Articles Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study Francois Raffi , Anita Rachlis, Hans-Jürgen Stellbrink, W David Hardy, Carlo Torti, Chloe Orkin, Mark Bloch, Daniel Podzamczer, Vadim Pokrovsky, Federico Pulido, Steve Almond, David Margolis, Clare Brennan, Sherene Min, on behalf of the SPRING-2 study group Summary Background Dolutegravir (S/GSK1349572) is a once-daily HIV integrase inhibitor with potent antiviral activity and a Lancet 2013; 381: 735–43 favourable safety profi le. We compared dolutegravir with HIV integrase inhibitor raltegravir, as initial treatment for Published Online adults with HIV-1. January 8, 2013 http://dx.doi.org/10.1016/ S0140-6736(12)61853-4 Methods SPRING-2 is a 96 week, phase 3, randomised, double-blind, active-controlled, non-inferiority study that See Comment page 705 began on Oct 19, 2010, at 100 sites in Canada, USA, Australia, and Europe. Treatment-naive adults (aged ≥18 years) University of Nantes, Nantes, with HIV-1 infection and HIV-1 RNA concentrations of 1000 copies per mL or greater were randomly assigned (1:1) via France (Prof F Raffi MD); a computer-generated randomisation sequence to receive either dolutegravir (50 mg once daily) or raltegravir (400 mg Sunnybrook Health Sciences twice daily). Study drugs were given with coformulated tenofovir/emtricitabine or abacavir/lamivudine. Randomisation Centre, University of Toronto, was stratifi ed by screening HIV-1 RNA (≤100 000 copies per mL or >100 000 copies per mL) and nucleoside reverse ON, Canada (Prof A Rachlis MD); Infektionsmedizinisches transcriptase inhibitor backbone. Investigators were not masked to HIV-1 RNA results before randomisation. The Centrum Hamburg Study primary endpoint was the proportion of participants with HIV-1 RNA less than 50 copies per mL at 48 weeks, with a Centre, Hamburg, Germany 10% non-inferiority margin. Main secondary endpoints were changes from baseline in CD4 cell counts, incidence and (Prof H-J Stellbrink MD); severity of adverse events, changes in laboratory parameters, and genotypic or phenotypic evidence of resistance. Our Cedars-Sinai Medical Centre–Geff en School of primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01227824. Medicine at UCLA, Los Angeles, CA, USA (W D Hardy MD); Findings 411 patients were randomly allocated to receive dolutegravir and 411 to receive raltegravir and received at University of Brescia, Brescia, least one dose of study drug. At 48 weeks, 361 (88%) patients in the dolutegravir group achieved an HIV-1 RNA Italy (C Torti MD); University Magna Graecia, Catanzaro, Italy value of less than 50 copies per mL compared with 351 (85%) in the raltegravir group (adjusted diff erence 2·5%; (C Torti); Royal London 95% CI –2·2 to 7·1). Adverse events were similar between treatment groups. The most common events were Hospital, London, UK nausea (59 [14%] patients in the dolutegravir group vs 53 [13%] in the raltegravir group), headache (51 [12%] vs (C Orkin MD); Holdsworth 48 [12%]), nasopharyngitis (46 [11%] vs 48 [12%]), and diarrhoea (47 [11%] in each group). Few patients had drug- House Medical Practice, Darlinghurst, NSW, Australia related serious adverse events (three [<1%] vs fi ve [1%]), and few had adverse events leading to discontinuation (M Bloch MD); Hospital (ten [2%] vs seven [2%] in each group). CD4 cell counts increased from baseline to week 48 in both treatment Universitari de Bellvitge, groups by a median of 230 cells per μL. Rates of graded laboratory toxic eff ects were similar. We noted no evidence Barcelona, Spain of treatment-emergent resistance in patients with virological failure on dolutegravir, whereas of the patients with (D Podzamczer MD); Russian Federal Guidance Centre of virologic failure who received raltegravir, one (6%) had integrase treatment-emergent resistance and four (21%) had AIDS, Moscow, Russia nucleoside reverse transcriptase inhibitors treatment-emergent resistance. (Prof V Pokrovsky MD); Hospital 12 Octubre, Madrid, Spain Interpretation The non-inferior effi cacy and similar safety profi le of dolutegravir compared with raltegravir means (F Pulido MD); GlaxoSmithKline, Mississauga, ON, Canada that if approved, combination treatment with once-daily dolutegravir and fi xed-dose nucleoside reverse transcriptase (S Almond MMath); and inhibitors would be an eff ective new option for treatment of HIV-1 in treatment-naive patients. GlaxoSmithKline, Research Triangle Park, NC, USA Funding ViiV Healthcare. (D Margolis MD, C Brennan DPT, S Min MD) Correspondence to: Introduction armamentarium, the integrase inhibitors (eg, ralte- Prof Francois Raffi , Infectious For almost two decades, HIV treatment guidelines gravir). Integrase inhibitors are a