HIV Salvage Therapy Does Not Require Nucleoside Reverse Transcriptase Inhibitors: A Randomized, Controlled Trial

Abstract

Background: Nucleoside reverse transcriptase inhibitors (NRTIs) are often included in antiretroviral regimens in treatment-experienced patients in the absence of data from randomized trials.

Objective: To compare treatment success between participants who omit versus those who add NRTIs to an optimized antiretroviral regimen of 3 or more agents.

Design: Multicenter, randomized, controlled trial. (ClinicalTrials.gov: NCT00537394).

Setting: Outpatient HIV clinics.

Participants: Treatment-experienced patients with HIV infection and viral resistance.

Intervention: Open-label optimized regimens (not including NRTIs) were selected on the basis of treatment history and susceptibility testing. Participants were randomly assigned to omit or add NRTIs.

Measurements: The primary efficacy outcome was regimen failure through 48 weeks using a noninferiority margin of 15%. The primary safety outcome was time to initial episode of a severe sign, symptom, or laboratory abnormality before discontinuation of NRTI assignment.

Results: 360 participants were randomly assigned, and 93% completed a 48-week visit. The cumulative probability of regimen failure was 29.8% in the omit-NRTIs group versus 25.9% in the add-NRTIs group (difference, 3.2 percentage points [95% CI, -6.1 to 12.5 percentage points]). No significant between-group differences were found in the primary safety end points or the proportion of participants with HIV RNA level less than 50 copies/mL. No deaths occurred in the omit-NRTIs group compared with 7 deaths in the add-NRTIs group.

Limitation: Unblinded study design, and the study may not be applicable to resource-poor settings.

Conclusion: Treatment-experienced patients with HIV infection starting a new optimized regimen can safely omit NRTIs without compromising virologic efficacy. Omitting NRTIs will reduce pill burden, cost, and toxicity in this patient population.

Primary funding sources: National Institute of Allergy and Infectious Diseases, Boehringer Ingelheim, Janssen, Merck, ViiV Healthcare, Roche, and Monogram Biosciences (LabCorp).

Figures

FIGURE 1

Participant Disposition (CONSORT diagram). The progress of all participants from screening through randomization and analysis are displayed. Key outcomes are identified within each block. Populations for key analyses are also summarized.

FIGURE 2

Primary outcome of regimen failure and its individual components (cumulative number of confirmed virologic failures and discontinuations of NRTI assignment). Because a participant may experience both virologic failure and discontinuation of the NRTI assignment, the number of events of the components exceeds the total number of regimen failures. Cumulative probabilities of outcomes by week 48 are given within the parentheses in the table (e.g., 29.8% regimen failure in the Omit NRTI arm). Between arm differences (Omit – Add NRTIs) in the cumulative probabilities with 95% CI are given in the right-most column and are plotted with the black squares and horizontal lines. The non-inferiority margin is denoted by the dashed vertical line. NRTIs = nucleoside reverse transcriptase inhibitors.

Figure 3A. Proportion of participants with HIV-1 RNA

Missing RNA values were excluded. The point estimate (circle) and 95% point-wise CI (vertical lines) are shown. 95% CIs calculated using normal approximation to the binomial. The number of observations in each group for each study week is also presented. All participants in each randomized arm were assessed at Week 0 (Omit NRTIs, N=179; Add NRTIs, N=181).

Figure 3B. CD4 cell count changes from baseline for the randomized study arms

The median change (circles) and IQR (lines) are plotted by scheduled study visit. The number of observations in each group for each study week is also presented.

Figure 4A. Primary safety outcome: Time to first Grade 3 or 4 sign or symptom, or laboratory abnormality that was at least one grade above baseline

The results presented are an as-treated analysis (including only those who started study treatment; events occurring after discontinuation of NRTI assignment are censored).

Figure 4B

Secondary safety outcome: Time to the first Grade 3 or 4 sign or symptom that was at least one grade above baseline. As-treated analysis (including only those who started study treatment, and events occurring after NRTI strategy discontinuation are censored).

Figure 4C

Secondary safety outcome: Time to the first Grade 3 or 4 laboratory abnormality that was at least one grade above baseline. As-treated analysis (including only those who started study treatment, and events occurring after NRTI strategy discontinuation are censored).