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Original Research |

Atazanavir Plus Ritonavir or Efavirenz as Part of a 3-Drug Regimen for Initial Treatment of HIV-1: A Randomized Trial FREE

Eric S. Daar, MD; Camlin Tierney, PhD; Margaret A. Fischl, MD; Paul E. Sax, MD; Katie Mollan, MS; Chakra Budhathoki, PhD; Catherine Godfrey, MD; Nasreen C. Jahed, MPH; Laurie Myers, MS; David Katzenstein, MD; Awny Farajallah, MD; James F. Rooney, MD; Keith A. Pappa, PharmD; William C. Woodward, DO; Kristine Patterson, MD; Hector Bolivar, MD; Constance A. Benson, MD; Ann C. Collier, MD, for the AIDS Clinical Trials Group Study A5202 Team
[+] Article and Author Information

Participating centers and individuals are listed in the Appendix.


From Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center and the University of California, Los Angeles, Los Angeles, California; Harvard School of Public Health, Boston, Massachusetts; University of Miami School of Medicine, Miami, Florida; Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; National Institute of Allergy and Infectious Diseases, Bethesda, Maryland; Social & Scientific Systems, Silver Spring, Maryland; Frontier Science & Technology Research Foundation, Amherst, New York; Stanford University, Palo Alto, California; Bristol-Myers Squibb, Plainsboro, New Jersey; Gilead Sciences, Foster City, California; GlaxoSmithKline, Research Triangle Park, North Carolina; Abbott Laboratories, Abbott Park, Illinois; University of North Carolina, Chapel Hill, North Carolina; University of California, San Diego, San Diego, California; and University of Washington and Harborview Medical Center, Seattle, Washington.


Portions of this study were presented at the 17th Conference on Retroviruses and Opportunistic Infections, San Francisco, California, 16–19 February 2010.

Note: The human subjects committees of all sites approved the study A5202 protocol, and written informed consent was obtained from all participants in adherence to the human experimentation guidelines of the U.S. Department of Health and Human Services.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health.

Acknowledgment: The authors thank the patients for their participation in this study. Abbott Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, and GlaxoSmithKline provided the study medications.

Grant Support: By award U01AI068636 from the National Institute of Allergy and Infectious Diseases, along with the previous grant for the AIDS Clinical Trials Group Central Group (AI38858) and the Statistical Data Management Center grants (AI38855 and AI68634). The study was supported in part by the General Clinical Research Center Units, funded by the National Center for Research Resources.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-1780.

Reproducible Research Statement:Study protocol, statistical code, and data set: Available through written agreement with the Division of AIDS.

Requests for Single Reprints: Eric S. Daar, MD, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 West Carson Street, N-24, Torrance, CA 90502; e-mail, EDaar@LABioMed.org.

Current Author Addresses: Dr. Daar: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 West Carson Street, N-24, Torrance, CA 90502.

Dr. Tierney: Harvard School of Public Health, FXB Building, Room 611, 651 Huntington Avenue, Boston, MA 02115-6017.

Drs. Fischl and Bolivar: University of Miami, 1800 Northwest 10th Avenue, Miami, FL 33136.

Dr. Sax: Brigham and Women's Hospital, 75 Francis Street, PBBA4, Boston, MA 02115.

Ms. Mollan: Harvard School of Public Health, FXB Building, Room 619, 651 Huntington Avenue, Boston, MA 02115.

Dr. Budhathoki: Harvard School of Public Health, FXB Building, Room 604C, 651 Huntington Avenue, Boston, MA 02115.

Dr. Godfrey: National Institutes of Health, Division of Acquired Immunodeficiency Syndrome, HIV Research Branch, 6700-B Rockledge Drive, MSC 7624, Bethesda, MD 20892-7624.

Mr. Jahed: Social & Scientific Systems, 8757 Georgia Avenue, 12th Floor, Silver Spring, MD 20910-3714.

Ms. Myers: Frontier Science & Technology Research Foundation, 4033 Maple Road, Amherst, NY 14226-1056.

Dr. Katzenstein: Stanford University, Center for AIDS Research, Division of Infectious Disease, S156, 300 Pasteur Drive, Stanford, CA 94305-5107.

Dr. Farajallah: Bristol-Myers Squibb Pharmaceutical Company, U.S. Pharmaceuticals, Virology Medical Affairs, 777 Scudders Mill Road, Room 1006, Plainsboro, NJ 08536.

Dr. Rooney: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404.

Dr. Pappa: GlaxoSmithKline, Infectious Diseases Medicine Development Center, North America HIV Collaborative Studies, 5 Moore Drive, PO Box 13398, Research Triangle Park, NC 27709-3398.

Dr. Woodward: Abbott Laboratories, Antiviral Global Project Team, 21 Pacific Avenue, Sinking Spring, PA 19608.

Dr. Patterson: Wake County Health and Human Services Clinical Research Site, Medicine-Infectious Diseases, 130 Mason Farm Road, Suite 2100, Bioinformatics Building, Chapel Hill, NC 27599-7215.

Dr. Benson: University of California, San Diego, Division of Infectious Diseases, 200 West Arbor Drive, Mail Code #8208, San Diego, CA 92103-8208.

Dr. Collier: University of Washington, Harborview Medical Center, Box 359929, 325 9th Avenue, Seattle, WA 98104.

Author Contributions: Conception and design: E.S. Daar, C. Tierney, M.A. Fischl, P.E. Sax, C. Godfrey, N.C. Jahed, D. Katzenstein, J.F. Rooney, K.A. Pappa, W.C. Woodward, A.C. Collier.

Analysis and interpretation of the data: E.S. Daar, C. Tierney, M.A. Fischl, P.E. Sax, K. Mollan, C. Budhathoki, C. Godfrey, D. Katzenstein, A. Farajallah, J.F. Rooney, K.A. Pappa, W.C. Woodward, C.A. Benson, A.C. Collier.

Drafting of the article: E.S. Daar, C. Tierney, M.A. Fischl, P.E. Sax, C. Budhathoki, C. Godfrey, N.C. Jahed, J.F. Rooney, C.A. Benson.

Critical revision of the article for important intellectual content: E.S. Daar, C. Tierney, M.A. Fischl, P.E. Sax, C. Budhathoki, C. Godfrey, N.C. Jahed, L. Myers, A. Farajallah, J.F. Rooney, K.A. Pappa, W.C. Woodward, K. Patterson, H. Bolivar, C.A. Benson, A.C. Collier.

Final approval of the article: E.S. Daar, C. Tierney, M.A. Fischl, P.E. Sax, C. Godfrey, N.C. Jahed, L. Myers, D. Katzenstein, A. Farajallah, J.F. Rooney, K.A. Pappa, W.C. Woodward, K. Patterson, H. Bolivar, C.A. Benson, A.C. Collier.

Provision of study materials or patients: E.S. Daar, M.A. Fischl, P.E. Sax, A. Farajallah, J.F. Rooney, K.A. Pappa, K. Patterson, H. Bolivar, C.A. Benson, A.C. Collier.

Statistical expertise: C. Tierney, K. Mollan, C. Budhathoki, J.F. Rooney, K. Patterson.

Obtaining of funding: E.S. Daar, D. Katzenstein, J.F. Rooney, W.C. Woodward, C.A. Benson.

Administrative, technical, or logistic support: C. Godfrey, N.C. Jahed, L. Myers, D. Katzenstein, J.F. Rooney, C.A. Benson.

