A Better Second Chance: A Top HIV Clinical Development of 2017
Deciding what to do after the failure of a first-line regimen has long entailed a bit of head-scratching. Aside from the investigation into what went wrong (e.g., adherence), there is the matter of selecting a salvage regimen that can suppress virus that might have developed resistance, especially to one or more nucleosides. In resource-limited settings, there are few antiretroviral options, and first-line therapy with a non-nucleoside-based regimen is still typically followed by a regimen of lopinavir/ritonavir (Kaletra) plus some combination of nucleosides. In the DAWNING trial, this long-standing approach was compared with a second-line regimen containing dolutegravir.
In this open-label trial conducted in Africa, Asia, South America, Eastern Europe, and Mexico, patients with a viral load greater than 400 copies/mL on a non-nucleoside-based regimen and at least one nucleoside predicted to be active by genotypic resistance testing at screening were randomized to lopinavir/ritonavir or dolutegravir plus two nucleosides. Of the 968 screened, 627 were randomized; the excluded were those without an active nucleoside on resistance testing. At entry, over 75% were on efavirenz (Sustiva, Stocrin) and about 60% on tenofovir disoproxil fumarate (TDF, Viread). After randomization, the nucleosides selected by clinicians were mostly zidovudine (AZT, Retrovir) plus lamivudine (3TC, Epivir) or TDF plus 3TC or emtricitabine (FTC, Emtriva).
At their review of the 24-week data, the Data Safety and Monitoring Board (DSMB) for the trial recommended discontinuation of the lopinavir/ritonavir arm due to excess virologic failures. With an intent-to-treat approach, 82% of the dolutegravir group compared with 69% of the lopinavir/ritonavir group had achieved viral suppression (<50 copies/mL). Similar rate differences between the arms were seen among those contributing to latter time points prior to the DSMB recommendation. Unsurprisingly, there was a higher rate of drug-related adverse events in the protease inhibitor arm. No integrase or protease resistance was detected.
The Bottom Line
With rumored plans for generic dolutegravir to become an option in resource-limited regions, these results will be welcomed by health care providers who have had to rely on a cumbersome protease inhibitor-based regimen to rescue first-line failures. However, the lack of resistance testing available in resource-limited regions might be an issue, considering that approximately 30% of those screened in this trial were excluded for not having an active nucleoside to pair with the anchors being studied. There are reasons to be concerned about the use of a regimen that is, in essence, dolutegravir monotherapy. Providers might have to play the odds and follow viral load response carefully.
However, this study is instructive in that it can be assumed that many of those entering the trial had resistance to 3TC and FTC. Therefore, an effective nucleoside and dolutegravir (plus the magic of maintaining the 184 mutation) produced high rates of suppression -- something we knew was likely with a protease inhibitor-based second-line regimen, and now we know extends also to this integrase inhibitor.
David Alain Wohl, M.D., is a professor of medicine in the Division of Infectious Diseases at the University of North Carolina (UNC). He is site leader of the UNC AIDS Clinical Trials Unit at Chapel Hill, director of the North Carolina AIDS Education and Training Center (AETC), and co-directs HIV services for the North Carolina state prison system. In 2014, he became co-director of the UNC-Duke Clinical RM Ebola Response Consortium.