI) for initial treatment of HIV infection in adults and children.

 

How the intervention might work

By suppressing HIV replication and, hence, forestalling progression to clinical AIDS and death.

 

Why it is important to do this review

To ascertain if antiretroviral regimens containing d4T are superior to those containing AZT for the initial treatment of HIV in antiretroviral-naïve individuals.

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms

To assess the efficacy of d4T compared to AZT in combination with one NRTI and one non-nucleoside reverse transcriptase inhibitor (NNRTI), two additional NNRTIs, or one NRTI and one protease inhibitor (PI), as part of first-line ART for HIV-infected people in low-resource settings.

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomised controlled trials that included data and analysis for the comparison of interest.

 

Types of participants

The study population is antiretroviral-naïve children ≥5 years old and non-pregnant and non-lactating adolescents and adults diagnosed with HIV who are initiating a first-line ART regimen.

Relevant subpopulations of interest were:

1. Children 5-13 years old

2. Patients with concurrent hepatitis B virus infection

3. Patients with concurrent hepatitis C virus infection

4. Patients with concurrent tuberculosis

 

Types of interventions

We compared triple-drug antiretroviral regimens containing d4T to those containing AZT for the initial treatment of HIV infection. Regimens need to include two NRTIs, at least one of which was d4T or AZT, plus a third NRTI, an NNRTI or a PI. Regimens that used two or fewer drugs or four or more drugs were excluded, as were regimens undertaken for pre- or post-exposure prophylaxis and regimens in children <5 and pregnant or lactating women, as these are the subject of a separate reviews.

 

Types of outcome measures

Both primary outcomes (those deemed critical) and secondary outcomes (those deemed important) were abstracted.

 

Primary outcomes

1. Mortality

2. Clinical progression to AIDS. We assessed clinical progression by the proportion of participants that progressed either to CDC-defined AIDS (that is stage III to stage IV disease) or who developed a second opportunistic infection or malignancy.

3. Severe adverse events. These were classified according to grade 1 to 4 of the Adverse Event Toxicity Scale (Division of AIDS 2009) and are reported as the proportion of participants that experienced grade 3 and 4 clinical and laboratory adverse events. Using this scale, grade 1 and 2 denote mild to moderate symptoms, grade 3 denotes serious symptoms and grade 4 denotes life-threatening events requiring significant clinical intervention.

4. Virologic response to ART. This was reported as the proportion of participants that did not reach a pre-defined concentration of HIV-1 RNA, typically <400 copies/mL or <500 copies/mL, or who failed to suppress viral replication to non-detectable levels, typically <40 copies/mL. For purposes of meta-analysis we used the lowest reported value.

5. Adherence/tolerance/retention. We defined this variable to be the proportion of study participants that reached the end of the study without changing or discontinuing their initially assigned regimen. This category, therefore, excludes participants whose regimens were altered because of toxicity, those lost to follow-up, those whose regimens were changed because of clinical or virologic failure and those who withdrew from the study for other reasons.

 

Secondary outcomes

6. Immunologic response to ART. We defined this as the mean change in the concentration of CD4 lymphocytes from baseline, as expressed in cells/µL. When studies presented median, instead of mean, we used the median values as reported.

7. Prevention of sexual transmission of HIV. We defined this as the risk of sexual partners not acquiring HIV from the study participant.

8. Development of ART drug resistance. This was defined as acquisition of major genotypic resistance mutations as reported by authors. Minor mutations were not reported. Reported as a dichotomous outcome as identified by study authors. 

 

Search methods for identification of studies

We followed standard Cochrane systematic review methodology and all searches were completed by July 2009, as part of a larger ART systematic review. See results of searches (Figure 1).

 FigureFigure 1. Diagram of search results from overall ART systematic review.

 

Electronic searches

Journal and trial databases

  • MEDLINE
  • EMBASE
  • CENTRAL (Cochrane Central Register of Controlled Trials)
  • LILACS (Latin American and Caribbean Health Sciences Literature)
  • Cochrane HIV/AIDS Group Trials Register
  • Web of Science

For all comparisons we used the following search strings:


#1 Search HIV Infections[MeSH] OR HIV[MeSH] OR hiv[tw] OR hiv-1[tw] OR hiv-2*[tw] OR hiv1[tw] OR hiv2[tw] OR hiv infect*[tw] OR human immunodeficiency virus[tw] OR human immune deficiency virus[tw] OR human immuno-deficiency virus[tw] OR human immune-deficiency virus[tw] OR ((human immun*) AND (deficiency virus[tw])) OR acquired immunodeficiency syndromes[tw] OR acquired immune deficiency syndrome[tw] OR acquired immuno-deficiency syndrome[tw] OR acquired immune-deficiency syndrome[tw] OR ((acquired immun*) AND (deficiency syndrome[tw])) or “sexually transmitted diseases, viral”[mh]

#2 Search Antiretroviral Therapy, Highly Active[MeSH] OR Anti-Retroviral Agents [MeSH] OR Antiviral Agents[MeSH:No Exp] OR ((anti) AND (hiv[tw])) OR antiretroviral*[tw] OR ((anti) AND (retroviral*[tw])) OR HAART[tw] OR ((anti) AND (acquired immunodeficiency[tw])) OR ((anti) AND (acquired immune deficiency[tw])) OR ((anti) AND (acquired immuno-deficiency[tw]) OR ((anti) AND (acquired immune-deficiency[tw])) OR ((anti) AND (acquired immun*) AND (deficiency[tw]))

#3 Search #1 and #2

#4 Search (ZERIT OR STAVUDINE OR D4T) AND (ZIDOVUDINE OR RETROVIR OR AZT OR AZT)

#5 Search (#3 AND #4) NOT (animals[mh] NOT human[mh])

#6 Search (#3 AND #4) NOT (animals[mh] NOT human[mh]) Limits” Publication date: 1995-2009



We also added the following terms to identify controlled trials, which would have also been identified in the broader search: 


#5 Search randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized controlled trials[mh] OR random allocation[mh] OR double-blind method[mh] OR single-blind method[mh] OR clinical trial[pt] OR clinical trials[mh] OR (“clinical trial”[tw]) OR ((singl[tw] OR doubl*[tw] OR trebl*[tw] OR tripl*[tw[ AND (mask*[tw] OR blind*[tw])) OR (placebos[mh] OR placebo*[tw] OR random*[tw] OR search design[mh:no exp] OR comparative study[mh] OR evaluation studies[mh] OR follow-up studies[mh] OR prospective studies[mh] OR control*[tw] OR prospectiv*[tw] OR volunteer*[tw]) NOT (animals[mh] NOT human[mh])

#6 Search #3 AND #4 AND #5

#7 Search #3 and #4 and #5 Limits; Publication date: 1995-2009



Limits. The searches were performed without limits to language or setting. The searches excluded studies conducted in pregnant or lactating women, infants <1 year of age and children <5 years of age. The searches were limited to human studies published from 1995 (start of the triple-drug combination ART era) to the present.

Inclusion criteria:

  • Randomised controlled trial
  • Evaluates first-line ART regimen comparing d4T to AZT as part of a three-drug initial ART regimen
  • Provides sufficient regimen-specific information about first-line drugs to compare regimens and outcomes of interest

Exclusion criteria:

  • Letter, editorial, non-systematic review, case report, case-series, cross-sectional study
  • Studies evaluating first-line or dual drug regimens
  • Studies evaluating first-line ART regimens with > 3 drugs

 

Searching other resources

Conference databases

  • Aegis: Aegis covers abstracts from a number of relevant international conferences including the International AIDS Conference, the International AIDS Society Conferences on HIV Pathogenesis, Treatment, and Prevention, the Conference on Retroviruses and Opportunistic Infections, the British HIV Association Conference and the International Congress on Drug Therapy in HIV infection.
  • NLM Gateway (for HIV/AIDS conference abstracts before 2005)

We also hand searched conference proceedings from the Conferences on Retroviruses and Opportunistic Infections, International AIDS Conferences and International AIDS Society Conferences on HIV Pathogenesis, Treatment, and Prevention from 2005 to 2009.