Collection and assembly of data: E.S. Daar, M.A. Fischl, P.E. Sax, L. Myers, D. Katzenstein, J.F. Rooney, H. Bolivar, C.A. Benson, A.C. Collier.


Ann Intern Med. 2011;154(7):445-456. doi:10.7326/0003-4819-154-7-201104050-00316
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Background: Limited data compare once-daily options for initial therapy for HIV-1.

Objective: To compare time to virologic failure; first grade-3 or -4 sign, symptom, or laboratory abnormality (safety); and change or discontinuation of regimen (tolerability) for atazanavir plus ritonavir with efavirenz-containing initial therapy for HIV-1.

Design: A randomized equivalence trial accrued from September 2005 to November 2007, with median follow-up of 138 weeks. Regimens were assigned by using a central computer, stratified by screening HIV-1 RNA level less than 100 000 copies/mL or 100 000 copies/mL or greater; blinding was known only to the site pharmacist. (ClinicalTrials.gov registration number: NCT00118898)

Setting: 59 AIDS Clinical Trials Group sites in the United States and Puerto Rico.

Patients: Antiretroviral-naive patients.

Intervention: Open-label atazanavir plus ritonavir or efavirenz, each given with with placebo-controlled abacavir–lamivudine or tenofovir disoproxil fumarate (DF)–emtricitabine.

Measurements: Primary outcomes were time to virologic failure, safety, and tolerability events. Secondary end points included proportion of patients with HIV-1 RNA level less than 50 copies/mL, emergence of drug resistance, changes in CD4 cell counts, calculated creatinine clearance, and lipid levels.

Results: 463 eligible patients were randomly assigned to receive atazanavir plus ritonavir and 465 were assigned to receive efavirenz, both with abacavir–lamivudine; 322 (70%) and 324 (70%), respectively, completed follow-up. The respective numbers of participants in each group who received tenofovir DF–emtricitabine were 465 and 464; 342 (74%) and 343 (74%) completed follow-up. Primary efficacy was similar in the group that received atazanavir plus ritonavir and and the group that received efavirenz and did not differ according to whether abacavir–lamivudine or tenofovir DF–emtricitabine was also given. Hazard ratios for time to virologic failure were 1.13 (95% CI, 0.82 to 1.56) and 1.01 (CI, 0.70 to 1.46), respectively, although CIs did not meet prespecified criteria for equivalence. The time to safety (P = 0.048) and tolerability (P < 0.001) events was longer in persons given atazanavir plus ritonavir than in those given efavirenz with abacavir–lamivudine but not with tenofovir DF–emtricitabine.

Limitations: Neither HLA-B*5701 nor resistance testing was the standard of care when A5202 enrolled patients. The third drugs, atazanavir plus ritonavir and efavirenz, were open-label; the nucleoside reverse transcriptase inhibitors were prematurely unblinded in the high viral load stratum; and 32% of patients modified or discontinued treatment with their third drug.

Conclusion: Atazanavir plus ritonavir and efavirenz have similar antiviral activity when used with abacavir–lamivudine or tenofovir DF–emtricitabine.

Primary Funding Source: National Institutes of Health.

Editors' Notes
Context

  • There are few comparisons of once-daily treatment regimens for HIV-1.

Contribution

  • This randomized trial in antiretroviral-naive patients with HIV-1 showed that a once-daily ritonavir-boosted protease inhibitor regimen had similar virologic efficacy to a once-daily efavirenz-based regimen when combined with either abacavir–lamivudine or tenofovir DF–emtricitabine. The ritonavir-boosted protease inhibitor regimen seemed to be safer and more tolerable than the efavirenz regimen when combined with abacavir–lamivudine but not when combined with tenofovir DF–emtricitabine.

Caution

  • Patients and their physicians knew who was receiving the ritonavir-boosted protease inhibitor and efavirenz-based regimens, and one third of the patients modified or discontinued their regimens.

—The Editors

Treatment guidelines for initial HIV-1 therapy recommend 2 nucleoside reverse transcriptase inhibitors (NRTIs) with a non-NRTI (NNRTI), ritonavir-boosted protease inhibitor, or integrase inhibitor (12). Abacavir–lamivudine and tenofovir disoproxil fumarate (DF)–emtricitabine are efficacious, once-daily NRTIs (35). The preferred NNRTI is efavirenz, and atazanavir plus ritonavir is 1 of the preferred protease inhibitors (1, 67).

AIDS Clinical Trials Group (ACTG) Study A5202 compared efficacy, safety, and tolerability of abacavir–lamivudine or tenofovir DF–emtricitabine with atazanavir plus ritonavir or efavirenz. After scheduled interim data review, the data and safety monitoring board noted inferior virologic efficacy of abacavir–lamivudine compared with tenofovir DF–emtricitabine among patients with HIV-1 RNA levels of 100 000 copies/mL or more at screening (8). We now report the final results of the primary study objectives comparing atazanavir plus ritonavir against efavirenz.

Design

Study A5202 was a phase 3b, randomized equivalence study of 4 regimens for initial treatment of HIV-1. The study enrolled participants from September 2005 to November 2007. Median (25th, 75th percentile) follow-up was 138 weeks (106 weeks, 169 weeks), with the last patients followed until November 2009. The protocol was amended in July 2006 to exclude patients with chronic hepatitis B infection because of new treatment guidelines. In February 2008, the data safety monitoring board of the National Institute of Allergy and Infectious Diseases Division of AIDS recommended that persons with screening HIV-1 RNA levels of 100 000 copies/mL or more be unblinded (8). Human subjects committees of all sites approved the protocol, and informed consent was obtained from all participants.

Setting and Participants

Fifty-nine ACTG sites in the United States and Puerto Rico enrolled patients aged 16 years or older with HIV-1 who had had, at most, 7 days of previous antiretroviral therapy. Patients were recruited from local clinics and excluded if they were pregnant or breastfeeding; were using immunomodulators; had any known allergies to the study drugs; abused substances that would interfere with the study; had a serious illness; had an important cardiac conduction disorder; required prohibited medications; showed evidence of major resistance mutations; were incarcerated; or, as of July 2006, had hepatitis B. Resistance testing was required for recently infected patients.

Randomization and Interventions

Patients were randomly assigned to receive open-label 300-mg atazanavir (Bristol-Myers Squibb, Plainsboro, New Jersey) plus 100-mg ritonavir (Abbott Laboratories, Abbott Park, Illinois) or 600-mg efavirenz (Bristol-Myers Squibb), along with placebo-controlled 600-mg abacavir–300-mg lamivudine (GlaxoSmithKline, Research Triangle Park, North Carolina) or 300-mg tenofovir DF–200-mg emtricitabine (Gilead Sciences, Gilead Sciences, Foster City, California). Randomization was stratified by HIV-1 RNA level (<100 000 copies/mL or ≥100 000 copies/mL) at screening and intent to participate in a metabolic substudy. Participants were randomly assigned through permuted blocks in a 1:1:1:1 ratio. Allocation used a centralized computer system, with assignment dynamically balanced by site. Balance was achieved by monitoring the total number of patients assigned to each study group by site and overriding assignments when imbalance would exceed a preset maximum. The NRTI treatment assignment was blinded to everyone except the site pharmacist. Unblinding occurred for patients in the high-screening viral load stratum (as a result of data safety monitoring board recommendations) and in persons with NRTI-related toxicity (suspected by the investigator) who had protocol-defined virologic failure or were enrolled with hepatitis B.

