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Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study

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Summary

Background

Antiretroviral regimens containing tenofovir disoproxil fumarate have been associated with renal toxicity and reduced bone mineral density. Tenofovir alafenamide is a novel tenofovir prodrug that reduces tenofovir plasma concentrations by 90%, thereby decreasing off-target side-effects. We aimed to assess whether efficacy, safety, and tolerability were non-inferior in patients switched to a regimen containing tenofovir alafenamide versus in those remaining on one containing tenofovir disoproxil fumarate.

Methods

In this randomised, actively controlled, multicentre, open-label, non-inferiority trial, we recruited HIV-1-infected adults from Gilead clinical studies at 168 sites in 19 countries. Patients were virologically suppressed (HIV-1 RNA <50 copies per mL) with an estimated glomerular filtration rate of 50 mL per min or greater, and were taking one of four tenofovir disoproxil fumarate-containing regimens for at least 96 weeks before enrolment. With use of a third-party computer-generated sequence, patients were randomly assigned (2:1) to receive a once-a-day single-tablet containing elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg (tenofovir alafenamide group) or to carry on taking one of four previous tenofovir disoproxil fumarate-containing regimens (tenofovir disoproxil fumarate group) for 96 weeks. Randomisation was stratified by previous treatment regimen in blocks of six. Patients and treating physicians were not masked to the assigned study regimen; outcome assessors were masked until database lock. The primary endpoint was the proportion of patients who received at least one dose of study drug who had undetectable viral load (HIV-1 RNA <50 copies per mL) at week 48. The non-inferiority margin was 12%. This study was registered with ClinicalTrials.gov, number NCT01815736.

Findings

Between April 12, 2013 and April 3, 2014, we enrolled 1443 patients. 959 patients were randomly assigned to the tenofovir alafenamide group and 477 to the tenofovir disoproxil fumarate group. Viral suppression at week 48 was noted in 932 (97%) patients assigned to the tenofovir alafenamide group and in 444 (93%) assigned to the tenofovir disoproxil fumarate group (adjusted difference 4·1%, 95% CI 1·6–6·7), with virological failure noted in ten and six patients, respectively. The number of adverse events was similar between the two groups, but study drug-related adverse events were more common in the tenofovir alafenamide group (204 patients [21%] vs 76 [16%]). Hip and spine bone mineral density and glomerular filtration were each significantly improved in patients in the tenofovir alafenamide group compared with those in the tenofovir disoproxil fumarate group.

Interpretation

Switching to a tenofovir alafenamide-containing regimen from one containing tenofovir disoproxil fumarate was non-inferior for maintenance of viral suppression and led to improved bone mineral density and renal function. Longer term follow-up is needed to better understand the clinical impact of these changes.

Funding

Gilead Sciences.

Introduction

Although most patients with HIV-1 infection have durable virological suppression with their first antiretroviral therapy (ART) regimen, switching to an alternative regimen could reduce pill burden or dosing frequency, improve adherence and tolerability, and reduce toxicity and costs.1 The clinical goal of patients switching a treatment regimen is to achieve one or more of these advantages, while maintaining virological suppression.

Tenofovir disoproxil fumarate is associated with excellent virological suppression, but some patients can develop clinically relevant nephrotoxicity over time,2 especially individuals with risk factors for renal disease.3 Some patients also have greater reductions in bone mineral density with tenofovir disoproxil fumarate than with other ART regimens, especially in the first 24 weeks of treatment.4, 5 In two double-blind randomised controlled studies of tenofovir alafenamide versus tenofovir disoproxil fumarate (both added to elvitegravir, cobicistat, and emtricitabine) in the initial treatment of HIV-1 infection, more than 90% of patients receiving tenofovir alafenamide had virological suppression at week 48, but renal and bone abnormalities were significantly reduced in patients allocated to tenofovir alafenamide compared with those allocated to tenofovir disoproxil fumarate.6

Research in context

Evidence before this study

We searched PubMed for articles published in English between 1970 and June 15, 2015, about the side-effects of tenofovir disoproxil fumarate-containing treatment. Our search terms included “tenofovir”, “creatinine”, “proteinuria”, “tubulopathy”, and “bone mineral density”. We reviewed about 50 articles. A phase 2 comparative study of tenofovir alafenamide versus tenofovir disoproxil fumarate as part of a single-tablet regimen with elvitegravir, cobicistat, and emtricitabine showed significant improvements in both renal and bone safety for patients in the tenofovir alafenamide group.