Researchers and relevant organizations. We contacted individual researchers working in the field, such as the AIDS Clinical Trials Group, and policymakers based in United Nations agencies, including UNAIDS and WHO to identify trials either completed or ongoing.

Reference lists. We checked the reference lists of all studies identified by the above methods and examine the bibliographies of any systematic reviews, meta-analyses, or current guidelines we identified during the search process.

 

Data collection and analysis

 

Selection of studies

AS and GR independently selected potentially relevant studies by scanning the titles, abstracts, and descriptor terms of all downloaded material from the electronic searches. Irrelevant reports were discarded, and the full article was obtained for all potentially relevant or uncertain reports. GR and AS independently applied the inclusion criteria. NS acted as arbiter where there was disagreement. Studies were reviewed for relevance, based on study design, types of participants, exposures and outcomes measures. Finally, where resolution was not possible because further information was required, the study was allocated to the list of those awaiting assessment. Attempts to contact authors to provide further clarification of data are ongoing.

 

Data extraction and management

After initial search and article screening, two reviewers (AS and GR) independently double-coded and entered information from each selected study onto standardised data extraction forms. Extracted information included: 

  • Study details: citation, start and end dates, location, study design and details.

  • Participant details: study population eligibility (inclusion and exclusion) criteria, ages, population size, attrition rate, details of HIV diagnosis and disease and any clinical, immunologic or virologic staging or lab information.

  • Interventions details: drug names, doses, duration, ancillary testing and monitoring, any other information on adherence or resistance.

  • Outcome details: mortality; response to ART [clinical (AIDS and non-AIDS events), virologic and immunologic]; severe adverse events; development of ART drug resistance; adherence/tolerability/retention; risk of sexual transmission of HIV.

 

Assessment of risk of bias in included studies

We applied Cochrane Collaboration tools to assess each individual study for risk for bias (Appendix 1). The Cochrane approach assesses risk of bias in individual studies across six domains: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other potential biases.

Sequence generation
• Adequate: investigators described a random component in the sequence generation process, such as the use of random number table, coin tossing, card or envelope shuffling, etc.
• Inadequate: investigators described a non-random component in the sequence generation process, such as the use of odd or even date of birth, algorithm based on the day or date of birth, hospital, or clinic record number.
• Unclear: insufficient information to permit judgement of the sequence generation process.

Allocation concealment
• Adequate: participants and the investigators enrolling participants cannot foresee assignment (e.g., central allocation; or sequentially numbered, opaque, sealed envelopes).
• Inadequate: participants and investigators enrolling participants can foresee upcoming assignment (e.g., an open random allocation schedule, a list of random numbers); or envelopes were unsealed or non-opaque or not sequentially numbered.
• Unclear: insufficient information to permit judgement of the allocation concealment or the method not described.

Blinding
• Adequate: blinding of the participants, key study personnel, and outcome assessor, and unlikely that the blinding could have been broken. No blinding in the situation where non-blinding is not likely to introduce bias.

• Inadequate: no blinding or incomplete blinding when the outcome is likely to be influenced by lack of blinding.

• Unclear: insufficient information to permit judgement of adequacy or otherwise of the blinding.

Incomplete outcome data
• Adequate: no missing outcome data, reasons for missing outcome data unlikely to be related to true outcome, or missing outcome data balanced in number across groups.
• Inadequate: reason for missing outcome data likely to be related to true outcome, with either imbalance in number across groups or reasons for missing data.
• Unclear: insufficient reporting of attrition or exclusions.

Selective reporting
• Adequate: a protocol is available which clearly states the primary outcome as the same as in the final trial report.
• Inadequate: the primary outcome differs between the protocol and final trial report.
• Unclear: no trial protocol is available or there is insufficient reporting to determine if selective reporting is present.

Other forms of bias
• Adequate: there is no evidence of bias from other sources.
• Inadequate: there is potential bias present from other sources (e.g., early stopping of trial, fraudulent activity, extreme baseline imbalance, or bias related to specific study design).
• Unclear: insufficient information to permit judgement of adequacy or otherwise of other forms of bias.

Assessment of Quality of Evidence Across Studies

We assessed the quality of evidence across a body of evidence with GRADE (Guyatt 2008; Appendix 2), defining the quality of evidence for each outcome as, “the extent to which one can be confident that an estimate of effect or association is close to the quantity of specific interest” (Higgins 2008). The quality rating across studies has four levels: high, moderate, low or very low. Randomised controlled trials are categorised as high quality but can be downgraded; similarly, other types of controlled trials and observational studies are categorised as low quality but can be upgraded. Factors that decrease the quality of evidence include limitations in design, indirectness of evidence, unexplained heterogeneity or inconsistency of results, imprecision of results, or high probability of publication bias.  Factors that can increase the quality level of a body of evidence include a large magnitude of effect, if all plausible confounding would reduce a demonstrated effect and if there is a dose-response gradient.

 

Measures of treatment effect

We used Review Manager 5 provided by the Cochrane Collaboration for statistical analysis and GradePro (GradePro 2008) software to produce Summary of Findings and Evidence Profile tables. We summarised dichotomous outcomes for effect in terms of risk ratio (RR), risk difference (RD) and number needed to treat (NNT) with their 95% confidence intervals. We summarised continuous outcomes with a weighted mean difference (WMD) and 95% confidence interval. Summary statistics using meta-analytic methods were performed and findings are presented in GRADE Evidence Profile Tables for all outcomes of interest ( Summary of findings for the main comparison).

 

Unit of analysis issues

The unit of analysis was the individual participant in each study.

 

Dealing with missing data

Study authors were contacted when missing data was an issue.

 

Assessment of heterogeneity

We examined heterogeneity among trials using the chi-square statistic with a significance level of 0.10 and the I-squared statistic. We interpreted an I-squared estimate greater than 50% as indicating moderate or high levels of heterogeneity and investigated its causes by sensitivity analysis. If heterogeneity persisted, we presented results separately and reported reasons for the observed heterogeneity.

 

Assessment of reporting biases

We assessed the potential for publication bias using funnel plots. We minimised the potential for publication bias by our comprehensive search strategy that included evaluating published and unpublished literature.

 

Data synthesis

When interventions and study populations were sufficiently similar across different studies, we statistically pooled the outcomes and examined the differences between the two models using both fixed and random-effects models.  Since there were no significant differences between the two models, final results are presented using random-effects models.

We summarised the quality of evidence for each outcome for which data were available in GRADE Summary of Findings and GRADE Evidence Profile Tables (Guyatt 2008) ( Summary of findings for the main comparison).

 

Subgroup analysis and investigation of heterogeneity

If data were available, we performed sub-group analysis for studies in which participants were 5-13 years old or co-infected with hepatitis B, hepatitis C or tuberculosis. Heterogeneity was explored using further sub-group analyses by trial quality, setting (middle- or low- versus high-income country) or other sub-groups judged relevant.

 

Sensitivity analysis

If pooled results were heterogeneous, we were prepared to conduct sensitivity analyses to identify studies with outlying results for further examination.

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

 

Results of the search

Searches were conducted on July 9, 2009, and produced 9,571 titles after duplicates were removed (Figure 1). After initial screening of titles by one reviewer, 874 titles and abstracts were selected for further review by two reviewers (AS and GR). AS and GR independently conducted the selection of potentially relevant studies by scanning the titles, abstracts, and descriptor terms of all downloaded material from the electronic searches. Irrelevant reports were discarded, and the full article was obtained for all potentially relevant or uncertain reports. AS and GR independently applied the inclusion criteria. NS acted as arbiter where there was disagreement. Studies were reviewed for relevance, based on study design, types of participants, exposures and outcomes measures. Finally, where resolution was not possible because further information was required, the study was allocated to the list of those awaiting assessment. Attempts to contact authors to provide further clarification of data are ongoing.