Outcomes and Follow-up

The primary efficacy end point was time from randomization to virologic failure (confirmed HIV-1 RNA level ≥1000 copies/mL at or after 16 weeks and before 24 weeks or ≥200 copies/mL at or after 24 weeks). The primary safety end point was time from treatment dispensation to first grade-3 or -4 sign, symptom, or laboratory abnormality (graded according to a toxicity rating scale developed by the Division of AIDS [version 1.0, December 2004]) at least 1 grade higher than at baseline, excluding unconjugated hyperbilirubinemia and creatine kinase. The primary tolerability end point was originally defined as time to change in assigned antiretroviral drugs. Study evaluations were done before entry; at entry; at weeks 4, 8, 16, and 24; and every 12 weeks thereafter regardless of treatment modifications. Adverse event reporting was done by local investigators in an open-ended manner, including study drug causality, at each visit. After screening, HIV-1 RNA measurement (Cobas Amplicor HIV-1 Monitor Test, version 1.5, Roche, Basel, Switzerland) was done at Johns Hopkins University. Planned and actual study duration was 96 weeks after enrollment of the last patient.

The ACTG Data Management Center oversaw the quality of completion of case report forms and computerized data. Monitors contracted by the National Institutes of Health visited all sites to review data. The data safety monitoring board reviewed study conduct and safety data at 2 planned annual reviews. Efficacy data were reviewed at the second review, and an additional safety and efficacy review was requested for 4 months later. Early stopping guidelines stated that a regimen would be considered inferior if the 99.95% 2-sided CI for the hazard ratio (HR) for virologic failure did not include 1.0.

Secondary outcomes included HIV-1 RNA level less than 50 copies/mL and change in CD4 cell count, calculated creatinine clearance, and fasting lipid levels. Emergence of a resistant virus was assessed by genotypic testing at Stanford University for all patients who met protocol-specified criteria for virologic failure and on their baseline samples. Major mutations were defined by the International AIDS Society–USA (9), as well as T69D, L74I, G190C/E/Q/T/V for reverse transcriptase, and L24I, F53L, I54V/A/T/S, G73C/S/T/A and N88D for protease. An adherence questionnaire (10) was administered at weeks 8 and 24 and every 24 weeks thereafter.

Statistical Analysis

The primary efficacy hypothesis was that in each of the NRTI groups, atazanavir plus ritonavir was equivalent to efavirenz. Regimens were prespecified to be equivalent if the 2-sided 95% CI for the HR from a Cox proportional hazards model was between 0.71 and 1.40. Assessment of the proportional hazards assumption provided mixed results. Graphical methods (1112) did not indicate that the proportionality assumption was violated, whereas addition of a time-by-treatment interaction term to the model indicated a significant decrease in the HR for each third-drug comparison over time, with effect changing direction at about 2 years of follow-up. The HRs we report may be viewed as an average of the treatment effect over the range of observed times (13).

A sample size of 1800 patients (450 per group) provided 89.8% probability of declaring equivalence if 2 regimens were the same, assuming uniform accrual, exponential virologic failure, and time distributions, with assumed virologic failure probability of 31.9% by 96 weeks. This assumption regarding virologic failure rate was based on available data at the time of protocol development from another ACTG trial using zidovudine–lamivudine plus efavirenz (8, 14). On the basis of this event rate, an HR of 1.40 would represent a 96-week difference in probability of virologic failure of approximately 10%.

Primary efficacy data were analyzed on the basis of each patient's randomly assigned regimen. The protocol originally defined safety events as events that occurred while receiving the assigned regimen and the tolerability end point as any change in the randomized regimen. After the high screening viral load stratum was unblinded, the safety end point was modified to include events that occurred while patients were receiving the assigned third drug (censored at the time of the modification), and the tolerability end point was based on the first modification of the third drug (ignoring NRTI switches). Time-to-event survival distributions were estimated by using the Kaplan–Meier method and compared with log-rank tests stratified by a screening viral load less than 100 000 copies/mL or 100 000 copies/mL or more. The HRs were estimated with Cox proportional hazards models stratified by screening viral load. For patients without virologic failure, the time was censored at the scheduled visit week of measured HIV-1 RNA. Similarly, for patients without safety or tolerability events, the time was censored at the date of the last sign or symptom evaluation or laboratory measure (safety) or at the date of the last reported antiretroviral treatment evaluation (tolerability).

Binary end points were compared by using a Cochran–Mantel–Haenszel (stratified) or Fisher exact test (unstratified), as appropriate. Changes in continuous measures (for example, CD4 count, fasting lipid levels, and calculated creatinine clearance) from baseline were compared by using a stratified Mann–Whitney test. Calculated creatinine clearance change within treatment regimen was assessed by using the signed rank test.

Data analyses are based on all follow-up, including follow-up after unblinding to NRTIs. P values and CIs are 2-sided and nominal, with no adjustment for interim analyses. The significance level for assessing modification of treatment effect was prespecified at 0.10. Analyses were done by using SAS, version 9 (SAS Institute, Cary, North Carolina), and Splus, version 6 (Insightful, Seattle, Washington).

Role of the Funding Source

Study A5202 was funded by the National Institutes of Health. The funding source had no role in the design, data collection, analysis, manuscript preparation, interpretation, or decision to submit the manuscript for publication.

Study Patients and Follow-up Disposition

Study A5202 enrolled 1857 eligible patients (7 others were ineligible and excluded from the analysis) from September 2005 to November 2007 (Table 1). Follow-up was 0 to 208 weeks (median [25th, 75th percentile], 138 weeks [106 weeks, 169 weeks]); there was no significant difference in time to premature discontinuation between study groups, censoring persons who died, completed the study, or stopped because their study site closed owing to loss of funding (P = 0.48). Figure 1 shows the flow of patients through the study. Nine patients who never started treatment with the study drug regimen were included in the primary efficacy analyses. A total of 83 patients switched from the assigned efavirenz regimen to atazanavir plus ritonavir: 6 before and 40 at or after virologic failure, and 37 without virologic failure. Forty-five patients switched from atazanavir plus ritonavir to efavirenz: 2 before and 16 at or after virologic failure, and 27 without virologic failure.

Table Jump PlaceholderTable 1.  Baseline Characteristics of the Patients in Study A5202
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Figure 1.
Study flow diagram.

Patients were to remain in follow-up regardless of whether antiretroviral therapy was modified; therefore, study follow-up and treatment modification disposition are both presented. Reasons for discontinued study follow-up are split into (number after/number without protocol-defined virologic failure) to summarize the frequency of premature study discontinuation with regard to the primary efficacy end point; reasons for treatment modification are split into (number before/number after/number without protocol-defined virologic failure) to summarize the amount of censoring of primary efficacy end points in analyses limited to follow-up while patients were receiving the assigned treatment. “3rd drug” refers to atazanavir–ritonavir or efavirenz. DF = disoproxil fumarate.

* Nucleoside reverse transcriptase inhibitors were blinded through 25 February 2008 for persons with HIV-1 RNA levels of 100 000 copies/mL or more at screening and until final visits starting 1 July 2009 for those with HIV-1 RNA levels less than 100 000 copies/mL at screening.