promising new class Diseases Department, University have recommended use of two nucleoside reverse of antiretroviral drug. The fi rst approved HIV integrase of Nantes, Hotel Dieu, transcriptase inhibitors (NRTIs) plus a third anti- inhibitor raltegravir is eff ective and well tolerated, but Nantes 44093, France francois.raffi @wanadoo.fr retroviral drug for treatment-naive patients with HIV/ requires twice-daily dosing.5,6 Elvitegravir, another HIV AIDS.1–4 Recommended drugs for use with NRTIs integrase inhibitor approved in the USA in August, include non-nucleoside reverse transcriptase inhibitors 2012,7 and under review in the European Union, (eg, efavirenz and rilpivirine), boosted protease inhib- must be taken with food and needs pharmacological itors (eg, daru navir plus ritonavir and atazanavir boosting, which can lead to clinically important plus ritonavir), and the latest addition to the HIV drug–drug interactions.8,9 www.thelancet.com Vol 381 March 2, 2013 735 Articles Dolutegravir (S/GSK1349572) is a new integrase inhib- staff were masked to treatment assignment until the itor with a 14 h plasma half-life that enables once-daily week 48 analysis; investigators, site staff , and patients dosing without pharmacokinetic boosters.10,11 No relevant were masked until week 96. cytochrome P450 enzyme inhibition or induction or food eff ect has been noted, reducing the potential for Procedures interactions.10,12 A phase 2 study led to selection of a The prespecifi ed primary endpoint was the proportion of 50 mg once-daily dose of dolutegravir for phase 3 studies patients with HIV-1 RNA of less than 50 copies per mL at in antiretroviral-naive patients, on the basis of rates of week 48. Main secondary endpoints were changes from virological response at 96 weeks being as high as 88% in baseline in CD4 cell counts, incidence and severity of patients in that dosage group.13,14 We therefore undertook adverse events, changes in laboratory parameters, and this phase 3 study to assess the effi cacy and safety of genotypic or phenotypic evidence of resistance. Other dolutegravir versus raltegravir, in combination with two secondary endpoints were dolutegravir pharmacokinetics, widely recom mended NRTI backbones, as fi rst-line pharmacokinetic and pharmacodynamic relations, and treatment for antiretroviral-naive adults with HIV-1. health outcomes. We used EQ-5D (EuroQol, Rotterdam, Netherlands), a generic, non-disease-specifi c, preference- Methods based utility measure that includes a descriptive system Study design and patients and a visual analogue scale, to measure health outcome On Oct 19, 2010, we started this 96 week phase 3, at baseline and weeks 24, 48, and 96. randomised, double-blind, active-controlled, double- Study visits were at baseline, and weeks 2, 4, 8, 12, 16, placebo, multicentre, parallel-group, non-inferiority 24, 32, 40, and 48, and every 12 weeks thereafter. Staff study at 100 sites in the USA, Canada, Europe, and assessed treatment compliance by doing pill counts of Australia. Eligible participants (aged ≥18 years) had a returned drug containers at each visit. Plasma HIV-1 RNA plasma HIV-1 RNA concentration of 1000 copies per mL was measured with the Abbott RealTime HIV-1 PCR assay or greater and no primary resistance in reverse trans- (Abbott Molecular, Des Plaines, IL, USA). Between criptase or protease enzymes. We in cluded no CD4 entry weeks 24 and 48, protocol-defi ned virological failure was criteria, but excluded patients with active US Centers for defi ned as two consecutive plasma HIV-1 RNA values of Disease Control and Prevention category C disease, 50 copies per mL or greater. Patients meeting this except for Kaposi’s sarcoma. We also excluded patients criterion before week 48 were withdrawn from the study. with defi ned laboratory values or medical characteristics, CD4 cell count and percentage were measured at each including pregnancy; moderate or severe hepatic study visit (except for week 2) to assess immunological impairment; an anticipated need for hepatitis C treat- response. Viral genotype (reverse transcriptase and ment during the study; estimated creatinine clearance of protease) was analysed by Quest Diagnostics (Valencia, less than 50 mL/min; recent or ongoing malignancy; or CA, USA) at screening. Genotypic and phenotypic treatment with an HIV-1 vaccine within 90 days of analyses (reverse transcriptase and integrase) of plasma screening or with any immuno modulator within 28 days. samples from day 1, and time of confi rmed virological Patients could receive abacavir only after exclusion of the failure for all patients with protocol-defi ned virological HLA-B*5701 allele. failure, were done with GenoSure, Standard