For almost two decades, HIV treatment guidelines have recommended use of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a third antiretroviral drug for treatment-naive patients with HIV/AIDS.1, 2, 3, 4 Recommended drugs for use with NRTIs include non-nucleoside reverse transcriptase inhibitors (eg, efavirenz and rilpivirine), boosted protease inhibitors (eg, darunavir plus ritonavir and atazanavir plus ritonavir), and the latest addition to the HIV armamentarium, the integrase inhibitors (eg, raltegravir). Integrase inhibitors are a promising new class of antiretroviral drug. The first approved HIV integrase inhibitor raltegravir is effective and well tolerated, but requires twice-daily dosing.5, 6 Elvitegravir, another HIV integrase inhibitor approved in the USA in August, 2012,7 and under review in the European Union, must be taken with food and needs pharmacological boosting, which can lead to clinically important drug–drug interactions.8, 9

Dolutegravir (S/GSK1349572) is a new integrase inhibitor with a 14 h plasma half-life that enables once-daily dosing without pharmacokinetic boosters.10, 11 No relevant cytochrome P450 enzyme inhibition or induction or food effect has been noted, reducing the potential for interactions.10, 12 A phase 2 study led to selection of a 50 mg once-daily dose of dolutegravir for phase 3 studies in antiretroviral-naive patients, on the basis of rates of virological response at 9…

Study design and patients

On Oct 19, 2010, we started this 96 week phase 3, randomised, double-blind, active-controlled, double-placebo, multicentre, parallel-group, non-inferiority study at 100 sites in the USA, Canada, Europe, and Australia. Eligible participants (aged ≥18 years) had a plasma HIV-1 RNA concentration of 1000 copies per mL or greater and no primary resistance in reverse transcriptase or protease enzymes. We included no CD4 entry criteria, but excluded patients with active US Centers for Disease Control and Prevention category C disease, except for Kaposi's sarcoma. We also excluded patients with defined laboratory values or medical characteristics, including pregnancy; moderate or severe hepatic impairment; an anticipated need for hepatitis C treatment during the study; estimated creatinine clearance of less than 50 mL/min; recent or ongoing malignancy; or treatment with an HIV-1 vaccine within 90 days of screening or with any immunomodulator within 28 days. Patients could receive abacavir only after exclusion of the HLA-B*5701 allele. Ethics committee approval was obtained at all participating centres in accordance with the principles of the 2008 Declaration of Helsinki. Each patient gave written informed consent before undergoing study procedures.

Randomisation and masking

Figure 1 shows the trial profile. 822 patients received at least one dose of study drug. Baseline demographics and disease characteristics were similar between treatment groups (table 1). Most patients had HIV subtype B (data not shown). At week 8, 350 (85%) of patients on dolutegravir and 323 (79%) on raltegravir had achieved plasma HIV-1 RNA of less than 50 copies per mL (figure 2). At week 48, 361 (88%) on dolutegravir and 351 (85%) on raltegravir had reached this threshold (figure 2, table 2). The adjusted treatment difference between groups was 2·5% (95% CI −2·2% to 7·1%), which met the non-inferiority criterion. Secondary efficacy analyses (table 3) and virological outcome (table 4) by baseline stratification supported the primary results by showing non-inferiority of dolutegravir. The number of patients who achieved the primary endpoint was similar between subgroups in analyses that combined high and low HIV-1 RNA strata and backbone NRTI (figure 3).

Table 1. Baseline demographics and disease characteristics

Data are n (%), or median (IQR), unless otherwise indicated. NRTI=nucleoside reverse transcriptase inhibitor.

Table 2. Patients with plasma HIV-1 RNA less than 50 copies per mL at wee…