One-hundred one abstracts or full articles were reviewed by two authors. Nine randomised trials were identified as meeting inclusion criteria for data extraction, coding, and potential meta-analysis.

 

Included studies

The nine randomised controlled trials which met inclusion criteria and were extracted included the OzCombo1 (Carr 2000 (1 vs 2) and OzCombo2 (French 2002 (1 vs 2), the START I (Squires 2000) and START II (Eron 2000) trials, the GEMCEI trial (Geijo Martinez 2006), ACTG 384 (Robbins 2003 (EFV)), ESS400002 (Kumar 2006), one Chinese study (Li 2008), and one study of enteric-coated ddI (Gathe 2002) (Appendix 3).

From these studies, two basic NRTI backbones were compared in the nine controlled trials we identified, AZT+3TC vs. d4T+3TC and AZT+3TC vs. d4T+ddI. We present these two sets of comparisons separately below.

AZT+3TC vs. d4T+3TC

For the AZT+3TC vs. d4T+3TC comparison, we identified 15 articles abstracts from four randomised controlled trials, including OzCombo 1 (Amin 2003; Carr 1999a; Carr 1999b; Carr 2000 (1 vs 2); Hudson 1998), ESS4002 (Kumar 2003; Kumar 2004; Kumar 2006), Li 2008, and START I (Gulick 1998; Pavia 2002; Squires 1998; Squires 1999; Squires 2000; Squires 2000a).

OzCombo 1 was a randomised, open-label, three-arm study that examined three NRTI backbones (AZT+3TC, d4T+3TC and d4T+ddI) in combination with indinavir (IDV) among ART-naïve adults. It was conducted in Australia and was primarily funded by the Australian National Council and AIDS and Related Diseases. Patients were followed for 52 weeks, and the primary endpoints were time to full viral suppression (HIV-1 RNA <50 copies/mL) and the proportion of patients with drug toxicities sufficiently severe to warrant dose adjustment or change. The primary results are found in Carr 2000 (Carr 2000 (1 vs 2). Other presentations of this study (Carr 1999a; Carr 1999b; Hudson 1998) are conference presentations for various stages of data, and Amin 2003 (Amin 2003) is a follow-up study of patients enrolled in OzCombo 1 and OzCombo 2.

ESS4002 was an industry-sponsored, phase IV, parallel group study of random-dose ABC-3TC-AZT (Trizivir®), random-dose AZT+3TC (Combivir®)+nelfinavir (NFV) and d4T+3TC+NFV in ART-naïve patients in the Dominican Republic, Guatemala, Panama, Puerto Rico and the United States of America (Kumar 2006). Its primary focus was on lipid metabolism with a primary outcome of change from baseline for low-density lipoprotein cholesterol. The study also collected efficacy endpoints, including HIV-1 RNA <50 and <400 copies/mL at 96 weeks.  

Li and colleagues compared three different NRTI backbones, AZT+ddI+NVP, AZT+3TC+NVP and d4T+3TC+NVP, in a randomised controlled trial in China that enrolled 198 patients with between 100 and 350 CD4 cells/µL and HIV-1 RNA>500 copies/mL. Its primary endpoints were immunologic, virologic and clinical response (Li 2008).

START I was a large industry-sponsored, randomised, open-label trial conducted in Puerto Rico and the United States of America that examined AZT+3TC+IDV and d4T+3TC+IDV in ART-naïve adults (Squires 2000). Its primary endpoints were suppression of viral replication to HIV-1 RNA <50 and <500 copies/mL at 24 and 48 weeks. 

AZT+3TC vs. d4T+ddI

For the AZT+3TC vs. d4T+ddI comparison, we identified 19 articles abstracts from six randomised controlled trials, including ACTG 384 and its sub-studies A5005s and A5152s (Dube 2004; Dube 2005; Dube 2007a; Dube 2007b; Gandhi 2006; Mulligan 2006; Robbins 2003 (EFV); Shafer 2003; Smeaton 2001; Torriani 2008), the GEMCEI study (Geijo Martinez 2006), OzCombo 2 (Amin 2003; French 2002; Hudson 1998), START II (Eron 1998a; Eron 1998b; Eron 2000; Squires 2000), and another study of enteric-coated ddI (Gathe 2002).

ACTG 384 and sub-studies A5005s and A5152s were a group of studies conducted in Italy and the United States of America and sponsored by the Instituto Superiore di Sanità and the National Institutes of Health (Smeaton 2001) The main study was a multicentre, partially blinded, factorial trial of NRTI therapies as sequential therapy (that is, with predetermined second-line regimens for use following virologic failure) with either NVP or EFV. We examined the pre-virologic failure arms, comparing AZT+3TC+EFV with d4T+ddI+EFV and AZT+3TC+NVP with d4T+ddI+NVP. The endpoints were virologic failure, defined as a decrease in HIV-1 RNA <10-fold by week 8 on therapy or an increase of >10-fold above a nadir of <200 copies/mL after week 24, and toxicity-related failure. Outcomes were measured through 144 weeks of follow up.  The main results paper is Robbins (Robbins 2003 (EFV); Gadhi (Gandhi 2006) reported on immunologic recovery, and Shafer (Shafer 2003) reported on efficacy of pre-planned second-line therapy. Other publications and presentations include studies on specific toxicities, including dyslipidaemias and fat redistribution (Dube 2004; Dube 2005; Dube 2007a; Dube 2007b; Mulligan 2006) and endothelial function (Torriani 2008).

Gathe and colleagues studies the use of once-daily enteric-coated ddI in a multicentre trial conducted in North America, South America, Europe, Russia, South Africa and Australia and sponsored by Bristol-Myers Squibb (Gathe 2002). The basic comparison involved AZT+3TC+NFV and d4T+enteric coated ddI+NFV. The main outcome variable was HIV-1 RNA <400 copies/mL and <50 copies/mL at 48 weeks.

Geijo Martinez (Geijo Martinez 2006) and colleagues conducted a four-arm study that compared two NRTI backbones, AZT+3TC and d4T+ddI, and two protease inhibitors, IDV and ritonvair (RTV), in combination in ART-naïve patients. The study was conducted in Spain and funded by local government. The primary endpoint was decline in HIV-1 RNA compared to baseline, and the follow-up period was 48 weeks.

OzCombo 2 was a randomised, open-label, three-arm study that examined three NRTI backbones (AZT+3TC, d4T+3TC and d4T+ddI) in combination with NVP among ART-naïve adults. It was conducted in Australia and primarily funded by the Australian National Council and AIDS and Related Diseases.  Patients were followed for 52 weeks, and the primary endpoints were time to full viral suppression (HIV-1 RNA <50 copies/mL) and the proportion of patients with drug toxicities sufficiently severe to warrant dose adjustment or change. The primary results are found in French (French 2002 (1 vs 2). Hudson 1998 (Hudson 1998) is conference presentation of initial data from OzCombo 1 and 2, and Amin (Amin 2003) is a follow-up study of patients enrolled in OzCombo 1 and OzCombo 2.

START II was a multicentre, randomised, open-label study that compared AZT+3TC+IDV with d4T+ddI+IDV in ART-naïve patients in Puerto Rico and the United States of America. The study was sponsored by Bristol-Myers-Squibb. The primary endpoints were HIV-1 RNA <50 copies/mL and <500 copies/mL and changes in CD4 cell counts at 48 weeks. The primary results are found in Eron 2000 (Eron 2000); two conference abstracts presented preliminary results (Eron 1998b; Eron 1998b), and Squires (Squires 2000) examined differences in response by gender from both START studies.

