Articles
Once-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

https://doi.org/10.1016/S1473-3099(13)70257-3Get rights and content

Summary

Background

In the primary analysis of SPRING-2 at week 48, dolutegravir showed non-inferior efficacy to and similar tolerability to raltegravir in adults infected with HIV-1 and naive for antiretroviral treatment. We present the 96 week results.

Methods

SPRING-2 is an ongoing phase 3, randomised, double-blind, active-controlled, non-inferiority study in treatment-naive adults infected with HIV-1 that started in Oct 19, 2010. We present results for the safety cutoff date of Jan 30, 2013. Patients had to be aged 18 years or older and have HIV-1 RNA concentrations of 1000 copies per mL or more. Patients were randomly assigned (1:1) to receive either dolutegravir (50 mg once daily) or raltegravir (400 mg twice daily), plus investigator-selected tenofovir–emtricitabine or abacavir–lamivudine. Prespecified 96 week secondary endpoints included proportion of patients with HIV-1 RNA less than 50 copies per mL, CD4 cell count changes from baseline, safety, tolerability, and genotypic or phenotypic resistance. We used an intention-to-treat exposed population (received at least one dose of study drug) for the analyses. Sponsor staff were masked to treatment assignment until primary analysis at week 48; investigators, site staff, and patients were masked until week 96. This study is registered with ClinicalTrials.gov, NCT01227824.

Findings

Of 1035 patients screened, 827 were randomly assigned to study group, and 822 received at least one dose of the study drug (411 patients in each group). At week 96, 332 (81%) of 411 patients in the dolutegravir group and 314 (76%) of 411 patients in the raltegravir group had HIV-1 RNA less than 50 copies per mL (adjusted difference 4·5%, 95% CI −1·1% to 10·0%) confirming non-inferiority. Secondary analyses of efficacy such as per protocol (HIV RNA <50 copies per mL: 83% for dolutegravir and 80% for raltegravir) and treatment-related discontinuation equals failure (93% without failure for dolutegravir; 91% for raltegravir) supported non-inferiority. Virological non-response occurred less frequently in the dolutegravir group (22 [5%] patients for dolutegravir vs 43 [10%] patients for raltegravir). Median increases in CD4 cell count from baseline were similar between groups (276 cells per μL for dolutegravir and 264 cells per μL for raltegravir). Ten patients (2%) in each group discontinued because of adverse events, with few such events between weeks 48 and 96 (zero in the dolutegravir group and one in the raltegravir group). No study-related serious adverse events occurred between week 48 and week 96. At virological failure, no additional resistance to integrase inhibitors or nucleotide reverse transcriptase inhibitors was detected since week 48 or in any patient receiving dolutegravir.

Interpretation

At week 96, once-daily dolutegravir was non-inferior to twice-daily raltegravir in treatment-naive, patients with HIV-1. Once-daily dosing without requirement for a pharmacokinetic booster makes dolutegravir-based therapy an attractive treatment option for HIV-1-infected treatment-naive patients.

Funding

ViiV Healthcare.

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,

References (28)

  • S Min et al.

    Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults

    AIDS

    (2011)
  • WG Powderly

    Integrase inhibitors in the treatment of HIV-1 infection

    J Antimicrob Chemother

    (2010)
  • I Song et al.

    Metabolism and drug-drug interaction profile of dolutegravir (DTG, S/GSK1349572) [abstract O-07]

    Rev Antivir Ther Infect Dis

    (2012)
  • JL Lennox et al.

    Raltegravir versus efavirenz regimens in treatment-naive HIV-1–infected patients: 96-week efficacy, durability, subgroup, safety, and metabolic analyses

    J Acquir Immune Defic Syndr

    (2010)
  • Cited by (0)

    View full text