Elsevier

The Lancet

Volume 379, Issue 9835, 30 June–6 July 2012, Pages 2429-2438
The Lancet

Articles
Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial

https://doi.org/10.1016/S0140-6736(12)60918-0Get rights and content

Summary

Background

The HIV integrase strand transfer inhibitor elvitegravir (EVG) has been co-formulated with the CYP3A4 inhibitor cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) into a once-daily, single tablet. We compared EVG/COBI/FTC/TDF with a ritonavir-boosted (RTV) protease inhibitor regimen of atazanavir (ATV)/RTV+FTC/TDF as initial therapy for HIV-1 infection.

Methods

This phase 3, non-inferiority study enrolled treatment-naive patients with an HIV-1 RNA concentration of 5000 copies per mL or more and susceptibility to atazanavir, emtricitabine, and tenofovir. Patients were randomly assigned (1:1) to receive EVG/COBI/FTC/TDF or ATV/RTV+FTC/TDF plus matching placebos, administered once daily. Randomisation was by a computer-generated random sequence, accessed via an interactive telephone and web response system. Patients, and investigators and study staff who gave treatments, assessed outcomes, or analysed data were masked to the assignment. The primary endpoint was HIV RNA concentration of 50 copies per mL or less after 48 weeks (according to the US FDA snapshot algorithm), with a 12% non-inferiority margin. This trial is registered with ClinicalTrials.gov, number NCT01106586.

Findings

1017 patients were screened, 715 were enrolled, and 708 were treated (353 with EVG/COBI/FTC/TDF and 355 with ATV/RTV+FTC/TDF). EVG/COBI/FTC/TDF was non-inferior to ATV/RTV+FTC/TDF for the primary outcome (316 patients [89·5%] vs 308 patients [86·8%], adjusted difference 3·0%, 95% CI −1·9% to 7·8%). Both regimens had favourable safety and tolerability; 13 (3·7%) versus 18 (5·1%) patients discontinued treatment because of adverse events. Fewer patients receiving EVG/COBI/FTC/TDF had abnormal results in liver function tests than did those receiving ATV/RTV+FTC/TDF and had smaller median increases in fasting triglyceride concentration (90 μmol/L vs 260 μmol/L, p=0·006). Small median increases in serum creatinine concentration with accompanying decreases in estimated glomerular filtration rate occurred in both study groups by week 2; they generally stabilised by week 8 and did not change up to week 48 (median change 11 μmol/L vs 7 μmol/L).

Interpretation

If regulatory approval is given, EVG/COBI/FTC/TDF would be the first integrase-inhibitor-based regimen given once daily and the only one formulated as a single tablet for initial HIV treatment.

Funding

Gilead Sciences.

Introduction

International treatment guidelines1, 2, 3, 4 recommend that initial therapy for treatment-naive patients with HIV-1 infection consists of two nucleoside/nucleotide reverse transcriptase inhibitors plus a non-nucleoside reverse transcriptase inhibitor (generally efavirenz; EFV), a ritonavir-boosted (RTV) protease inhibitor (generally darunavir or atazanavir; ATV), or the integrase strand transfer inhibitor raltegravir. Guidelines also include a fixed-dose combination tablet of emtricitabine (FTC) plus tenofovir disoproxil fumarate (TDF), as a preferred backbone for initial therapy. Ritnoavir-boosted protease inhibitor regimens have antiviral potency and a high barrier for development of drug resistance, and are an alternative to non-nucleoside reverse transcriptase inhibitors for some patients, including those with transmitted resistance to non-nucleoside reverse transcriptase inhibitors, those unlikely to adhere to therapy, and women of childbearing potential, or to avoid the neuro-psychiatric disorders associated with efavirenz.1, 2, 3, 4, 5, 6 Regimens including ritonavir are generally well tolerated but are associated with metabolic complications such as dyslipidaemia, lipodystrophy, insulin resistance, and multiple drug interactions.1 The main limitation of ritonavir-based therapy is the additional pill and prescription burdens and tolerability profiles of the protease inhibitors and ritonavir.

Clinical studies show better adherence and treatment satisfaction, and persistent suppression of viral load with simple, once-daily highly active antiretroviral therapy regimens than with complex multi-pill ones.7, 8, 9, 10 Only two single-tablet regimens are available, both based on non-nucleoside reverse transcriptase inhibitors: EFV/FTC/TDF and FTC/rilpivirine/TDF. Alternative single-tablet regimens are needed, especially those with new drug classes or mechanisms of action that provide sustained efficacy with favourable tolerability and safety profiles for patients with HIV infection.

Elvitegravir (EVG) is a once-daily investigational HIV integrase strand transfer inhibitor with potent antiviral activity that has been co-formulated with cobicistat (COBI), an investigational cytochrome P450 3A inhibitor (a pharmacoenhancer that has no anti-HIV activity), plus the nucleoside/nucleotide reverse transcriptase inhibitor backbone FTC/TDF (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir disoproxil fumarate 300 mg). This formulation had potent and durable antiretroviral efficacy and favourable safety in a phase 2 trial.11 Here, we report the results of GS-236-0103, an ongoing study to assess the safety and efficacy of EVG/COBI/FTC/TDF versus ATV/RTV+FTC/TDF for first treatment of HIV infection.

Section snippets

Study design and patients

GS-236-0103 is a phase 3, randomised, double-blind study done at 146 sites in Australia, Europe, North America, and Thailand, in accordance with the Declaration of Helsinki. The study was reviewed and approved by central or site-specific review boards or ethics committees. Each patient gave written informed consent.

Adults (aged ≥18 years) were enrolled if they had HIV-1 and had had no previous antiretroviral treatment, with a plasma HIV RNA concentration of 5000 copies per mL or higher and an

Results

1017 patients were screened, of whom 715 were randomly assigned treatment. 708 received at least one dose of study drug: 353 in the EVG/COBI/FTC/TDF group and 355 in the ATV/RTV+FTC/TDF group (figure 1). Baseline characteristics were similar between groups (table 1).

EVG/COBI/FTC/TDF was non-inferior to ATV/RTV+FTC/TDF: 316 (89·5%) patients in the EVG/COBI/FTC/TDF group and 308 (86·8%) patients in the ATV/RTV+FTC/TDF group had viral suppression (adjusted treatment difference 3·0%, 95% CI −1·9%

Discussion

This study is the first assessment of a once-daily single-tablet regimen based on an integrase strand transfer inhibitor compared with ATV/RTV+FTC/TDF for first treatment of HIV infection in patients who have not previously received any antiretroviral treatment. In addition to meeting the primary endpoint of non-inferiority to ATV/RTV+FTC/TDF, EVG/COBI/FTC/TDF had high viral suppression according to secondary and tertiary efficacy analyses and demographic subgroup analyses. Sax and colleagues18

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