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Integrase Inhibitor Dolutegravir First ARV Superior to Efavirenz in ART-Naive
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52nd ICAAC, September 9-12, 2012, San Francisco
Mark Mascolini
Dolutegravir, an investigational integrase inhibitor, proved superior to efavirenz in a 48-week double-blind trial that enrolled antiretroviral-naive adults [1]. Only 4% in each study arm had virologic failure, but 10% withdrew from the efavirenz group because of adverse events, compared with 2% who quit the dolutegravir group, and that difference explained the main outcome. Other antiretrovirals have proved noninferior to efavirenz in randomized trials, but dolutegravir is the first ranked superior to efavirenz.
In an earlier, smaller trial, the 48-week response rate was higher with dolutegravir (at 10, 25, or 50 mg daily) than with efavirenz (87% versus 82%), but there were 3 virologic failures in the dolutegravir group and 1 in the efavirenz group [2]. Drug-related adverse events of moderate or higher intensity were more frequent with efavirenz than dolutegravir in this phase 2 study.
The phase 3 double-blind, double-dummy SINGLE trial randomized 833 previously untreated adults to dolutegravir at a once-daily dose of 50 mg plus coformulated abacavir/lamivudine or to once-daily Atripla--efavirenz plus tenofovir/emtricitabine. (Different nucleoside backbones are unusual in randomized trials not designed to compare backbones, and this difference suggests ViiV is considering a 3-in-1 pill combining dolutegravir and the two nucleosides.) The primary endpoint was the proportion of participants with a viral load below 50 copies at week 48 in a snapshot analysis (which evaluates responses at a single point in time).
Most study participants (84%) were men, and 32% were nonwhite. Median pretreatment viral loads were approximately 4.7 log10 copies/mL (about 50,000 copies) in both treatment arms, and about one third in each arm had a pretreatment load above 100,000 copies. Median pretreatment CD4 counts were 335 in the dolutegravir group and 339 in the efavirenz group.
During the trial 12% of those randomized to dolutegravir withdrew (2% because of adverse events and 3% for lack of efficacy). A higher proportion, 20%, withdrew from the efavirenz group (10% because of adverse events and 3% for lack of efficacy).
Among people who took at least one dose, 88% randomized to dolutegravir and 81% randomized to efavirenz had a viral load below 50 copies at week 48 in the snapshot analysis. That result met predefined criteria indicating that the dolutegravir regimen was statistically superior to the efavirenz regimen at 48 weeks (+7.4% difference, 95% confidence interval +2.5% to +12.3%, P = 0.003). Among people with a pretreatment viral load above 100,000 copies, a higher proportion in the dolutegravir group had a week-48 viral load below 50 copies in the snapshot analysis (83% versus 76%).
Virologic nonresponse rates were similar with dolutegravir (5%) and efavirenz (6%). A lower proportion assigned to dolutegravir than to efavirenz (2% versus 10%) discontinued because of adverse events or death. There were 2 deaths, both in the efavirenz arm and neither attributed to study drugs.
Among people with virologic failure and with genotypic test results, none of 9 in the dolutegravir arm had detectable integrase or reverse transcriptase mutations. Among 9 people with genotypic results in whom Atripla failed, one nucleoside mutation (K65R) and four nonnucleoside mutations emerged.
Protocol-defined virologic failure rates were identical in the two arms at 4%, but as noted a higher proportion taking efavirenz than dolutegravir had to discontinue treatment because of adverse events (10% versus 2%). Individual adverse events leading to discontinuation were consistently higher with efavirenz: psychiatric disorders (4% versus less than 1%), nervous system disorders (3% versus 0%), skin and subcutaneous tissue disorders (2% versus less than 1%), and gastrointestinal disorders (2% versus 0%). Among adverse events affecting 10% or more study participants, insomnia was more frequent with dolutegravir than efavirenz (15% versus 10%).
Median time to virologic suppression was significantly shorter with dolutegravir than efavirenz (28 versus 84 days, P < 0.0001). (Faster virologic suppression also distinguished the integrase inhibitor raltegravir from efavirenz in previous studies.) Median CD4 gains were significantly greater with dolutegravir than efavirenz (267 versus 208 cells, P < 0.001), but it is not clear whether this difference is clinically significant because of the relatively high starting CD4 counts in this trial.
Clinical investigator Joel Gallant (Johns Hopkins University, Baltimore), who was not a study investigator, observed during the discussion after this report that the discontinuation rate with Atripla in this trial is higher than observed in previous studies or clinical practice, and those differences drove the significant 48-week response difference between the two regimens.
References
1. Walmsley S, Antela A, Clumeck N, et al. Dolutegravir (DTG; S/GSK1349572) + abacavir/lamivudine once daily statistically superior to tenofovir/emtricitabine/efavirenz: 48-week results--SINGLE (ING114467). 52nd Interscience Conference on Antimicrobials and Chemotherapy (ICAAC). September 9-12, 2012. San Francisco. Abstract H-556b.
2. van Lunzen J, Maggiolo F, Arribas JR, et al. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis. 2012;12:111-118.
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