Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study

Summary

Background

Dolutegravir (GSK1349572), a once-daily HIV integrase inhibitor, has shown potent antiviral response and a favourable safety profile. We evaluated safety, efficacy, and emergent resistance in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV-1 with at least two-class drug resistance.

Methods

ING111762 (SAILING) is a 48 week, phase 3, randomised, double-blind, active-controlled, non-inferiority study that began in October, 2010. Eligible patients had two consecutive plasma HIV-1 RNA assessments of 400 copies per mL or higher (unless >1000 copies per mL at screening), resistance to two or more classes of antiretroviral drugs, and had one to two fully active drugs for background therapy. Participants were randomly assigned (1:1) to once-daily dolutegravir 50 mg or twice-daily raltegravir 400 mg, with investigator-selected background therapy. Matching placebo was given, and study sites were masked to treatment assignment. The primary endpoint was the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48, evaluated in all participants randomly assigned to treatment groups who received at least one dose of study drug, excluding participants at one site with violations of good clinical practice. Non-inferiority was prespecified with a 12% margin; if non-inferiority was established, then superiority would be tested per a prespecified sequential testing procedure. A key prespecified secondary endpoint was the proportion of patients with treatment-emergent integrase-inhibitor resistance. The trial is registered at ClinicalTrials.gov, NCT01231516.

Findings

Analysis included 715 patients (354 dolutegravir; 361 raltegravir). At week 48, 251 (71%) patients on dolutegravir had HIV-1 RNA less than 50 copies per mL versus 230 (64%) patients on raltegravir (adjusted difference 7·4%, 95% CI 0·7 to 14·2); superiority of dolutegravir versus raltegravir was then concluded (p=0·03). Significantly fewer patients had virological failure with treatment-emergent integrase-inhibitor resistance on dolutegravir (four vs 17 patients; adjusted difference −3·7%, 95% CI −6·1 to −1·2; p=0·003). Adverse event frequencies were similar across groups; the most commonly reported events for dolutegravir versus raltegravir were diarrhoea (71 [20%] vs 64 [18%] patients), upper respiratory tract infection (38 [11%] vs 29 [8%]), and headache (33 [9%] vs 31 [9%]). Safety events leading to discontinuation were infrequent in both groups (nine [3%] dolutegravir, 14 [4%] raltegravir).

Interpretation

Once-daily dolutegravir, in combination with up to two other antiretroviral drugs, is well tolerated with greater virological effect compared with twice-daily raltegravir in this treatment-experienced patient group.

Funding

ViiV Healthcare.

Introduction

Although the first-generation integrase inhibitors raltegravir and elvitegravir are potent and well tolerated in treatment-naive and treatment-experienced adults with HIV,1, 2, 3, 4 improved integrase inhibitor-based therapy options would benefit these patients. Raltegravir requires twice-daily dosing⁵ and has variable pharmacokinetic characteristics. Elvitegravir must be taken with food and requires coadministration with a pharmacokinetic boosting agent, creating the potential for clinically significant drug interactions.⁶ Additionally, treatment-experienced patients who fail raltegravir-based or elvitegravir-based regimens commonly develop integrase inhibitor resistance; cross-resistance between raltegravir and elvitegravir has been reported.4, 7, 8, 9, 10, 11 Thus, the development of new unboosted integrase inhibitors with once-daily dosing and an improved resistance profile is desirable.

Dolutegravir (GSK1349572) is a next-generation integrase inhibitor in clinical development. Dolutegravir dissociates slowly from integrase-DNA complexes (t_½=71 h, wildtype integrase) in vitro,¹² and has a 14-h plasma half-life in patients, supporting once-daily dosing without pharmacokinetic boosters.¹³ It has the potential for a high barrier to resistance and has shown potent efficacy in antiretroviral-naive patients and patients with multiclass resistance.14, 15, 16 No significant food effect or significant cytochrome P450 inhibition or induction has been observed, suggesting a low potential for interactions.13, 17

We report results from ING111762 (SAILING), comparing clinical efficacy, safety, and virology outcomes in treatment-experienced, integrase-inhibitor-naive patients who received dolutegravir 50 mg once daily or raltegravir 400 mg twice a day, plus investigator-selected background therapy.