Atazanavir plus ritonavir or efavirenz as part of a 3-drug regimen for initial treatment of HIV-1

Abstract

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.

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.”

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).

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.