† Death was censored for premature study discontinuation and counted as a reason for treatment discontinuation if there was no previous modification to the third drug (number of treatment modifications due to death can be fewer than the number of deaths during the study follow-up owing to previous modifications for other reasons). Site closure was censored for premature study and treatment discontinuation.

‡ Site-declared virologic failure was by clinical determination of the site investigator, whereas protocol-defined virologic failure was determined strictly by the quantitative definition set forth in the protocol. Numbers may differ because not all patients who had protocol-defined virologic failure modified the third drug, or the drug modification may have been attributed to another reason, such as “nonadherent with medications or visits.”

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Primary Virologic Outcome

Among persons randomly assigned to receive atazanavir plus ritonavir or efavirenz with abacavir–lamivudine, the HR (efavirenz being the reference) for time to virologic failure was 1.13 (95% CI, 0.82 to 1.56), with no difference in treatment effect by viral load stratum (P = 0.147) (Figure 2, Table 2, and Appendix Table 1). For atazanavir plus ritonavir or efavirenz with tenofovir DF–emtricitabine, the HR was 1.01 (CI, 0.70 to 1.46), with no difference by viral load strata (P = 0.37). Although both CIs include an HR of no difference (1.0), neither met prespecified equivalence boundaries. The probability of remaining free of virologic failure at week 96 for atazanavir plus ritonavir or efavirenz with abacavir–lamivudine was 83.4% and 85.3%, respectively (difference, −1.9 percentage points [CI, −6.8 to 2.9 percentage points]). Values for atazanavir plus ritonavir or efavirenz with tenofovir DF–emtricitabine were 89.0% and 89.8% (difference, −0.8 percentage point [CI, −4.9 to 3.3 percentage points]). Table 2 and Appendix Table 1 summarize results and the probability of virologic failure.

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Figure 2.
Time to primary virologic, safety, and tolerability end points.

Each of these plots presents 1 minus the probability of remaining event-free, as estimated by the Kaplan–Meier method. The presented numbers of events are the total numbers of events during the entire follow-up (through 208 weeks). Presentation of time in figures was truncated because the numbers at risk declined after this point. By study design, follow-up was scheduled to be 96 weeks after the last participant enrolled. ATV–rtv + ABC–3TC = atazanavir + ritonavir with abacavir–lamivudine; ATV–rtv + TDF–FTC = atazanavir + ritonavir with tenofovir disoproxil fumarate–emtricitabine; EFV + ABC–3TC = efavirenz + abacavir–lamivudine; EFV + TDF–FTC = efavirenz plus tenofovir disoproxil fumarate–emtricitabine. Top. Time to protocol-defined virologic failure (confirmed plasma HIV-1 RNA level ≥1000 copies/mL at or after 16 weeks and before 24 weeks or ≥200 copies/mL at or after 24 weeks). Middle. Time to first primary safety end point (first grade-3 or -4 sign, symptom, or laboratory abnormality while receiving the originally assigned third drug [atazanavir plus ritonavir or efavirenz] that was ≥1 grade higher than baseline, excluding isolated unconjugated hyperbilirubinemia and creatine kinase). Bottom. Time to primary tolerability end point (first change in therapy, ignoring nucleoside reverse transcriptase inhibitors).

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Table Jump PlaceholderTable 2.  Summary of Primary End Points at Baseline, 96 Weeks, and Full Follow-up, With Efavirenz as the Reference in All Comparisons
Table Jump PlaceholderAppendix Table 1.  Summary of Primary End Points at Baseline, 48 Weeks, 96 Weeks, and Full Follow-up, With Efavirenz as the Reference in All Comparisons

A prespecified sensitivity analysis included potential virologic failures without confirmation (n = 34) and suggested that third-drug treatment effect differed by screening viral load stratum (P for interaction = 0.096). In the high viral load stratum, persons assigned to receive abacavir–lamivudine with atazanavir plus ritonavir had a higher rate of virologic failure than persons assigned to receive efavirenz (HR, 1.68 [CI, 1.08 to 2.60]; P = 0.019), a difference not seen in the low viral load stratum (HR, 0.99 [CI, 0.64 to 1.54]; P = 0.97). For comparison of the third drugs with tenofovir DF–emtricitabine, this sensitivity analysis was similar to primary results. In another prespecified sensitivity analysis that classified unconfirmed virologic failure, death, and discontinued follow-up as failures, results were similar to those of the primary efficacy analysis. Additional prespecified sensitivity analyses included censoring at first modification of the third drug, censoring at first modification of any assigned drugs, and censoring persons in the high viral load stratum at the time of the data safety monitoring board action; all had similar results to those of the primary analyses (Appendix Table 2).

Table Jump PlaceholderAppendix Table 2.  Summary of Sensitivity Analyses for Atazanavir Plus Ritonavir Versus Efavirenz, With Efavirenz as the Reference in All Comparisons
Secondary Virologic End Point Analyses

A prespecified comparison of atazanavir plus ritonavir and efavirenz with NRTIs combined (factorial analysis) was done because there was no evidence that the treatment effect differed by NRTIs (P = 0.65). For atazanavir plus ritonavir versus efavirenz, the HR for time to virologic failure was 1.08 (CI, 0.85 to 1.38), with CIs within the prespecified equivalence boundaries. However, for this comparison, there was a significant interaction with screening viral load (P = 0.080), in which the HRs were 1.35 (CI, 0.96 to 1.92) and 0.88 (CI, 0.62 to 1.23) for the high and low viral load stratum, respectively.

A cross-sectional analysis that assessed the proportion of patients with HIV-1 RNA levels less than 50 copies/mL (regardless of previous virologic failure or regimen change) was done in 1642 (88%) and 1498 (81%) of patients with HIV-1 RNA results available at weeks 48 and 96, respectively. Data were missing primarily because of premature discontinuation of the study (for example, because the patient moved, was incarcerated, or was deported) or the patient was lost to follow-up. Patients with missing data were more likely than persons with results to be younger, to be a non-Hispanic black person, to report previous intravenous drug use, and to have hepatitis B or C infection. Among patients with available HIV-1 RNA data, 78% of those assigned to receive atazanavir plus ritonavir and 87% of those assigned to receive efavirenz combined with abacavir–lamivudine had an HIV-1 RNA level less than 50 copies/mL at week 48 (difference, −8 percentage points [CI, −13 to −3 percentage points]; P = 0.03); respective values at week 96 were 85% and 91% (difference, −6 percentage points [CI, −11 to −1 percentage point]; P = 0.012). Values for atazanavir plus ritonavir versus efavirenz with tenofovir DF–emtricitabine were 84% and 90% at week 48 (difference, −6 percentage points [CI, −11 to −1 percentage point]; P = 0.012) and 90% and 91% at week 96 (difference, −1 percentage point [CI, −5 to 3 percentage points]; P = 0.58). In a prespecified, worst-case sensitivity analysis, in which patients with missing data were assigned to the group with HIV-1 RNA levels of 50 copies/mL or more, 48-week results were similar to primary analyses, and at 96 weeks, abacavir–lamivudine no longer favored efavirenz. Finally, in the analysis of time to regimen failure, with the end point defined as time to first confirmed virologic failure or discontinuation of assigned protease inhibitor or NNRTI, no significant treatment differences were found between atazanavir plus ritonavir and efavirenz with abacavir–lamivudine (HR, 0.87 [CI, 0.71 to 1.08]) or tenofovir DF–emtricitabine (HR, 0.93 [CI, 0.74 to 1.17]) (Appendix Figure).

