ArticlesOnce-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial
Introduction
HIV integrase inhibitors are a promising new class of antiretroviral drugs with reported potency and a favourable safety profile. The first two approved integrase inhibitors, raltegravir (Isentress; Merck & Co, Inc, Whitehouse Station, NJ, USA) and elvitegravir are effective but have some limitations. Although well tolerated, raltegravir requires twice-daily doses and has a low genetic barrier to resistance compared with ritonavir-boosted protease inhibitors.1, 2, 3 Elvitegravir (as coformulated with cobicistat, tenofovir, and emtricitabine; Stribild; Gilead Sciences, Inc, Foster City, CA, USA) must be taken with food, requires pharmacological boosting that can lead to substantial drug interactions, has a low genetic barrier to resistance compared with ritonavir-boosted protease inhibitors, and is available only as a fixed-dose combination of tenofovir, emtricitabine, elvitegravir, and cobicistat with a possible increased risk of proximal renal tubulopathy.4, 5, 6
Dolutegravir is a next-generation integrase inhibitor with a plasma half-life of 14 h, which supports once-daily dosing without pharmacological boosting.7, 8, 9 No relevant inhibition or induction of cytochrome P450 or food effect has been reported, suggesting low potential for interactions.7, 10
Results from the week 48 primary analysis for SPRING-211 showed that dolutegravir provides non-inferior efficacy compared with raltegravir in antiretroviral-naive patients, with a similar safety profile.11 Here, we provide longer-term efficacy and safety data from the week 96 analysis of SPRING-2, the first phase 3 study in treatment-naive patients assessing dolutegravir versus raltegravir in combination with the two most widely recommended nucleoside reverse transcriptase inhibitor (NRTI) backbones.
Section snippets
Study design and participants
SPRING-2 (ING113086) is an ongoing phase 3, randomised, double-blind, active-controlled, double-placebo, multicentre, parallel-group, non-inferiority study that started on Oct 19, 2010. Adults (aged ≥18 years) naive for antiretroviral therapy with HIV-1 infection and HIV-1 RNA of 1000 copies per mL or more were recruited from 100 sites in Australia, Europe, Canada, and the USA. Study methods and eligibility criteria have been published previously.11 Results presented here are through the safety
Results
Of the 1035 patients screened, 827 were randomly assigned to treatment, and 822 received at least one dose of study medication (411 in each group; figure 1). Baseline demographics and disease characteristics were balanced across treatment groups and were presented previously.11 Patients predominantly had HIV-1 subtype B, with A1 being the next most common.11 In other patients, various subtypes were noted in small numbers, including AG, BF, C, F1, and G. HIV-1 subtype did not affect treatment
Discussion
Supporting the week 48 primary analysis, dolutegravir 50 mg once daily was again non-inferior to raltegravir 400 mg twice daily when given in combination with coformulated tenofovir–emtricitabine or abacavir–lamivudine. The change in response rates from week 48 to week 96 mostly was due to discontinuations after week 48 for administrative reasons (ie, not related to efficacy or tolerability). SPRING-2 is to our knowledge the first randomised, double-blind trial in HIV-1-infected,
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