Comparison of 48-Week Efficacies of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide and Nucleoside/Nucleotide Reverse Transcriptase Inhibitor-Sparing Regimens

A Systematic Review and Network Meta-analysis

S Gallien; M Massetti; P Flandre; H Leleu; D Descamps; E Lazaro

Disclosures

HIV Medicine. 2018;19(8):559-571. 

In This Article

Abstract and Introduction

Abstract

Objectives: To compare nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)-sparing regimens with tenofovir alafenamide (TAF)-based combinations in HIV-1-infected adults, we performed a network meta-analysis (NMA) to provide estimates of relative efficacy for these two regimens.

Methods: A systematic literature review (SLR) was performed to identify phase 3/4 randomized controlled clinical trials evaluating the efficacy of commonly used combination antiretroviral therapy (cART) including an NRTI backbone or that of commonly used NRTI-sparing regimens. A Bayesian random-effect model was used to compare virological suppression rates at 48 weeks for NRTI-sparing regimens and elvitegravir/cobicistat/emtricitabine/TAF (E/C/F/TAF).

Results: Twenty-three studies in treatment-naïve patients identified by the SLR were included in the NMA, including four studies assessing NRTI-sparing regimens. In treatment-naïve patients, the probability of achieving virological suppression at 48 weeks was between 40% and 60% higher with E/C/F/TAF than with NRTI-sparing strategies. The credible interval vs. darunavir/ritonavir (DVR/r) + raltegravir (RAL) and LPV/r monotherapy did not include 1. In the subgroup of naïve patients with viral load < 100 000 HIV-1 RNA copies/mL, a credible difference was found between NRTI-sparing treatments and E/C/F/TAF. Studies in treatment-experienced patients were too heterogeneous to allow for an NMA.

Conclusions: The NMA results suggest that E/C/F/TAF represents a more effective option than NRTI-sparing regimens in terms of 48-week efficacy in treatment-naïve patients. Furthermore, TAF pharmacological properties, as well as tolerability results in clinical studies, suggest a safety profile similar to that of NRTI-sparing regimens. Thus, the E/C/F/TAF combination might represent a more appropriate option than NRTI-sparing regimens for initiation of antiretroviral therapy in treatment-naïve HIV-infected patients.

Introduction

Combination antiretroviral therapy (cART) including two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) dosed together with a third agent is the current global guideline-recommended first-line treatment strategy for HIV-1-infected patients.[1–3] Third agents include nonnucleoside reverse transcriptase inhibitors (NNRTIs), boosted protease inhibitors (PIs) and integrase inhibitors (INIs). cART including the newest available drugs from the INI class [i.e. dolutegravir (DTG) or cobicistat-boosted elvitegravir (EVG/COBI)] has been found to achieve high levels of efficacy, with > 90% virological suppression at 48 weeks in naïve patients.[4,5] Nevertheless, lifelong exposure to cART has been associated with severe drug-related toxicity, including renal toxicity, bone fractures resulting from osteoporosis and increased cardiovascular risk. In particular, tenofovir disoproxil fumarate (TDF), one of the most widely used NRTIs, has been associated with a significantly higher renal dysfunction risk as well as greater bone mineral density losses and higher risk of osteoporotic fractures than other antiretroviral therapies.[6–11] Similarly, abacavir (ABC), another commonly used NRTI, was first found to be a risk factor for myocardial infarction in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study, an observational study of > 49 000 HIV-infected patients specifically established to evaluate adverse events, and this was subsequently confirmed in a number of observational studies and meta-analyses, but not in all studies.[12–14] Therefore, NRTI-sparing regimens have attracted much attention, as these combinations make it possible to avoid NRTI-associated toxicity.

A number of studies assessing the efficacy and safety of NRTI-sparing regimens have been carried out.[15–19] The European AIDS Treatment Network (NEAT) 001 study was a large randomized, open-label, noninferiority trial conducted in 805 treatment-naïve adults. The included patients received either standard cART containing ritonavir-boosted darunavir (DRV/r) combined with TDF and emtricitabine (FTC) or an NRTI-sparing regimen combining DRV/r and raltegravir (RAL).[19] The study showed that the NRTI-sparing regimen had a higher rate of failure at 96 weeks, although the difference was not significant. Another study comparing the same regimens in 85 patients also showed that DRV/r + RAL had a significantly inferior efficacy at 48 weeks.[17] Similarly, the GARDEL study (Global AntiRetroviral Design Encompassing Lopinavir/r and Lamivudine vs LPV/r based standard therapy) compared ritonavir-boosted lopinavir (LPV/r) + TDF/FTC to LPV/r + RAL in 206 treatment-naïve adults and showed a trend for lower efficacy of the NRTI-sparing regimen.[20] Thus, although NRTI-sparing regimens may be associated with reduced long-term toxicity, clinical studies suggest that they come with an efficacy trade-off.

In this setting, tenofovir alafenamide (TAF) is a promising agent that might allow cART toxicity to be avoided while preserving its efficacy. TAF is a tenofovir (TFV) prodrug that achieves higher intracellular concentrations of tenofovir-diphosphate (TFV-DP) than those obtained with TDF, with much lower TFV exposure in plasma, reducing the risk of renal and bone toxicity events.[21] TAF-based cART has shown similar efficacy in treatment-naïve HIV-1-infected patients to TDF-based cART, with evidence of a more favourable renal and bone safety profile.[5] Moreover, TAF-based cART, which appears to have reduced renal and bone consequences in lifelong exposure with similar efficacy compared with TDF-based cART, has not been compared in head-to-head studies to alternative NRTI-sparing regimens. Thus, the objective of this study was to compare the efficacy of NRTI-sparing regimens with that of TAF-based cART, EVG/cobicistat/FTC/TAF (E/C/F/TAF), based on a systematic literature review (SLR) and a Bayesian network meta-analysis (NMA).

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