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Appendix Figure.
Time to regimen failure.

Time to regimen failure (first confirmed virologic failure or discontinuation of therapy with the assigned nonnucleoside reverse transcriptase inhibitor) is shown. The plot presents 1 minus the probability of remaining event-free, as estimated by the Kaplan–Meier method. The presented numbers of events are the total numbers of events during the entire follow-up (through 208 weeks). Presentation of time in figures was truncated because the numbers at risk declined after this point. By study design, follow-up was scheduled to be 96 weeks after the last participant enrolled. ATV–rtv + ABC–3TC = atazanavir plus ritonavir with abacavir–lamivudine; ATV–rtv + TDF–FTC = atazanavir + ritonavir with tenofovir disoproxil fumarate–emtricitabine; EFV + ABC–3TC = efavirenz plus abacavir–lamivudine; EFV + TDF–FTC = efavirenz plus tenofovir disoproxil fumarate–emtricitabine.

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Safety End Point

Time to safety event was longer among persons who received atazanavir plus ritonavir than those who received efavirenz combined with abacavir–lamivudine (HR, 0.81 [CI, 0.66 to 1.00]; P = 0.048), with no significant difference in treatment effect by viral load stratum (P = 0.71) (Figure 2, Table 2, and Appendix Table 1). Table 3 summarizes the main differences in triggering safety events. No significant difference in rate of safety events was found between persons given atazanavir plus ritonavir versus those given efavirenz combined with tenofovir DF–emtricitabine (HR, 0.91 [CI, 0.72 to 1.15]; P = 0.44), and no significant difference in treatment effect by screening viral load stratum was found (P = 0.85). Sensitivity analyses included censoring at the time of the first modification of any part of the original assigned regimen and time to first safety end point, regardless of whether the original regimen had been modified. The results did not differ from those of the primary analyses (Appendix Table 2).

Table Jump PlaceholderTable 3.  Selected Safety Events, Median Change in Lipid Levels, and Median Change in Calculated Creatinine Clearance
Tolerability End Point

The third drug in the regimen was modified in 596 patients who initiated treatment (Figure 1). Time to regimen change was longer with atazanavir plus ritonavir than with efavirenz with abacavir–lamivudine (HR 0.69 [CI, 0.55 to 0.86]; P < 0.001), without significant evidence that results differed by viral load stratum (P = 0.63) (Figure 2, Table 2, and Appendix Table 1). No significant difference in the time to tolerability end point was found in persons who received these drugs with tenofovir DF–emtricitabine (HR, 0.84 [CI, 0.66 to 1.07]; P = 0.166), and no significant evidence was found that rates differed by viral load stratum (P = 0.90). Figure 1 shows reasons for modification. When analyzed as originally specified by the protocol, in which the end point was time to first change in any part of the assigned regimen, time to regimen change was longer among persons who received atazanavir plus ritonavir than those who received efavirenz with abacavir–lamivudine (P = 0.06); this difference was not seen with tenofovir DF–emtricitabine (P = 0.22) (Appendix Table 2).

Immunologic Outcome

Change in CD4 cell counts from baseline to weeks 48 and 96 was examined in 1645 (89%) and 1493 (80%) of patients with results available, respectively. Reasons for missing CD4 values were similar to reasons noted for HIV-1 RNA. Change in CD4 cell counts did not differ between persons given atazanavir plus ritonavir or efavirenz with abacavir–lamivudine, with a median change of 0.178 versus 0.188 × 109 cells/L (P = 0.94) and 0.250 versus 0.251 × 109 cells/L (P = 0.89), respectively. Change in CD4 cell count was greater in persons given atazanavir plus ritonavir than those given efavirenz with tenofovir DF–emtricitabine at weeks 48 and 96, with a median change of 0.175 versus 0.163 × 109 cells/L (P = 0.040) and 0.252 versus 0.221 × 109 cells/L (P = 0.002), respectively.

Clinical Events and Laboratory Measures

Prespecified clinical and laboratory events were events of interest in persons with HIV-1 and events related to known toxicities of study drugs. These included 31 deaths (Figure 1) and 95 AIDS-defining events in 82 patients. No significant difference was found in time to AIDS or death in persons assigned to receive atazanavir plus ritonavir and those assigned to receive efavirenz with abacavir–lamivudine (HR, 0.93 [CI, 0.56 to 1.54]; P = 0.77) or tenofovir DF–emtricitabine (HR, 1.23 [CI, 0.70 to 2.39]; P = 0.42). Other events of interest for patients assigned to receive atazanavir plus ritonavir and efavirenz with abacavir–lamivudine were vascular events (coronary artery disease, infarction, ischemia, angina, cerebrovascular accident, transient ischemic attack, or peripheral vascular disease) in 2 (<1%) patients in each treatment group; renal diagnoses of the Fanconi syndrome, toxic nephropathy, proteinuria, or renal failure in 4 (1%) and 5 (1%) patients; bone fractures in 16 (3%) and 22 (5%) patients; and suspected hypersensitivity reaction in 34 (7%) and 53 (11%) patients, respectively. Respective numbers for patients assigned to receive atazanavir plus ritonavir and efavirenz with tenofovir DF–emtricitabine were vascular events in 1 (<1%) and 6 (1%); renal diagnoses in 6 (1%) and 3 (1%); bone fractures in 21 (5%) and 21 (5%); and suspected hypersensitivity reaction in 27 (6%) and 25 (5%).

Analyses of change in lipid levels included persons with available fasting measurements at baseline and while receiving the originally assigned protease inhibitor or NNRTI at weeks 48 and 96. Data were available in 82% and 80% of these patients at weeks 48 and 96, respectively. Most patients with missing lipid values provided nonfasting samples. Patients with fasting lipid values did not seem to differ systematically from those with missing or nonfasting lipid values. Table 3 summarizes changes in fasting values from baseline. Persons who received efavirenz compared with atazanavir plus ritonavir with abacavir–lamivudine or tenofovir DF–emtricitabine had significantly greater increases in all cholesterol levels but not in total–high-density lipoprotein cholesterol ratios.

Table 3 summarizes changes from baseline in calculated creatinine clearance (among persons receiving an assigned protease inhibitor or NNRTI) at weeks 48 and 96. An increase from baseline in calculated creatinine clearance occurred in patients who received atazanavir plus ritonavir or efavirenz with abacavir–lamivudine (P < 0.001 for both), with no significant difference in the distribution of change at weeks 48 and 96. Calculated creatinine clearance was increased at weeks 48 and 96 in persons who received tenofovir DF–emtricitabine with efavirenz (P < 0.001 for both) but not in persons who received atazanavir plus ritonavir at week 48 (P = 0.53 for week 48 and P = 0.38 for week 96). The distribution of change in calculated creatinine clearance differed significantly at both weeks 48 and 96 between recipients of atazanavir plus ritonavir and recipients of efavirenz given with tenofovir DF–emtricitabine. Treatment with tenofovir DF–emtricitabine was discontinued or the dose was reduced because of changes in renal function in 6 patients receiving atazanavir plus ritonavir and 3 receiving efavirenz.

HIV-1 Drug Resistance

Of the 269 patients with protocol-defined virologic failure, 265 had resistance data available at failure and baseline; of these, 25 had major mutations at baseline. Among patients with virologic failure, emergent resistance mutations were less frequent in those assigned to received atazanavir plus ritonavir than in those assigned to receive efavirenz, combined with either NRTI (P < 0.001 for both) (Appendix Table 3). There was also a lower frequency of NRTI-associated mutations among persons assigned to receive atazanavir plus ritonavir than those assigned to receive efavirenz with abacavir–lamivudine (P < 0.001) or tenofovir DF–emtricitabine (P = 0.046).