 

Excluded studies

We excluded data from Shlay 2008 (Shlay 2008) because the investigators focused solely on subcutaneous fat thickness as its sole outcome, as this was not a key outcome for this study.

We excluded Bussman 2009 (Bussmann 2009) since the investigators reported only comparison between the AZT+ddI arms and the combined AZT+3TC and d4T+3TC arms to isolate the effect of ddI vs. 3TC.

We excluded Negredo 2004 (Negredo 2004) since this study compared different NRTI backbones (AZT+3TC vs. d4T+ddI) and two different third drugs (EFV vs. NFV) at same time.

We excluded Nieuwkirk 2001 (Nieuwkirk 2001) because the investigators did not differentiate among NRTI backbones (compared standard triple therapy with treatment intensification) and induction-maintenance regimens with endpoint of QOL, presumably related to pill burden.        

We excluded Rockstroh 2001 (Rockstroh 2000) because the investigators studied 4-drug combinations (high dose ritonavir + indinavir + 3 double NRTI backbones) compared to 3-drug combinations.

We excluded Shafer 2003 (Shafer 2003) because the investigators compared 4-drug combinations to 3-drug combinations for ART.

 

Risk of bias in included studies

The following information applies to the nine included randomised trials (Figure 2; Figure 3).

 FigureFigure 2. Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
 FigureFigure 3. Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

 

Allocation

Generation of allocation sequence

All nine studies reported randomly generating allocation sequences.

Allocation concealment

None of the nine studies reported allocation concealment.

 

Blinding

All the studies except Robbins 2003 (Robbins 2003 (EFV)) were open-label; this study blinded the EFV and NFV components of the study but not the AZT vs. d4T components.

 

Incomplete outcome data

All studies reported on all patients randomised. None of the nine studies reported on all key outcomes of interest for this study. Mortality was not reported by Carr 2000 (Carr 2000 (1 vs 2) or Geijo Martinez 2006 (Geijo Martinez 2006). Kumar 2006 (Kumar 2006) did not report clinical progression, and acquired drug resistance was reported only by Kumar 2006 (Kumar 2006).

 

Selective reporting

There was no evidence of selective reporting, per our search of clinical trial protocols at www.clinicaltrials.gov.

 

Other potential sources of bias

Kumar 2006 (Kumar 2006) and Squires 2000 (Squires 2000) were funded by GlaxoSmithKline and Bristol-Myers Squibb, respectively. All other studies were funded from governmental sources.

 

Effects of interventions

See:  Summary of findings for the main comparison d4T compared to AZT for initial treatment of HIV infection in antiretroviral-naive individuals

ACTG 384 and its sub-studies A5005s and A5152s randomised 620 patients into four arms: AZT+3TC+EFV, d4T+ddI+EFV, AZT+3TC+NFV and d4T+ddI+NFV, allowing for direct comparison between AZT+3TC and d4T+ddI with both an NNRTI and a protease inhibitor (Robbins 2003 (EFV)). Six patients died, and 20 progressed clinically in the trial, although it was not reported in which treatment arm these events occurred. Among patients receiving EFV, 63/155 (41%) in the AZT+3TC failed to reach viral suppression at 144 weeks compared to 58/155 (37.4%) in the d4T+ddI arm. Ninety-four (60.6%) in the AZT+3TC arm remained on their original regimen at 144 weeks compared to 60 (38.7%) in the d4T+ddI arm. Among patients receiving NFV, 20 (12.9%) of 155 maintained viral suppression at 144 weeks in the AZT+3TC arm compared to 49 (31.6%) of 155 in the d4T+ddI arm. Sixty-four (41.3%) in the AZT+3TC arm remained on their original regimen compared to 49 (31.6%) of 155 in the d4T+ddI arm. No significant differences were reported in immunologic recovery across the four arms. In examining time to a grade 3 or 4 adverse event, the initial use of AZT+3TC delayed occurrence of the first serious toxic effect and the occurrence of the first symptom or diagnosis of peripheral neuropathy compared to d4T+ddI (p<0.001 for both).

ESS4002 was an industry-sponsored study that randomised 261 patients into three arms, including AZT+3TC+ABC, AZT+3TC+NFV and d4T+3TC+NFV (Kumar 2006). This analysis is restricted to the latter two arms. At 96 weeks there had been no deaths; clinical progression and grade 3/4 adverse events were not reported. Fifty-seven (62.6%) of 91 in the AZT+3TC+NFV arm failed to achieve viral suppression, as measured by HIV-1 RNA <50 copies/mL, compared to 56 (67.5%) of 83 in the d4T+3TC+NFV arm. CD4 cell counts increased by an average of 270 cells/µL in the AZT+3TC+NFV arm and 289 in the d4T+3TC+NFV arm, and there were 10 acquired mutations in the AZT arm than in the d4T arm. The principal comparison of interest for the authors was comparing risk of dyslipidaemia and adherence in the AZT+3TC+ABC (Trizivir®) arm compared to the other two, for both which it was superior.

Gathe (2002) and colleagues studied the equivalency of once-daily enteric-coated ddI in a trial that compared AZT+3TC+NFV and d4T+enteric coated ddI+NFV in patients with >200 CD4 cells/µL. They randomised 511 ART-naïve patients into the two arms and followed them for 48 weeks (Geijo Martinez 2006). The proportion that did not achieve HIV-1 RNA <400 copies/mL was 45% in both treatment arms and the proportion that did not achieve HIV-1 RNA <50 copies/mL was 68% in both arms. There was a mean increase in CD4 cells of 189 cells/µL in the AZT+3TC arm compared to 157 cells/µL in the d4T+ddI arm (p=NS). Grade 3/4 adverse events occurred in 8% of the AZT+3TC arm and 13% of the d4T+ddI arm.

The GEMCEI study randomised 84 patients into four arms: AZT+3TC+IDV, d4T+ddI+IDV, AZT+3TC+RTV and d4T+ddI+RTV (Geijo Martinez 2006). Deaths were not reported, but four patients progressed clinically in the two AZT+3TC arms compared to three in the two d4T+ddI arms. At 48 weeks, viral load was still detectable (HIV-1 RNA <400 copies/mL) in 29 (69%) of 42 in the two AZT+3TC arms compared to 25 (59.5%) of 42 in the two d4T+ddI arms. Fifteen (34.1%) of 44 remained on their assigned regimens at the completion of the trial in the two AZT+3TC arms compared to 17 (40.4%) of 42 in the two d4T+ddI arms.  Sixteen (36.4%) discontinued therapy because of adverse events in the two AZT+3TC arms compared to 12 (28.6%) in the d4T+3TC arms.

Li (2008) randomised 198 patients with 100-300 CD4 cells/µL into three arms, AZT+ddI, AZT+3TC and d4T+3TC, all in combination with NVP. For this study, we focused on the comparison between AZT+3TC and d4T+3TC. At 52 weeks, the proportion of patients failing to achieve HIV-1 RNA <50 copies/mL was 31.3% in those receiving AZT+3TC and 31.9% in those receiving d4T+3TC. One patient on AZT+3TC and none on d4T+3TC acquired antiretroviral resistance. Hepatotoxicity was common (20%) and was associated with HCV infection and CD4 counts >250 cells/µL (Li 2008).

OzCombo 1 randomised 106 patients into three arms, including AZT+3TC, d4T+3TC and d4T+ddI, all with IDV (Carr 2000 (1 vs 2); Carr 2000 (1 vs 3)). At 52 weeks, one patient in each arm had progressed clinically. The proportion of patients that did not achieve HIV-1 RNA <50 copies/mL were 34.3% in the AZT+3TC arm, 41.2% in the d4T+3TC arm and 51.3% in the d4T+ddI arm (p=0.34). Fifty-four percent in the AZT+3TC arm completed the study on their original regimen compared to 58.8% in the d4T+3TC arm and 35.1% in the d4T+ddI arm (p=0.18). CD4 cell counts increased most in the d4T+3TC arm (+237 cells/µL) compared to the AZT+3TC arm (+175 cells/µL) and the d4+ddI arm (+176 cells/µL). No data were presented on mortality or acquired resistance.

