Antiretroviral therapy: dolutegravir sets SAIL(ING).

Of all the antiretroviral therapy (ART) drugs in recent development, few have generated as much expectation as the HIV integrase strand transfer inhibitor dolutegravir. Raltegravir, the fi rst in this class, has proved to be a very valuable drug, from treatment initiation to late salvage. However, in an era in which once daily therapy and single tablet regimens dominate the treatment initiation market, raltegravir has the relative disadvantage of twice daily dosing. In 2012 the second-in-class integrase strand transfer inhibitor, elvitegravir, gained US Food and Drug Administration approval as a component of the new four-in-one single tablet regimen Stribild (Gilead Sciences Inc, Foster City, CA, USA). Elvitegravir requires pharmacological boosting because it does not support once daily dosing in its own right. Although this quadruple regimen has shown non-inferiority versus the fi rst single tablet ART regimen of efavirenz, tenofovir, and emtricitabine (Atripla, Gilead Sciences Inc and BristolMyers Squibb Co, Princeton, NJ, USA) and ritonavirboosted atazanavir, tenofovir, and emtricitabine, the need for boosting is a relative drawback with an increased potential for drug–drug interactions. Elvitegravir is not currently available as a single agent. The third-in-class integrase strand transfer inhibitor likely to obtain approval, possibly within the next year, is dolutegravir. Dolutegravir’s half-life supports once daily dosing, and it is therefore the fi rst stand-alone once daily drug in this class. Dolutegravir has shown non-inferiority in a double-blind comparison with raltegravir. Results presented at a recent conference were consistent with dolutegravir having superior effi cacy in ART-naive participants when used as a component of a single tablet regimen (combined with abacavir and lamivudine) in a double-blind comparison with Atripla. In The Lancet, Pedro Cahn and colleagues publish the results of SAILING, a double-blind randomised controlled comparison of dolutegravir versus ralte gravir with optimised background regimen, in 715 participants with HIV with previous failure of combination ART regimens and demonstrable resistance to drugs in at least two ART drug classes, but no history of previous exposure to an integrase strand transfer inhibitor. The investigators found that not only was dolutegravir non-inferior to raltegravir in the primary analysis of proportion of patients with plasma HIV-1 RNA of fewer than 50 copies per mL at 48 weeks, but that dolutegravir reached predefi ned criteria for superiority (251 [71%] vs 230 [64%] patients; adjusted diff erence 7·4%, 95% CI 0·7–14·2; p=0·03). Adverse event rates were similar between groups and led to discontinuation in nine (3%) participants on dolutegravir and 14 (4%) on raltegravir. SAILING helps to broaden our understanding of dolutegravir through enrolment of a diverse cohort from countries in North and Latin America, Europe, Africa, and Asia. The study population was 32% female, nearly half had previously developed AIDS, and participants had a mix of HIV subtypes. The resistance results are provocative. Of those with virological failure and determinable genotypes or phenotypes, integrase-associated mutations were shown in four (25%) of 17 participants on dolutegravir and 16 (42%) of 38 on raltegravir. In those four participants on dolutegravir, none selected a treatment-emergent mutation conferring high-level resistance to dolutegravir or ralte gravir, although two selected a unique integrasemutation conferring minor loss of susceptibility to both drugs. For the 16 participants on raltegravir the treatment-emergent mutations were consistent with those described to date, conferring substantial resistance to raltegravir but limited cross-resistance to Published Online July 3, 2013 http://dx.doi.org/10.1016/ S0140-6736(13)61456-7