Table Jump PlaceholderAppendix Table 3.  Summary of Drug-Resistant Mutations, With Specific Major Mutations of Interest
Adherence

Among persons with adherence data, no missed doses in the previous week were self-reported at weeks 8, 48, and 96 by 87% to 92% of those assigned to receive abacavir–lamivudine plus atazanavir plus ritonavir and by 89% to 90% of persons assigned the same NRTIs with efavirenz (P ≥ 0.26 for all comparisons). Among persons with adherence data, no missed doses in the previous week were self-reported at weeks 8, 48, and 96 by 91% to 93% of those assigned to receive tenofovir DF–emtricitabine with atazanavir plus ritonavir and by 92% of those assigned to receive the same NRTIs with efavirenz (P ≥ 0.60 for all comparisons).

Our analyses show, for the first time to our knowledge in a large, randomized study, that a ritonavir-boosted protease inhibitor had similar virologic efficacy as an efavirenz-based regimen with either abacavir–lamivudine or tenofovir DF–emtricitabine. Rates of safety and tolerability end points were lower among persons assigned to receive atazanavir plus ritonavir than among those who received efavirenz with abacavir–lamivudine; no differences were observed when these agents were combined with tenofovir DF–emtricitabine.

Review of MEDLINE through August 2010 and meeting abstracts from the past 3 years showed that the largest previous study to compare a ritonavir-boosted protease inhibitor with efavirenz was study A5142, which compared lopinavir plus ritonavir with efavirenz with nonrandomized NRTIs and showed that protocol-defined efficacy favored efavirenz (15). Our study differs from study A5142 in that randomized and blinded NRTIs and atazanavir plus ritonavir (6) was used. Several recent studies reported similar efficacy of ritonavir-boosted protease inhibitors and nevirapine-containing regimens (1617). Another study (219 participants) compared atazanavir plus ritonavir with efavirenz, both combined with tenofovir DF–emtricitabine, and showed virologic noninferiority of atazanavir at 48 weeks for a mean change from baseline in HIV-1 RNA level (18).

In study A5202, there were greater increases in CD4 cell counts, albeit of unknown clinical relevance, among persons assigned to atazanavir plus ritonavir compared with efavirenz when combined with tenofovir DF–emtricitabine. This is consistent with the lower immunologic responses in persons who were assigned to receive efavirenz compared with lopinavir plus ritonavir in study A5142 (15). In addition, the frequency of emergent resistance to protease inhibitors was very rare (Appendix Table 3), which is consistent with other studies (56, 15). We also showed that NRTI resistance emerged more often among patients with virologic failure who were assigned to receive efavirenz than among those assigned to receive atazanavir plus ritonavir (Appendix Table 3). Mutations included those associated with NNRTI resistance in the efavirenz groups and the M184V/I mutations associated with lamivudine and emtricitabine resistance in all groups. Other NRTI mutations were only seen in persons who were assigned efavirenz. The L74I/V mutation that is associated with abacavir resistance (1920) emerged in 6 and 1 persons randomly assigned to receive abacavir–lamivudine and tenofovir DF–emtricitabine, respectively. Seven patients had emergent K65R: 3 had received abacavir–lamivudine (1 had switched to alternative NRTIs before the time of virologic failure), and 4 had received tenofovir DF–emtricitabine. This mutation is seen in patients who have virologic failure while receiving tenofovir DF plus lamivudine and efavirenz (4) and is rarely seen in patients with virologic failure who are receiving tenofovir DF–emtricitabine (56) and abacavir-lamivudine–based regimens (20).

Renal toxicity has been reported with tenofovir DF (21), and data are conflicting on whether ritonavir-based regimens increase nephrotoxicity induced by tenofovir DF (2224). We observed no significant change from baseline in calculated creatinine clearance in persons who received atazanavir plus ritonavir with tenofovir DF–emtricitabine, compared with small but statistically significant increases in this measure within the other 3 study groups (Table 3). Change in calculated creatinine clearance from baseline at 48 and 96 weeks differed between persons who received tenofovir DF–emtricitabine with efavirenz and those who received atazanavir plus ritonavir. Nevertheless, few patients assigned to receive tenofovir DF–emtricitabine had a decrease of 25% or more in renal function from baseline (data not shown) or had NRTIs discontinued or dose reduced because of changes in renal function. Moreover, targeted renal events were not demonstrably different from the other study groups and were rare, as seen in other studies (7, 25).

Despite efficacy results in study A5202 being similar, we were unable to declare equivalence on the basis of prespecified HR boundaries probably resulting from the low rate of virologic failure at week 96 (11% to 17%) rather than the projected rate (32%). Nevertheless, in a post hoc assessment, the difference in probability of remaining free of virologic failure at 96 weeks did not exceed the 10% to 12% threshold typically used for defining equivalence or noninferiority (56, 26). Other limitations of this study included that atazanavir plus ritonavir and efavirenz were given on an open-label basis, tenofovir DF–emtricitabine with efavirenz was not provided as the single fixed-dose combination pill, the NRTIs were prematurely unblinded in the high-screening viral load stratum, and approximately 32% of participants modified or discontinued their third drug regimen. In addition, resistance testing before treatment initiation was done in only 40% to 50% of patients, and when study A5202 enrolled participants, it was not routine to do HLA-B*5701 testing before use of abacavir; the latter would probably have influenced rates of selected safety and tolerability end points.

Results from study A5202 provide useful information for clinicians and patients making decisions about the initial treatment of HIV-1 infection. Atazanavir plus ritonavir and efavirenz provide similar antiviral activity when used with either of the NRTI pairs. There were, however, differences between regimens in CD4 cell count increases, frequency of emergent resistance, rates of safety and tolerability events, and changes in fasting lipid levels and renal variables. These factors should be considered when selecting initial treatment of patients with HIV-1 infection.

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Appendix
Study Team Members

Frontier Science & Technology Research Foundation, Amherst, New York: Courtney Ashton, BS, MT, Bernadette Jarocki, MS, Amanda Zadzilka, BS, and Anthony Bloom; Global Community Advisory Board, Barcelona, Spain: Rob Camp; University of North Carolina at Chapel Hill, Chapel Hill, North Carolina: David Currin, RN, CCRC; University of Rochester Medical Center, Rochester, New York: Lisa Demeter, MD; Gilead Sciences, Foster City, California: Sabina Pfister, RN, and Renard Descallar; National Institutes of Health, Division of AIDS, Bethesda, Maryland: Ana Martinez, RPh; Ohio State University, Columbus, Ohio: Lori Mong-Kryspin, BS, MT; State University of New York at Buffalo, Buffalo, New York: Gene Morse, PharmD; University of Miami School of Medicine, Miami, Florida: Savita Pahwa, MD; GlaxoSmithKline, Research Triangle Park, North Carolina: Belinda Ha, PhD; The Miriam Hospital, Providence, Rhode Island: Helen Patterson, LPN; University of California, Davis, Sacramento, California: Richard Pollard, MD; University of Maryland School of Medicine, Baltimore, Maryland: Ronald Reisler, MD, MPH; Roche, Palo Alto, California: Nancy Shulman, MD; Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois: Kimberly Smith, MD, MPH; Bristol-Myers Squibb Company, Princeton, New Jersey: Gary Thal, MD; and Georgetown University Medical Center, Washington, District of Columbia: Joseph Timpone, MD.

