More Real-World Testing for Dual Antiretroviral Therapy: A Top HIV Clinical Development of 2017
As described above, there is a growing interest in identifying antiretroviral regimens that contain as few agents as necessary to achieve and maintain viral suppression. The combination of dolutegravir and lamivudine (3TC, Epivir), first studied in the small, single-arm PADDLE study, is the poster child of this movement. The bona fides of dolutegravir as a potent agent with a fairly high barrier to resistance were established in several clinical trials and, therefore, it is an attractive candidate to pair with 3TC, which is cheap, well-tolerated, and has a track record of being useful as part of a dual combination with lopinavir/ritonavir (Kaletra).
In the single-arm AIDS Clinical Trials Group (ACTG) study A5353, dolutegravir plus 3TC was administered to 120 antiretroviral-naive patients with a screening HIV RNA level between 1,000 and 500,000 copies/mL (31% had a viral load greater than 100,000 copies/mL). At 24 weeks, 90% had a viral load of less than 50 copies/mL (snapshot analysis) including 89% of the 37 participants with a screening HIV RNA above 100,000 copies/mL. There were five participants with virologic non-success (HIV RNA ≥50 copies/mL at week 24), three of these from the higher viral load stratum. Of those with virologic non-success, three (one from high viral load stratum) had protocol-defined virologic failure (a confirmed load above 400 copies/mL at week 16 or 20 or a confirmed load above 200 copies/mL at week 24 or later). Suboptimal adherence, based on dolutegravir levels, was evident in all three cases of virologic failure. In one of these cases, genotype resistance testing detected the R263RK and the M184V mutations, the former signaling evolving integrase resistance. There were no discontinuations for adverse events.
The Bottom Line
This ACTG study provides a more real-world stress test for the dual combination of dolutegravir and 3TC than did PADDLE, which had a viral load ceiling of 100,000. Further, the ACTG generally enrolls a more diverse and challenged population of participants than most studies conducted outside the U.S. Therefore, through this study, we might be able to get a better sense of how this dual combination would fare in the proving ground outside a clinical trial.
Overall, the dual regimen performed well at 24 weeks with only three protocol-defined virologic failures, largely attributed to adherence issues. Suboptimal adherence to any regimen will lead to viral rebound and, of the three participants with protocol-defined virologic failure, drops in dolutegravir levels were promptly followed by rebounding viremia with wild-type virus. In one case, however, where dolutegravir levels appeared to fluctuate, some evidence of resistance was detected.
How much more vulnerable the dual combination is to failure with resistance compared with a three-drug regimen is not completely clear and will be better addressed by the ongoing GEMINI trials: large trials comparing dolutegravir plus 3TC with dolutegravir plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC, Truvada). But, one can wonder whether, even if a slightly increased risk of integrase resistance exists with dual therapy -- which might not -- will that be enough to dissuade its use if it is substantially more affordable?
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.