Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy

Abstract

Background: The use of fixed-dose combination nucleoside reverse-transcriptase inhibitors (NRTIs) with a nonnucleoside reverse-transcriptase inhibitor or a ritonavir-boosted protease inhibitor is recommended as initial therapy in patients with human immunodeficiency virus type 1 (HIV-1) infection, but which NRTI combination has greater efficacy and safety is not known.

Methods: In a randomized, blinded equivalence study involving 1858 eligible patients, we compared four once-daily antiretroviral regimens as initial therapy for HIV-1 infection: abacavir-lamivudine or tenofovir disoproxil fumarate (DF)-emtricitabine plus efavirenz or ritonavir-boosted atazanavir. The primary efficacy end point was the time from randomization to virologic failure (defined as a confirmed HIV-1 RNA level > or = 1000 copies per milliliter at or after 16 weeks and before 24 weeks, or > or = 200 copies per milliliter at or after 24 weeks).

Results: A scheduled interim review by an independent data and safety monitoring board showed significant differences in virologic efficacy, according to the NRTI combination, among patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more. At a median follow-up of 60 weeks, among the 797 patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more, the time to virologic failure was significantly shorter in the abacavir-lamivudine group than in the tenofovir DF-emtricitabine group (hazard ratio, 2.33; 95% confidence interval, 1.46 to 3.72; P<0.001), with 57 virologic failures (14%) in the abacavir-lamivudine group versus 26 (7%) in the tenofovir DF-emtricitabine group. The time to the first adverse event was also shorter in the abacavir-lamivudine group (P<0.001). There was no significant difference between the study groups in the change from the baseline CD4 cell count at week 48.

Conclusions: In patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more, the times to virologic failure and the first adverse event were both significantly shorter in patients randomly assigned to abacavir-lamivudine than in those assigned to tenofovir DF-emtricitabine. (ClinicalTrials.gov number, NCT00118898.)

Figure 1. Time to Virologic Failure, Time to Regimen Failure, and Proportion of Patients with HIV-1 RNA of Less Than 50 Copies per Milliliter

Panel A shows the time to protocol-defined virologic failure, and Panel B shows the time to the first occurrence of either virologic failure or modification of a nucleoside reverse-transcriptase inhibitor (NRTI). Panel C shows the proportions of patients with an HIV-1 RNA level below 50 copies per milliliter in an analysis involving patients with available data, regardless of whether they had previously discontinued their assigned NRTI or had virologic failure. The vertical bars denote 95% binomial confidence intervals at each study week. All three analyses were restricted to patients with a screening HIV-1 RNA level of 100,000 copies per milliliter or more and compared abacavir–lamivudine (ABC-3TC) with tenofovir DF–emtricitabine (TDF-FTC), both combined with efavirenz or with ritonavir-boosted atazanavir.

Figure 2. Estimated Effect of Abacavir–Lamivudine (ABC-3TC) versus Tenofovir DF–Emtricitabine (TDF-FTC) on the Hazard of Virologic Failure, According to Baseline Characteristics

In the univariate analysis, modeling for treatment-effect modification used the continuous form for age, CD4 cell count, and HIV-1 RNA level. Estimated treatment effects are shown as example values for these continuous variables. Multivariate analysis showed similar results.

Figure 3. Time to Safety End Point

Shown is the probability of not having a first grade 3 or 4 sign, symptom, or laboratory abnormality that was at least one grade higher than the grade at baseline (excluding hyperbilirubinemia and elevation in the creatine kinase level) among patients with a screening HIV-1 RNA level of 100,000 copies per milliliter or more who were initially assigned to a regimen containing either abacavir–lamivudine (ABC-3TC) or tenofovir DF–emtricitabine (TDF-FTC). This was an as-treated analysis involving patients receiving the randomly assigned nucleoside reverse-transcriptase inhibitor regimen.