ArticlesCo-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks
Introduction
Since the mid-1990s, standard of care for initial treatment of HIV infection has been a combination of at least three active agents from two or more classes of antiretroviral drugs. In the treatment guidelines1 of the US Department of Health and Human Services and the International Antiviral Society–USA, preferred initial therapy consists of the nucleoside reverse transcriptase inhibitors emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) combined with a third agent: the non-nucleoside reverse transcriptase inhibitor efavirenz (EFV), one of the ritonavir-boosted protease inhibitors atazanavir and darunavir, or the integrase inhibitor raltegravir.1, 2 Of these preferred regimens, only emtricitabine, tenofovir, and efavirenz are co-formulated as a single tablet (EFV/FTC/TDF). On the basis of high virological efficacy and safety in prospective clinical trials,3, 4, 5, 6 and ease of administration, this regimen is widely used and considered a gold standard for initial treatment in clinical trials and practice.7, 8
Despite these advantages, EFV/FTC/TDF is not suitable for all patients because it is associated with more CNS side-effects, rash, and hyperlipidaemia than are some comparators,5, 6, 9 and it increases the risk of teratogenicity when used during pregnancy.10 Additionally, among newly diagnosed patients resistance is more common to non-nucleoside reverse transcriptase inhibitors (including efavirenz) than to any other drug class.11, 12 A second single-tablet regimen combining emtricitabine, tenofovir, and rilpivirine is available for initial treatment of HIV-1 infection but is not indicated for patients with high plasma concentrations of HIV-1 RNA in some countries.13, 14
Elvitegravir (EVG) is an investigational HIV integrase inhibitor with potent antiretroviral activity that can be given once daily when administered with pharmacokinetic boosting.15, 16 In previously treated patients, once daily elvitegravir was non-inferior to raltegravir when combined with regimens that included a boosted protease inhibitor.17 A single-tablet regimen of elvitegravir, emtricitabine, tenofovir, and the investigational CYP3A4 inhibitor cobicistat (COBI) has been developed; in a phase 2 study, this combination had much the same antiretroviral activity as EFV/FTC/TDF.18 This phase 3 study was designed to assess safety and efficacy of EVG/COBI/FTC/TDF versus EFV/FTC/TDF for treatment-naive patients; it is the first adequately powered, double-blind study comparing different single-tablet regimens for treatment of HIV infection.
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Study design and patients
This study (GS–US–236–0102) is a phase 3 study being done in outpatient clinics in North America and was approved by institutional review boards or ethics committees at all investigation centres. All patients gave written informed consent.
Participants were adults infected with HIV-1 aged at least 18 years with plasma HIV-1 RNA concentrations of 5000 copies per mL or more and no previous use of antiretroviral drugs. Participants had to have an estimated glomerular filtration rate of at least 70
Results
Screening began in March, 2010, and by August, 2010, 917 patients had been screened, and 707 of them were randomly assigned treatment (figure 1). 700 received study medication; 348 in the EVG/COBI/FTC/TDF group and 352 in the EFV/FTC/TDF group. Baseline characteristics were much the same in the two treatment groups (table 1). 34% of patients had a baseline HIV RNA concentration of more than 100 000 copies per mL. Study drug discontinuation rates and reasons for discontinuation were similar
Discussion
Efficacy of EVG/COBI/FTC/TDF was non-inferior to standard-of-care for a range of endpoints. Additionally, subgroup analyses that included various demographic and clinical characteristics indicate that the response to EVG/COBI/FTC/TDF did not differ substantially from that to EFV/FTC/TDF and that virological success in patients with HIV RNA concentration of more than 100 000 copies per mL was high in both groups. In a parallel study, DeJesus and colleagues25 report that virological success of
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