Other Investigators and Contributors

University of Miami (site 901) Clinical Trials Unit grant AI069477, AIDS Clinical Trials Group grant AI27675, and Center for AIDS Research grant AI073961: Sandra Navarro, MD, and Lillian Colon, RN, BSN; Ohio State University (site 2301) Clinical Trials Unit grant AI069474: Susan L. Koletar, MD, and Diane Gochnour, RN; University of California, San Diego (site 701) Clinical Trials Unit grant AI69432: Julie Hoffman, RN, and Edward Seefried, RN; University of Cincinnati (site 2401) Clinical Trials Unit grant AI069513: Judith Feinberg, MD, and Michelle Saemann, RN; University of North Carolina (site 3201) Clinical Trials Unit grant AI69423, Center for AIDS Research grant AI50410, General Clinical Research Center grant RR00046, and grant RR025747: Donna Pittard, RN, and David Ragan, RN, MSN; University of Alabama (site 5801) Clinical Trials Unit grant U01 AI069452-03, Center for Clinical and Translational Sciences grant 1UL1 RR025777-01: Elizabeth Lindsey, RN, and Tamara James, BS; University of Colorado Health Sciences Center (site 6101) Clinical Trials Unit grant RR025780: Graham Ray, RN, MSN, and Steven Johnson, MD; University of Southern California (site 1201) Clinical Trials Unit grant 5U01 AI069428: P. Jan Geiseler, MD, and Connie A. Funk, RN, MPH; Vanderbilt Therapeutics Clinical Research Site (site 3652) Clinical Trials Unit grant AI069439: Michael Morgan, FNP, and Brenda Jackson, RN; University of Pennsylvania, subunit of Children's Hospital of Philadelphia (site 6201) Clinical Trials Unit grant U01 AI069467-03, Center for AIDS Research grant 5P30 AI045008-10: Pablo Tebas, MD, and Aleshia Thomas, RN; Washington University (site 2101) Clinical Trials Unit grant AI069495: Ge-Youl Kim, RN, BSN, and Mark Rodriguez, RN, BSN; University of Puerto Rico (site 5401) Clinical Trials Unit grant 5U01 AI069415-03: Jorge L. Santana, MD, and Santiago Marrero, MD; Stanford University (site 501) Clinical Trials Unit grant AI69556: Jane Norris, PA-C, and Sandra Valle, PA-C; Duke University Medical Center (site 1601) Clinical Trials Unit grant 5U01 AI069484-02: Gary Matthew Cox, MD, and Martha Silberman, RN; Harbor-UCLA Medical Center (site 603) Clinical Trials Unit grant AI069424: Sadia Shaik, MD, and Ruben Lopez, MD; New York University/New York City Health and Hospitals Corporation at Bellevue Hospital Center (site 401) Clinical Trials Unit grant AI069532: Margie Vasquez, RN, and Demetre Daskalakis, MD; Cornell Chelsea (site 7804) Clinical Trials Unit grant AI69419, CSTC grant RR024996: Valery Hughes, NP, and Christina Megill, PA; Northwestern University Clinical Research Site (site 2701) Clinical Trials Unit grant AI069471: Jessica Shore, BSN, and Babafemi Taiwo, MBBS; Indiana University (site 2601) Clinical Trials Unit grant UO1 AI025859: Mitchell Goldman, MD, and Molly Boston, RN; The Ponce de Leon Center (A5802) Clinical Trials Unit grant 5U01 AI069418, Center for AIDS Research grant P30 AI050409: Jeffrey Lennox, MD, and Carlos del Rio, MD; Moses H. Cone Memorial Hospital (site 3203) Clinical Trials Unit grant 1U01 A1069423-01: Timothy W. Lane, MD, and Kim Epperson, RN; University of California, San Francisco (Site 801) Clinical Trials Unit grant 1U01 AI069502-01: Annie Luetkemeyer, MD, and Mary Payne, RN; Case Western Reserve University (site 2501) Clinical Trials Unit grant AI69501: Barbara Gripshover, MD, and Dawn Antosh, RN; University of Rochester (site 1101) Clinical Trials Unit grant U01 AI069511, General Clinical Research Center grant UL1 RR024160: Jane Reid RN, MS, APN-BC, and Mary Adams, RN, MPh; University of Washington (site 1401) Clinical Trials Unit grant AI069434: Sheryl S. Storey, PA-C, and Shelia B. Dunaway, MD; Johns Hopkins University (site 201) Clinical Trials Unit grant AI69465, CTSA grant U54 RR023561: Ilene Wiggins, RN, and Eric Zimmerman, RN; Rush University Medical Center (site 2702) Clinical Trials Unit grant 5U01 AI069471:Kimberly Y. Smith, MD, MPH, and Joan A. Swiatek, RN, APN; Georgetown University (site 1008) Clinical Trials Unit grant 1U01 AI069494-01: Joseph Timpone, MD, and Princy Kumar, MD; University of California, Los Angeles Care Center (site 601) Clinical Trials Unit grant AI069424: Ardis Moe, MD, and Maria Palmer PA-C; Brigham and Women's Hospital (site 107) Clinical Trials Unit grant AI069472: Jon Gothing, RN, BSN, ACRN, and Joanne Delaney, RN, BSN; Metro Health Center (site 2503) Clinical Trials Unit grant AI069501: Kim Whitely, RN, and Robert Kalayjian, MD; HIV Prevention & Treatment (Columbia University) (site 30329) Clinical Trials Unit grant 5U01 AI069470, grant 1UL1 RR024156: Scott M. Hammer and Michael T. Yin; University of Texas Southwestern Medical Center at Dallas (site 3751) Clinical Trials Unit grant 3U01 AI046376 05S4: Mamta Jain, MD, and Tianna Petersen, MS; AIDS Community Health Center (site 1108) Clinical Trials Unit grant U01 AI069511, General Clinical Research Center grant UL1 RR024160: Roberto Corales, DO, and Christine Hurley, RN; Hennepin County Medical Center (site 1502) grant N01 AI72626: Keith Henry, MD, and Bette Bordenave, RN; Beth Israel Deaconess (Partners/Harvard) Clinical Research Site (site 103) Clinical Trials Unit grant UOI A106947203: Amanda Youmans, NP, and Mary Albrecht, MD; University of California, Davis Medical Center (site 3851) grant AI38858: Richard B. Pollard, MD, and Abimbola Olusanya, NP; Boston Medical Center Clinical Research Site (site 104) Clinical Trials Unit grant AI069472: Paul R. Skolnik, MD, and Betsy Adams, RN; The Miriam Hospital-Brown University (Partners/Harvard) (site 2951) Clinical Trials Unit grant 1U01 AI069472-01: Karen T. Tashima and Helen Patterson, LPN; Peabody Health Center (site 31443) Clinical Trials Unit grant AI069471: Michelle Ukwu and Lauren Rogers; University of Minnesota (site 1501) Clinical Trials Unit grant AI27661: Henry H. Balfour Jr., MD, and Kathy A. Fox, RN, MBA; University of Nebraska Medical Center (site 1505) Clinical Trials Unit grant AI27661: Susan Swindells, MBBS, and Frances Van Meter, APRN; University of Hawaii (site 5201) Clinical Trials Unit grant AI34853; Massachusetts General Hospital from the Partners/Harvard/BMC AIDS Clinical Trials Unit (site 101) Clinical Trials Unit grant 1U01 AI069472-01: Gregory Robbins, MD, and Nicole Burgett-Yandow, RN, BSN; IHV Baltimore Treatment Clinical Research Site (site 4651) Clinical Trials Unit grant 5U01 AI069447 03: Charles E. Davis Jr., MD, and Colleen Boyce, RN; University of Texas Medical Branch (site 6301) Clinical Trials Unit grant AI032782: William A. O'Brien, MD, and Gerianne Casey, RN; State University of New York, Buffalo (site 1102) Clinical Trials Unit grant 5U01 A1027658: Gene D. Morse, PharmD, and Chiu-Bin Hsaio, MD; San Mateo County AIDS Program (site 505) Clinical Trials Unit grant AI27666: Gene D. Morse, PharmD, and Chiu-Bin Hsaio, MD; University of Iowa Healthcare (site 1504) National Institutes of Allergy and Infectious Diseases grant AI27661 and grant AI58740: Jeffrey L. Meier, MD, and Jack T. Stapleton, MD; Beth Israel Medical Center AIDS Clinical Trials Unit (site 2851) Clinical Trials Unit grant AI46370: Donna Mildvan, MD, and Manuel Revuelta, MD; Wake County Health and Human Services (site 30076) Clinical Trials Unit grant AI25868: David Currin, RN; Harlem AIDS Clinical Trials Group Clinical Research Site (site 31483) Clinical Trials Unit grant 5U01 AI069470-03: Wafaa El Sadr, MD, MPH, MPA, and Avelino Loquere, RN; McCree McCuller Wellness Center (site 1107) Clinical Trials Unit grant U01 AI069511, General Clinical Research Center grant UL1 RR024160: Nyef El-Daher, MD, and Tina Johnson, RN; University of Pennsylvania Health (site 6206) Clinical Trials Unit grant 1U01 AI69467-01: Robert Gross, MD, MSCE, and Kathyrn Maffei, RN, BSN; University of Pittsburgh (site 1001) Clinical Trials Unit grant 1UO1 AI069494-01: Deborah McMahon, MD, and Barbara Rutecki, CRNP, MPH; Gilead Sciences: Michael Wulfsohn, MD, PhD, Andrew Cheng, MD, PhD, Michael Miller, PhD, Norbert Bischofberger, PhD; GlaxoSmithKline: Sara Hughes, PhD.