Added value of this study

This large study in virologically suppressed patients with HIV showed non-inferiority for elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide over tenofovir disoproxil fumarate-containing regimens on efficacy at week 48. Importantly, patients who switched to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide after at least 96 weeks on a tenofovir disoproxil fumarate-containing regimen had significant improvements in proteinuria, specific proximal tubular proteinuria, bone mineral density, and diagnoses of osteopenia and osteoporosis. These data also show that post-switch improvements occur irrespective of the third drug used. The improvements in measures of renal and bone safety could represent a clinical confirmation of the effect of lower plasma tenofovir concentrations in patients switched to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide. Moreover, both the speed of improvement in these objective tests (week 2 after the switch) and the magnitude of the improvement over time have not been previously described.

Implications of all available evidence

Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is a highly potent regimen that could be used in treatment-naive patients, with or without risk of renal or bone comorbidities, and it might be used as a strategic switch in patients using tenofovir-containing regimens who want to reduce their risk of tenofovir-related renal or bone toxicity.

In this study, we aimed to evaluate whether efficacy, safety, and tolerability (including bone and renal outcomes) were non-inferior in patients switched to a single tablet regimen of tenofovir alafenamide plus elvitegravir, cobicistat, and emtricitabine, compared with patients who remained on one of four regimens containing tenofovir disoproxil fumarate.

Section snippets

Study design and participants

GS-US-292-0109 is a randomised, active-controlled, open-label, multicentre, non-inferiority study. All patients were HIV-1-infected adults drawn from predefined Gilead clinical studies at 168 sites in 19 countries in North America, Europe, Latin America, Asia, and Australia in which patients were taking a tenofovir disoproxil fumarate-containing regimen recommended by treatment guidelines (appendix).1 All patients were virologically suppressed (HIV-1 RNA <50 copies per mL), had an estimated

Results

Between April 12, 2013 and April 3, 2014, we randomly assigned 1443 patients; 1436 received at least one dose of study drug (figure 1). Of these 1436 patients, regimens received pre-randomisation were: elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir disoproxil fumarate 300 mg (n=459); efavirenz 600 mg, emtricitabine 200 mg, and tenofovir disoproxil fumarate 300 mg (n=376); and cobicistat-boosted (n=216) or ritonavir-boosted (n=385) atazanavir 300 mg, emtricitabine

Discussion

As far as we are aware, this was the largest randomised controlled switch study ever done in virologically suppressed patients with HIV. After establishing non-inferiority of the tenofovir alafenamide regimen (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg) to four tenofovir disoproxil fumarate-containing regimens at week 48, this study also showed that switching to the open-label tenofovir alafenamide regimen was also superior to continuing with

References (42)

  • A Mocroft et al.

    A comparison of estimated glomerular filtration rates using Cockcroft-Gault and the Chronic Kidney Disease Epidemiology Collaboration estimating equations in HIV infection

    HIV Med

    (2014)
  • K Murata et al.

    Relative performance of the MDRD and CKD-EPI equations for estimating glomerular filtration rate among patients with varied clinical presentations

    Clin J Am Soc Nephrol

    (2011)
  • F Ibrahim et al.

    Comparison of CKD-EPI and MDRD to estimate baseline renal function in HIV-positive patients

    Nephrol Dial Transplant

    (2012)
  • Guidance for industry. Human immunodeficiency virus-1 infection: developing antiretroviral drugs for treatment

  • SL Hodder et al.

    Patient-reported outcomes in virologically suppressed, HIV-1-Infected subjects after switching to a simplified, single-tablet regimen of efavirenz, emtricitabine, and tenofovir DF

    AIDS Patient Care STDS

    (2010)
  • AW Wu et al.

    Responsiveness of the MOS-HIV and EQ-5D in HIV-infected adults receiving antiretroviral therapies

    Health Qual Life Outcomes

    (2013)
  • PC Hsiung et al.

    Comparison of WHOQOL-bREF and SF-36 in patients with HIV infection

    Qual Life Res

    (2005)
  • Sustiva (efavirenz) package insert

  • C Marzolini et al.

    Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients

    AIDS

    (2001)
  • DB Clifford et al.

    Impact of efavirenz on neuropsychological performance and symptoms in HIV-infected individuals

    Ann Intern Med

    (2005)
  • DE McCloskey

    FRAX® Identifying people at high risk of fracture

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