OzCombo 2 randomised 65 patients into three arms: AZT+3TC+NVP, d4T+3TC+NVP and d4T+ddI+NVP (French 2002). There were no deaths and no cases of clinical progression in any of the arms. Six (30%) of 20 patients in the AZT+3TC arm did not have viral suppression at 52 weeks as measured by HIV-1 RNA <50 copies/mL, compared to seven (31.8%) of 22 in the d4T+3TC arm and 3 (13%) 23 in the d4T+ddI arm (p=NS). Eighty percent of patients in the AZT+3TC arm completed 52 weeks of assigned therapy, compared to 76% in the d4T+3TC arm and 70% in the d4T+ddI arm. Mean increases in CD4 counts were 172 cells/µL, 201 cells/µL and 190 cells/µL, respectively. Four (20%) patients in the AZT+3TC arm had severe adverse events, compared to 8 (36%) in the d4T+3TC arm and 7 (30%) in the d4T+ddI arm. Five (11%) of the 45 patients in the d4T-containing arms experienced peripheral neuropathy compared to none in the AZT+3TC arm.

START I was an industry-sponsored study that randomised 205 patients into two arms, AZT+3TC+IDV and d4T+3TC+IDV (Squires 2000). There were two deaths in the d4T arm and a single clinical progression both treatment arms. At 48 weeks, 61 (61.1%) of 103 patients in the AZT arm had failed to surpress viral replication as measured by HIV-1 RNA <50 copies/mL compared to 51/102 (50%) in the d4T arm. Sixty-four (63.4%) patients in the AZT arm completed the trial on their originally assigned regimen compared to 58 (56.3%) in the d4T arm. The median CD4 cell count increase from baseline was 198 in the AZT arm and 227 in the d4T arm. Eight (7.7%) of 103 patients that received study drugs in the AZT arm had grade 3/4 clinical toxicity, compared to eight (7.8%) of the 102 patients in the d4T arm. There were no data presented on drug resistance.

START II randomised 204 patients with CD4 cell counts <200 cells/µL to AZT+3TC+IDV and d4T+ddI+IDV (Eron 2000). One patient died in the d4T+ddI arm; clinical progression was not reported. Fifty-two percent of patients in the AZT+3TC arm did not have HIV-1 RNA <50 copies/mL at 48 weeks, compared to 44% in the d4T+ddI group (p>0.2). There was a significantly greater increase in CD4 cell counts from baseline in the d4T+ddI arm (+214 cells/µL) than in the AZT+3TC arm (+142 cells/µL, p=0.026). Sixty-eight (66%) of 103 in the AZT+3TC arm completed the trial on their assigned treatment compared to 64 (63%) in the d4T+ddI arm. Twenty-two (21.3%) grade 3/4 adverse events occurred in the AZT+3TC arm, compared to 30 (29.7%) in the d4T+ddI arm.

Meta-analysis

Nine trials contributed to the meta-analysis ( Summary of findings for the main comparison; Figure 4; Figure 5; Figure 6;Figure 7; Figure 8;Figure 9; Figure 10). There were no differences between d4T- and AZT-containing regimens with respect to death (5/586 [0.9%] in the d4T arm vs. 3/593 [0.5%] in the AZT arm, Mantel-Haenzel random effects relative risk (RRMHRE) 1.36, 95% CI 0.34-.542 [6 studies]) (Figure 4), clinical progression (6/361 [1.7%] vs.8/358 [2.2%], RRMHRE 0.78, 95% CI 0.28-2.13 [7 studies]) (Figure 5), severe adverse events (169/685 [24.7%] vs. 137/678 [20.2%], RRMHRE 1.17, 95% CI 0.97-1.40 [7 studies]) (Figure 6), virologic response (466/1078 [43.2%] vs. 458/1079 [42.4%] , RRMHRE 1.03, 95% CI 0.88-1.05 [12 studies]) (Figure 7), adherence/tolerability/retention (591/1078 [54.8%] vs. 632/1079 [58.6%], RRMHRE 0.94, 95% CI 0.84-1.05 [12 studies]) (Figure 8) and immunologic response (768 in d4T arm vs. 769 in AZT arm, WMDRE 9.61, 95% -17.62-36.84 [10 studies]) (Figure 9). Only a single study (Kumar 2006) contributed data on acquired drug resistance, and the investigators found no relationship (RR 0.66, 95% CI 0.25-1.73) (Figure 10). No studies reported risk of transmission to sexual partners.

 FigureFigure 4. Forest plot of comparison: 1 d4T vs. AZT, outcome: 1.1 Mortality.
 FigureFigure 5. Forest plot of comparison: 1 d4T vs AZT, outcome: 1.2 Clinical response.
 FigureFigure 6. Forest plot of comparison: 1 d4T vs AZT, outcome: 1.3 Severe adverse events.
 FigureFigure 7. Forest plot of comparison: 1 d4T vs AZT, outcome: 1.4 Virologic response.
 FigureFigure 8. Forest plot of comparison: 1 d4T vs AZT, outcome: 1.5 Adherence/tolerability/retention.
 FigureFigure 9. Forest plot of comparison: 1 d4T vs AZT, outcome: 1.6 Immunologic response.
 FigureFigure 10. Forest plot of comparison: 1 d4T vs AZT, outcome: 1.7 Drug resistance.

No statistically significant heterogeneity was found for any of the key outcomes and we were unable to identify any randomised controlled trials that assessed the efficacy of d4T compared to AZT in 5-to-13 year old children, or in those with hepatitis B, hepatitis C, or tuberculosis.

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms
 

Summary of main results

Nine separate randomised controlled trials contributed to this literature. The nine trials enrolled 2,159 participants in nine different drug combinations. The multiplicity of combinations, including using 3TC as the second NRTI in some studies and ddI in others, and using ABC, EFV, NVP, IDV, NFV and RTV as the third drug make this a complex literature. However, laying aside the confounding that may accompany making comparisons across these various regimens, there is a reasonably robust literature to suggest that the regimens are roughly equivalent as no statistically significant differences were found between the two drug combinations. There was a non-significant trend towards d4T being slightly less tolerated compared to AZT (RRMHRE 1.17 in the meta-analysis for severe adverse events and RRMHRE 0.94 for maintenance of regimen to completion of study); moreover, d4T has a host of well-recognised side effects including mitochondrial toxicity and dyslipidaemia, while AZT is associated with anaemia making its use somewhat problematic in regions where anaemia from malaria, intestinal parasitoses and repeated pregnancies is common.

 

Overall completeness and applicability of evidence

These studies taken collectively suffer from a variety of limitations and the overall GRADE rating was very low. Five of the six studies were open-label, several studies compared AZT+3TC to d4T+ddI potentially obscuring the head-to-head comparison of AZT and d4T, and several others used protease inhibitors as a third drug, studying combinations that will not be widely available in the developing world. However, no differences were found in these studies between d4T and AZT in terms of clinical efficacy, virologic response, immunologic response, the incidence of severe adverse events or the proportion of participants that completed the study without regimen changes (data not shown), whether or not the second NRTI was FTC or ddI. While side effects have reported in patients taking d4T, and especially d4T+ddI (Laurent 2008; Njoroge 2009; Pazare 2008), these are infrequent enough to not reach statistical significance in comparison to AZT in trials of the magnitude included in this systematic review, which may be due to true equivalence or to type II error. These findings highlight the need for SAE registries, so that these data can be collected and quantified. Additionally, several of the studies were small, leading to imprecision and potential for type II error; only one study (which involved four arms) enrolled more than 300 patients, and few enrolled patients from the developing world.