Figures

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Figure 1.
Study flow diagram.

Patients were to remain in follow-up regardless of whether antiretroviral therapy was modified; therefore, study follow-up and treatment modification disposition are both presented. Reasons for discontinued study follow-up are split into (number after/number without protocol-defined virologic failure) to summarize the frequency of premature study discontinuation with regard to the primary efficacy end point; reasons for treatment modification are split into (number before/number after/number without protocol-defined virologic failure) to summarize the amount of censoring of primary efficacy end points in analyses limited to follow-up while patients were receiving the assigned treatment. “3rd drug” refers to atazanavir–ritonavir or efavirenz. DF = disoproxil fumarate.

* Nucleoside reverse transcriptase inhibitors were blinded through 25 February 2008 for persons with HIV-1 RNA levels of 100 000 copies/mL or more at screening and until final visits starting 1 July 2009 for those with HIV-1 RNA levels less than 100 000 copies/mL at screening.

† Death was censored for premature study discontinuation and counted as a reason for treatment discontinuation if there was no previous modification to the third drug (number of treatment modifications due to death can be fewer than the number of deaths during the study follow-up owing to previous modifications for other reasons). Site closure was censored for premature study and treatment discontinuation.

‡ Site-declared virologic failure was by clinical determination of the site investigator, whereas protocol-defined virologic failure was determined strictly by the quantitative definition set forth in the protocol. Numbers may differ because not all patients who had protocol-defined virologic failure modified the third drug, or the drug modification may have been attributed to another reason, such as “nonadherent with medications or visits.”

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Figure 2.
Time to primary virologic, safety, and tolerability end points.

Each of these plots presents 1 minus the probability of remaining event-free, as estimated by the Kaplan–Meier method. The presented numbers of events are the total numbers of events during the entire follow-up (through 208 weeks). Presentation of time in figures was truncated because the numbers at risk declined after this point. By study design, follow-up was scheduled to be 96 weeks after the last participant enrolled. ATV–rtv + ABC–3TC = atazanavir + ritonavir with abacavir–lamivudine; ATV–rtv + TDF–FTC = atazanavir + ritonavir with tenofovir disoproxil fumarate–emtricitabine; EFV + ABC–3TC = efavirenz + abacavir–lamivudine; EFV + TDF–FTC = efavirenz plus tenofovir disoproxil fumarate–emtricitabine. Top. Time to protocol-defined virologic failure (confirmed plasma HIV-1 RNA level ≥1000 copies/mL at or after 16 weeks and before 24 weeks or ≥200 copies/mL at or after 24 weeks). Middle. Time to first primary safety end point (first grade-3 or -4 sign, symptom, or laboratory abnormality while receiving the originally assigned third drug [atazanavir plus ritonavir or efavirenz] that was ≥1 grade higher than baseline, excluding isolated unconjugated hyperbilirubinemia and creatine kinase). Bottom. Time to primary tolerability end point (first change in therapy, ignoring nucleoside reverse transcriptase inhibitors).

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Appendix Figure.
Time to regimen failure.

Time to regimen failure (first confirmed virologic failure or discontinuation of therapy with the assigned nonnucleoside reverse transcriptase inhibitor) is shown. The plot presents 1 minus the probability of remaining event-free, as estimated by the Kaplan–Meier method. The presented numbers of events are the total numbers of events during the entire follow-up (through 208 weeks). Presentation of time in figures was truncated because the numbers at risk declined after this point. By study design, follow-up was scheduled to be 96 weeks after the last participant enrolled. ATV–rtv + ABC–3TC = atazanavir plus ritonavir with abacavir–lamivudine; ATV–rtv + TDF–FTC = atazanavir + ritonavir with tenofovir disoproxil fumarate–emtricitabine; EFV + ABC–3TC = efavirenz plus abacavir–lamivudine; EFV + TDF–FTC = efavirenz plus tenofovir disoproxil fumarate–emtricitabine.

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Tables

Table Jump PlaceholderTable 1.  Baseline Characteristics of the Patients in Study A5202
Table Jump PlaceholderTable 2.  Summary of Primary End Points at Baseline, 96 Weeks, and Full Follow-up, With Efavirenz as the Reference in All Comparisons
Table Jump PlaceholderAppendix Table 1.  Summary of Primary End Points at Baseline, 48 Weeks, 96 Weeks, and Full Follow-up, With Efavirenz as the Reference in All Comparisons
Table Jump PlaceholderAppendix Table 2.  Summary of Sensitivity Analyses for Atazanavir Plus Ritonavir Versus Efavirenz, With Efavirenz as the Reference in All Comparisons
Table Jump PlaceholderTable 3.  Selected Safety Events, Median Change in Lipid Levels, and Median Change in Calculated Creatinine Clearance
Table Jump PlaceholderAppendix Table 3.  Summary of Drug-Resistant Mutations, With Specific Major Mutations of Interest

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