Abstract

SummaryBackgroundMillions of HIV-infected people worldwide receive antiretroviral therapy (ART) in programmes using WHO-recommended standardised regimens. Recent WHO guidelines recommend a boosted protease inhibitor plus raltegravir as an alternative second-line combination. We assessed whether this treatment option offers any advantage over the standard protease inhibitor plus two nucleoside reverse-transcriptase inhibitors (NRTIs) second-line combination after 144 weeks of follow-up in typical programme settings.MethodsWe analysed the 144-week outcomes at the completion of the EARNEST trial, a randomised controlled trial done in HIV-infected adults or adolescents in 14 sites in five sub-Saharan African countries (Uganda, Zimbabwe, Malawi, Kenya, Zambia). Participants were those who were no longer responding to non-NRTI-based first-line ART, as assessed with WHO criteria, confirmed by viral-load testing. Participants were randomly assigned to receive a ritonavir-boosted protease inhibitor (lopinavir 400 mg with ritonavir 100 mg, twice per day) plus two or three clinician-selected NRTIs (protease inhibitor plus NRTI group), protease inhibitor plus raltegravir (400 mg twice per day; protease inhibitor plus raltegravir group), or protease inhibitor monotherapy (plus raltegravir induction for first 12 weeks, re-intensified to combination therapy after week 96; protease inhibitor monotherapy group). Randomisation was by computer-generated randomisation sequence, with variable block size. The primary outcome was viral load of less than 400 copies per mL at week 144, for which we assessed non-inferiority with a one-sided α of 0·025, and superiority with a two-sided α of 0·025. The EARNEST trial is registered with ISRCTN, number 37737787.FindingsBetween April 12, 2010, and April 29, 2011, 1837 patients were screened for eligibility, of whom 1277 patients were randomly assigned to an intervention group. In the primary (complete-case) analysis at 144 weeks, 317 (86%) of 367 in the protease inhibitor plus NRTI group had viral loads of less than 400 copies per mL compared with 312 (81%) of 383 in the protease inhibitor plus raltegravir group (p=0·07; lower 95% confidence limit for difference 10·2% vs specified non-inferiority margin 10%). In the protease inhibitor monotherapy group, 292 (78%) of 375 had viral loads of less than 400 copies per mL; p=0·003 versus the protease inhibitor plus NRTI group at 144 weeks. There was no difference between groups in serious adverse events, grade 3 or 4 adverse events (total or ART-related), or events that resulted in treatment modification.InterpretationProtease inhibitor plus raltegravir offered no advantage over protease inhibitor plus NRTI in virological efficacy or safety. In the primary analysis, protease inhibitor plus raltegravir did not meet non-inferiority criteria. A regimen of protease inhibitor with NRTIs remains the best standardised second-line regimen for use in programmes in resource-limited settings.FundingEuropean and Developing Countries Clinical Trials Partnership (EDCTP), UK Medical Research Council, Instituto de Salud Carlos III, Irish Aid, Swedish International Development Cooperation Agency, Instituto Superiore di Sanita, Merck, ViiV Healthcare, WHO.

Highlights

  • Over 17 million people currently receive antiretroviral therapy (ART) for HIV infection worldwide, most of whom live in resource-limited settings

  • Evidence before this study We searched PubMed using terms including “second-line therapy”, “protease inhibitors”, and the individual drug names, and reviewed relevant HIV conference abstracts to identify clinical trials done in patients who had failed on a first-line non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based combination, which compared the standard-of-care protease inhibitor plus nucleo­ side reverse-transcriptase inhibitors (NRTIs) combination for second-line therapy with either a protease inhibitor plus raltegravir combination or with protease inhibitor monotherapy

  • Added value of this study This trial provides the first comparative, randomised data on long-term (144 weeks) outcomes with the protease inhibitor plus raltegravir regimen in second-line therapy. With this longer duration of follow-up, we found that non-inferiority was not consistently demonstrated across all analyses, and there was no evidence of a safety benefit with the protease inhibitor plus raltegravir regimen compared with the standard-of-care protease inhibitor plus NRTI combination

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Summary

Introduction

Over 17 million people currently receive antiretroviral therapy (ART) for HIV infection worldwide, most of whom live in resource-limited settings. Evidence before this study We searched PubMed using terms including “second-line therapy”, “protease inhibitors”, and the individual drug names, and reviewed relevant HIV conference abstracts to identify clinical trials done in patients who had failed on a first-line non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based combination, which compared the standard-of-care protease inhibitor plus NRTI combination for second-line therapy with either a protease inhibitor plus raltegravir combination or with protease inhibitor monotherapy. An updated search on June 1, 2017, using the same terms, identified three published randomised controlled trials reporting outcomes after 48 or 96 weeks’ treatment with the protease inhibitor plus raltegravir combination (including the earlier report from this trial) that concluded that this option was non-inferior, and two randomised controlled trials reporting outcomes after 48 or 96 weeks’ treatment with protease inhibitor monotherapy (including the earlier report from this trial), which concluded that this option was inferior to standard of care

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