Interestingly the most direct comparisons will likely come from the two ongoing studies in Africa, the Tshepo study in Botswana (Bussmann 2009) and the Optimizing Pediatric HIV-Treatments in Infants with Prophylactic Exposure to Nevirapine in Kenya. Both of these will provide direct comparisons of standard therapeutic combinations of AZT+3TC+NVP or EFV and d4T+3TC+NVP or EFZ. Additional analysis of the more recent large cohort studies from low- and middle-income countries may provide additional data to assess this comparison.

 

Quality of the evidence

GRADE

Based on the nine randomised controlled trials included in this review, the quality of evidence for all five critical outcomes and two important outcomes is low ( Summary of findings for the main comparison). This is due largely to design limitations such as seven of the eight studies were open-label studies, only three of the studies were conducted at least partly in developing country settings, there were indirect comparisons (e.g., comparing AZT+3TC to d4T+ddI, especially with protease inhibitors, which will not be widely available in low- and middle-income countries), many had small sample sizes, and there was industry funding in the four of the larger studies (Eron 2000; Gathe 2002; Kumar 2006; Squires 2000) which accounted for almost half of all patients randomised.

 

Potential biases in the review process

Biases in the review process were minimised by not limiting the search by language and by performing a comprehensive search of databases, conference proceedings, and contacting experts.

 

Agreements and disagreements with other studies or reviews

See discussion above.

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms

 

Implications for practice

While d4T and AZT appear to be clinically equivalent in the trial literature, there is a large literature about severe metabolic side effects with d4T (Laurent 2008; Njoroge 2009; Pazare 2008), and for this reason WHO has recently recommended against using d4T for first-line ART (WHO 2009a). Its use may evolve to be restricted to patients with severe anaemia who cannot tolerate AZT or in second-line therapy. Clinical and public health judgment will be needed to weigh the risks and benefits of d4T compared to AZT.

 
Implications for research

It is unlikely that d4T and AZT will be compared directly in future studies. Observational data will be important in differentiating safety, tolerability and how rapidly resistance emerges between the two compounds.

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms

We gratefully acknowledge the contributions of Nancy Santesso and Holger Schunemann for their consultation and technical expertise with GRADEPro and Grade Tables presented in this review. We would also like to thank Tara Horvath and Joy Oliver for their assistance with searches. We would like to thank Gail Kennedy, Eliza Humphreys, Larry Chang and Jamal Harris for their collaboration and support.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms
Download statistical data

 
Comparison 1. d4T vs. AZT

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mortality61179Risk Ratio (M-H, Random, 95% CI)1.36 [0.34, 5.42]

 2 Clinical progression7719Risk Ratio (M-H, Random, 95% CI)0.78 [0.28, 2.13]

 3 Severe adverse events91363Risk Ratio (M-H, Random, 95% CI)1.17 [0.97, 1.40]

 4 Virologic response122157Risk Ratio (M-H, Random, 95% CI)1.03 [0.88, 1.19]

 5 Adherence/tolerability/retention122157Risk Ratio (M-H, Random, 95% CI)0.94 [0.84, 1.05]

 6 Immunologic response101537Mean Difference (IV, Random, 95% CI)9.61 [-17.62, 36.84]

 7 Drug resistance1174Risk Ratio (M-H, Random, 95% CI)0.66 [0.25, 1.73]

8 Sexual transmission of HIV00Risk Ratio (M-H, Random, 95% CI)Not estimable

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms
 

Appendix 1. The Cochrane Collaboration tool for assessing risk of bias


DomainDescriptionReview authors' judgement

Sequence generation.Describe the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.Was the allocation sequence adequately generated?

Allocation concealment.Describe the method used to conceal the allocation sequence in sufficient detail to determine whether intervention allocations could have been foreseen in advance of, or during, enrolment.Was allocation adequately concealed?

Blinding of participants, personnel and outcome assessors Assessments should be made for each main outcome (or class of outcomes). Describe all measures used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. Provide any information relating to whether the intended blinding was effective.Was knowledge of the allocated intervention adequately prevented during the study?

Incomplete outcome data Assessments should be made for each main outcome (or class of outcomes). Describe the completeness of outcome data for each main outcome, including attrition and exclusions from the analysis. State whether attrition and exclusions were reported, the numbers in each intervention group (compared with total randomised participants), reasons for attrition/exclusions where reported, and any re-inclusions in analyses performed by the review authors.Were incomplete outcome data adequately addressed?

Selective outcome reporting.State how the possibility of selective outcome reporting was examined by the review authors, and what was found.Are reports of the study free of suggestion of selective outcome reporting?

Other sources of bias.State any important concerns about bias not addressed in the other domains in the tool.

If particular questions/entries were pre-specified in the review's protocol, responses should be provided for each question/entry.
Was the study apparently free of other problems that could put it at a high risk of bias?



 

Appendix 2. GRADE approach to assessing the quality of evidence across studies


Quality of Evidence

(summary score)
Study DesignDowngrading FactorsUpgrading Factors

High (4) = Further research is very unlikely to change our confidence in the estimate of effect.Randomized trials or valid accuracy studies for  diagnostic tests begin with a score of High (4)Study limitations:

-1 Serious

-2 Very serious

 

Consistency:

-1 Serious

-2 Very serious

 

Directness:

-1 Serious

-2 Very serious

 

Precision:

-1 Serious

-2 Very serious

 

Publication Bias

-1 Serious

-2 Very serious
Large effect

+1 Large

+2 Very Large

 

Plausible confounding would change the effect

+1

 

Dose-response gradient

+1 if Present

 

Moderate (3) = Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. 

Low (2) = Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.Observational studies or indirect accuracy studies for diagnostic tests begin with a score of low (2).

 

Very low (1) = Any estimate of effect is very uncertain. 



Note: We specifically considered whether evidence directly addressed low- and middle-income country settings in assessing quality of evidence. If the question being addressed only has evidence from high-resource settings, the quality of evidence will be downgraded by -1 for lack of directness.

 

Appendix 3. Characteristics of included studies, d4T vs. AZT


StudyDesignParticipantsInterventions

Carr 2000

OzCombo 1

Arm 1 vs. 2 and Arm 1 vs. 3
Randomised, open label, multicentre106 ART-naïve adults in Australia1. AZT+3TC+IDV

2. d4T+3TC+IDV

3. d4T+ddI+IDV

Eron 2000

START II
Randomised, open label, multicentre205 ART-naïve adults in USA and Puerto Rico1. AZT+3TC+IDV

2. d4T+ddI+IDV

French 2002

OzCombo 2

Arm 1 vs. 2 and Arm 1 vs. 3.
Randomised, open label, multicentre65 ART-naïve adults in Australia1. AZT+3TC+NVP

2. d4T+3TC+NVP

3. d4T+ddI+NVP

Gathe 2002Randomised, open label, multicentre511 ART-naïve adults with ?200 CD4 cells/µL in North America, Europe, South American, Russia, South Africa, Australia1. AZT+3TC+NFV

2. d4T+ddI (enteric coated)+NFV

Geijo Martínez 2006

GEMCEI

Arms 1+2 vs. Arms 3 +4
Randomised, open label, multicentre84 ART-naïve adults in Spain1. AZT+3TC+IDV

2. AZT+3TC+RTV

3. d4T+ddI+IDV

4. d4T+ddI+RTV

Kumar 2006

ESS40002

Arm 2 vs. 3
Phase IV, randomised, open-label parallel group261 ART-naïve adults in Dominican Republic, Guatemala, Panama, Puerto Rico, USA1. AZT+3TC+ABC

2. AZT+3TC+NFV

3. d4T+3TC+NFV

Li 2008

 
Randomised, open-label, multicentre198 ART-naïve adults in China1. AZT+ddI+NVP

2. 3TC+d4T+NVP

3. 3TC+AZT+NVP

Robbins 2003

ACTG 384

Arms 1 and 3 vs. Arms 2 and 4
Randomised, partially double-blinded, factorial, multicentre620 ART-naïve adults in Italy and USA1. AZT+3TC+NFV

2. d4T+ddI+NFV

3. AZT+3TC+EFV

4. d4T+ddI+EFV

Squires 2000

START I
Randomised, open-label, multicentre204 ART-naïve adults with >200 CD4 cells/µL in USA and Puerto Rico1. AZT+3TC+IDV

2. d4T+3TC+IDV



SAE, severe adverse events; SD, standard deviation

 

 

What's new

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms

Last assessed as up-to-date: 8 July 2009.


DateEventDescription

16 March 2011Review declared as stableThis review will not need to be updated.



 

History

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms

Review first published: Issue 8, 2010


DateEventDescription

6 January 2011Amendedamended sources of support



 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms

All authors contributed to the design and conduct of this study, as well as with manuscript drafting and submission.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms

None.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms
 

Internal sources

  • Cochrane HIV/AIDS Group, University of California, San Francisco, USA, Not specified, Not specified.

 

External sources

  • Centers for Disease Control and Prevention (CDC), USA.
    Cooperative Agreement #U2GPS001468, "Atlanta HQ UCSF Technical Assistance to Support the President's Emergency Plan for AIDS Relief" from the Centers for Disease Control and Prevention (CDC), with funds from National Center for HIV, Viral Hepatitis, STDs and TB Prevention (NCHSTP). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of CDC.
  • World Health Organization, Switzerland.
    World Health Organization #200106621, Systematic reviews and development of GRADE profiles, based on the new WHO GRC guidelines, for the "WHO Guidelines on antiretroviral therapy for HIV infection in adults and adolescents - 2009 revision."

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms

None.

 

Notes

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms

None.

References

References to studies included in this review

  1. Top of page
  2. AbstractResumen摘要Résumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Notes
  20. Characteristics of studies
  21. References to studies included in this review
  22. References to studies excluded from this review
  23. Additional references
Carr 2000 (1 vs 2) {published data only}
  • Carr A, Chuah J, Hudson J, French M, Hoy J, Law M, Sayer D, Emery S, Cooper DA. A randomised, open-label comparison of three highly active antiretroviral therapy regimens including two nucleoside analogues and indinavir for previously untreated HIV-1 infection: the OzCombo I study. AIDS 2000;14:1171-80.
Carr 2000 (1 vs 3) {published data only}
  • Carr A, Chuah J, Hudson J, French M, Hoy J, Law M, Sayer D, Emery S, Cooper DA. A randomised, open-label comparison of three highly active antiretroviral therapy regimens including two nucleoside analogues and indinavir for previously untreated HIV-1 infection: the OzCombo I study. AIDS 2000;14:1171-80.
Eron 2000 {published data only}
  • Eron JJ Jr, Murphy RL, Peterson D, Pottage J, Parenti DM, Jemsek J, Swindells S, Sepulveda G, Bellos N, Rashbaum BC, Esinhart J, Schoellkopf N, Grosso R, Stevens M. A comparison of stavudine, didanosine and indinavir with zidovudine, lamivudine and indinavir for the initial treatment of HIV-1 infected individuals: selection of thymidine analog regimen therapy (START II). AIDS 2000;14:1601-10.
French 2002 (1 vs 2) {published data only}
  • French M, Amin J, Roth N, Carr A, Law M, Emery S, Drummond F, Cooper D, OzCombo 2 investigators. Randomized, open-label, comparative trial to evaluate the efficacy and safety of three antiretroviral drug combinations including two nucleoside analogues and nevirapine for previously untreated HIV-1 Infection: the OzCombo 2 study. HIV Clin Trials 2002;3:177-85.
French 2002 (1 vs 3) {published data only}
  • French M, Amin J, Roth N, Carr A, Law M, Emery S, Drummond F, Cooper D, OzCombo 2 investigators. Randomized, open-label, comparative trial to evaluate the efficacy and safety of three antiretroviral drug combinations including two nucleoside analogues and nevirapine for previously untreated HIV-1 Infection: the OzCombo 2 study. HIV Clin Trials 2002;3:177-85.
Gathe 2002 {published data only}
  • Gathe J Jr, Badaro R, Grimwood A, Abrams L, Klesczewski K, Cross A, McLaren C. Antiviral activity of enteric-coated didanosine, stavudine, and nelfinavir versus zidovudine plus lamivudine and nelfinavir. J Acquir Immune Defic Syndr 2002;31:399-403.
Geijo Martinez 2006 {published data only}
  • Geijo Martínez MP, Maciá Martínez MA, Solera Santos J, Barberá Farré JR, Rodríguez Zapata M, Marcos Sánchez F, Martínez Alfaro E, Cuadra García-Tenorio F, Sanz Moreno J, Moreno Mendaña JM, Beato Pérez JL, Sanz Sanz J, GECMEI. Ensayo clínico comparativo de eficacia y seguridad de cuatro pautas de tratamiento antirretroviral de alta eficacia (TARGA) en pacientes con infección por VIH avanzada. Rev Clin Esp 2006; 206:67-76.. Rev Clin Esp 2006;206:67-76.
Kumar 2006 {published data only}
  • Kumar PN, Rodriguez-French A, Thompson MA, Tashima KT, Averitt D, Wannamaker PG, Williams VC, Shaefer MS, Pakes GE, Pappa KA, ESS40002 Study Team. A prospective, 96-week study of the impact of Trizivir, Combivir/nelfinavir and lamivudine/stavudine/nelfinavir on lipids, metabolic parameters and efficacy in antiretroviral-naïve patients: effect of sex and ethnicity. HIV Med 2006;7:85-98.
Li 2008 {published data only}
  • Li T, Dai Y, Kuang J, Jiang J, Han Y, Qiu Z, Xie J, Zuo L, Li Y. Three generic nevirapine-based antiretroviral treatments in Chinese HIV/AIDS patients: multicentric observation cohort. PLoS One 2008;3:e3918.
Robbins 2003 (EFV) {published data only}
  • Robbins GK, De Gruttola V, Shafer RW, Smeaton LM, Snyder SW, Pettinelli C, Dubé MP, Fischl MA, Pollard RB, Delapenha R, Gedeon L, van der Horst C, Murphy RL, Becker MI, D'Aquila RT, Vella S, Merigan TC, Hirsch MS, AIDS Clinical Trials Group 384 Team. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 2003;349:2293-202.
Robbins 2003 (NFV) {published data only}
  • Robbins GK, De Gruttola V, Shafer RW, Smeaton LM, Snyder SW, Pettinelli C, Dubé MP, Fischl MA, Pollard RB, Delapenha R, Gedeon L, van der Horst C, Murphy RL, Becker MI, D'Aquila RT, Vella S, Merigan TC, Hirsch MS, AIDS Clinical Trials Group 384 Team. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 2003;349:2293-303.
Squires 2000 {published data only}
  • Squires KE, Gulick R, Tebas P, Santana J, Mulanovich V, Clark R, Yangco B, Marlowe SI, Wright D, Cohen C, Cooley T, Mauney J, Uffelman K, Schoellkopf N, Grosso R, Stevens M. A comparison of stavudine plus lamivudine versus zidovudine plus lamivudine in combination with indinavir in antiretroviral naive individuals with HIV infection: selection of thymidine analog regimen therapy (START I). AIDS 2000;14:1591-600.

References to studies excluded from this review

  1. Top of page
  2. AbstractResumen摘要Résumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Notes
  20. Characteristics of studies
  21. References to studies included in this review
  22. References to studies excluded from this review
  23. Additional references
Bussmann 2009 {published data only}
  • Bussmann H, Wester CW, Thomas A, Novitsky V, Okezie R, Muzenda T, Gaolathe T, Ndwapi N, Mawoko N, Widenfelt E, Moyo S, Musonda R, Mine M, Makhema J, Moffat H, Essex M, Degruttola V, Marlink RG. Response to zidovudine/didanosine-containing combination antiretroviral therapy among HIV-1 subtype C-infected adults in Botswana: two-year outcomes from a randomized clinical trial. J Acquir Immune Defic Syndr 2009;51:37-46.
Negredo 2004 {published data only}
  • Negredo E, Paredes R, Peroire J, Pedrol E, Côte H, Gel S, Fumaz CR, Ruiz L, Abril V, Rodriguez de Castrol E, Ochoa C, Martinez-Picado J, Montaner J, Rey-Joly C, Clotet B, Swatch Study Team. Alteration of antiretroviral drug regimens for HIV infection. Efficacy, safety and tolerability at week 96 of the Swatch Study. Antiviral Ther 2004;9:889-93.
Nieuwkirk 2001 {published data only}
  • Nieuwkirk PT, Gisolf EH, Reijers  MF, Lange JMA, Sanner SA, Sprangers MAG, NATIVE, PROMETHEUS and ADAM study groups. Long-term quality of life outcomes in three antiretroviral treatment strategies for HIV-1 infection. AIDS 2001;15:1985-93.
Rockstroh 2000 {published data only}
  • Rockstroh JK, Bergman F, Wiesl W, Rieke A, Theisen A, Fätkenheur G, Oettter M, Carls H, Fenske S, Nadler M, Knechten H, German Ritonavir/Indinavir Study Group. Efficacy and safety of twice daily first-line ritonavir/indinavir plus double nucleoside combination therapy in HIV-infected individuals. AIDS 2000;14:1181-85.
Shafer 2003 {published data only}
  • Shafer RW, Smeaton LM, Robbins GK, De Gruttola V, Snyder SW, D'Aquila RT, Johnson VA, Morse GD, Nokta MA, Martinez AI, Gripshover MB, Kaul P, Haubrich R, Swingle M, McCarty SD, Vella S, Hirsch MS, Merigan TC, AIDS Clinical Trials Group 384 Team. Comparison of four-drug regimens and pairs of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 2003;349:2304-15.
Shlay 2008 {published data only}
  • Shlay JC, Sharma S, Peng G, Gibert CL, Grunfeld C, Terry Beirn Community Programs for Clinical Research in AIDS, International Network for Strategic Initiatives in Global HIV Trials. Long-term subcutaneous tissue changes among antiretroviral-naive persons initiating stavudine, zidovudine, or abacavir with lamivudine. J Acquir Immune Defic Syndr 2008;48:53-62.

Additional references

  1. Top of page
  2. AbstractResumen摘要Résumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Notes
  20. Characteristics of studies
  21. References to studies included in this review
  22. References to studies excluded from this review
  23. Additional references
Amin 2003
  • Amin J, Moore A, Carr A, French MA, Law M, Emery S, Cooper DA, OzCombo 1 and 2 Investigators. Combined analysis of two-year follow-up from two open-label randomized trials comparing efficacy of three nucleoside reverse transcriptase inhibitor backbones for previously untreated HIV-1 infection: OzCombo 1 and 2. HIV Clin Trials 2003;4:252-61.
Bendavid 2009
Carr 1999a
  • Carr A, Hudson J, Chuah J, Law M, Hoy J. French MA, Emery S, Cooper D. The OzCombo 1 study: a randomised trial of combination antiretroviral therapy (ART) in treatment naive patients [Abstract OR102]. Australasian Society for HIV Medicine Conference, Perth, Australia, 9-11 December 1999.
Carr 1999b
  • Carr A, Hudson J, Hoy J, Chuah J, French M. OzCombo I: control of HIV replication in treatment naive patients in a randomised trial of HAART [Abstract 633]. Conference on Retroviruses and Opportunistic Infections, Boston, USA, 31 January-4 February 1999.
Division of AIDS 2009
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Dube 2004
  • Dubé M, Zackin R, Parker R, Yang Y, Grinspoon S, Tebas P, Robbins G, Shafer R, Snyder S, Mulligan K.  Prospective study of glucose and lipid metabolism in antiretroviral-naive subjects randomized to receive nelfinavir, efavirenz, or Both Combined with zidovudine+lamivudine (ZDV+3TC) or didanosine+stavudine: A5005s, a substudy of ACTG 384 [Abstract 74]. 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, USA, 8-11 February 2004.
Dube 2005
  • Dubé MP, Parker RA, Tebas P, Grinspoon SK, Zackin RA, Robbins GK, Roubenoff R, Shafer RW, Wininger DA, Meyer WA 3rd, Snyder SW, Mulligan K. Glucose metabolism, lipid, and body fat changes in antiretroviral-naive subjects randomized to nelfinavir or efavirenz plus dual nucleosides. AIDS 2005;19:1807-18.
Dube 2007a
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Dube 2007b
  • Dubé MP, Parker MA, Mulligan K, Tebas P, Robbins GK, Roubenoff R, Ginspoon SK. Effects of potent antiretroviral therapy on free testosterone levels and fat-free mass in men in a prospective, randomized trail: A5005s, a substudy of AIDS Clinical Trials Group 384. Clin Infect Dis 2007;45:120-6.
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  • Eron J, Peterson D, Murphy R, Jemsek J, Pottage J, Parenti D, Esinhart J, Schoellkopf N, Stevens M. An open-label, randomized, comparative study of d4T + ddI + IDV versus ZDV + 3TC + IDV in treatment naive HIV  infected patients, START II [Abstract 381]. 5thConference on Retroviruses, Opportunistic Infections. Chicago, USA, 1-5 February 1998.
Eron 1998b
  • Eron J, Peterson D, Murphy R, Pottage J, Mauney J, Schoellkoph N, Stevens M. An open-label, randomized, comparative study of d4T + ddI + IDV versus ZDV + 3TC + IDV in treatment naive  HIV-infected patients (START II) [Abstract 12225]. International Conference on AIDS, Geneva, Switzerland, 28 June-3 July 1998.
Eron 2000
  • Eron JJ Jr, Murphy RL, Peterson D, Pottage J, Parenti DM, Jemsek J, Swindells S, Sepulveda G, Bellos N, Rashbaum BC, Esinhart J, Schoellkopf N, Grosso R, Stevens M. A comparison of stavudine, didanosine and indinavir with zidovudine, lamivudine and indinavir for the initial treatment of HIV-1 infected individuals: selection of thymidine analog regimen therapy (START II). AIDS 2000;14:1601-10.
French 2002
  • French M, Amin J, Roth N, Carr A, Law M, Emery S, Drummond F, Cooper D, OzCombo 2 investigators. Randomized, open-label, comparative trial to evaluate the efficacy and safety of three antiretroviral drug combinations including two nucleoside analogues and nevirapine for previously untreated HIV-1 Infection: the OzCombo 2 study. HIV Clin Trials 2002;3:177-85.
Gandhi 2006
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Kumar 2003
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Kumar 2004
  • Kumar P, Williams V, Tahima K, Rodriquez-French A, Thompson M, Wannamaker P, Hernandez J, Pappa K. Determinants of hyperlipidemia in ART-naive subjects treated with trizivir, combivir/nelfinavir, or stavudine/lamivudine  [Abstract 713]. 11thConference on Retroviruses, Opportunistic Infections. San Francisco, USA, 8-11 February 2004.
Laurent 2008
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Pavia 2002
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Smeaton 2001
Squires 1998
  • Squires K, Gulick R, Santana J, Powderly W, Esinhart J, Schoellkopf N, Stevens M. An open-label, randomized, comparative study of d4T+3TC+IDV versus ZDV+3TC+IDV in treatment naive HIV-infected patients. START I [Abstract 380]. 5th Conference on Retroviruses and Opportunistic Infections, Chicago, USA, 1-5 February 1998.
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