The concept of a three-drug minimum for HIV therapy is rooted in a sequentialism that emerged with the dawning of antiretroviral treatment: one drug = nothing; two drugs = meh; three drugs = bingo! Over the years, in an effort to avoid peskier antiretrovirals or to reduce cost, some researchers have tinkered with alternatives, but these generally went nowhere (at least in the U.S.). Since the days of the first protease inhibitor trial, triple-drug therapy has dominated.
But apostasy is at hand, and like all movements, antiretroviral minimalism started small and then grew. Pilot studies involving a handful of participants fed bigger studies, leading to randomized trials. These demonstrations that two drugs could maintain HIV suppression planted the dual-therapy flag, and in late 2017, the U.S. Food and Drug Administration (FDA) approved a fixed-dose combination of rilpivirine and dolutegravir (Juluca, RPV/DTG) as a two-drug switch option.
However, maintaining viral suppression is one thing; achieving it is another. Incrementally, a series of investigations that started with the toe-in-the-water PADDLE study introduced us to the unlikely couple of DTG and the cherry-on-top antiretroviral, lamivudine (Epivir, 3TC). That this combination could succeed where superpower duos -- such as an integrase inhibitor plus a boosted protease inhibitor -- did not shows how playing matchmaker with antiretrovirals can be as complicated and unpredictable as playing matchmaker with people.
This leads us to the results of the GEMINI-1 and -2 trials and, unassailably, the biggest HIV story of the year. These identical twin, phase III trials compared an initial two-drug regimen of DTG and 3TC against a three-drug combination of tenofovir disoproxil fumarate and emtricitabine (Truvada, TDF/FTC) plus DTG. Being large and double-blind trials, their results were heavily anticipated. In fact, before the results were first presented in a sweltering Amsterdam at the 2018 International AIDS Conference, betting types were already handicapping the two-drug regimen, weighing how many virologic failures with drug resistance the treatment community would tolerate in this arm before declaring it dead on arrival.
As it turns out, such risk-benefit calculating was unnecessarily pessimistic. In the DTG+3TC arm, a more-than-reassuring 91% had no HIV RNA detected in their blood at week 48, statistically no different than the 93% of those randomized to TDF/FTC+DTG (difference: -1.7%; 95% CI: -4.4% to 1.1%). And, for all that handwringing about barrier to resistance, no emergence of viral resistance to any study drugs was observed in any participants. Drop the mic.
Subgroup analyses of minimal antiretroviral regimens have revealed unpleasantness in the past and are important to this tale. In the GEMINI trials, there were no differences between the study arms among those entering with plasma HIV RNA levels above and below 100,000 copies/mL. However, 79% (50 of 63 participants) of those in the two-drug arm who had a baseline CD4 cell count below 200 cells/mm³ had a week-48 viral load that was undetectable compared with 93% (51 of 55 participants) of those entering with counts below this level assigned the three-drug regimen.
The study team explained this away by noting how most, but not all, of those with CD4 cell counts below 200 cells/mm³ counted as failures in the DTG+3TC arm discontinued treatment for reasons unrelated to drug efficacy, such as adverse events not considered by the investigator to be treatment related, protocol violations, loss to follow-up, consent withdrawal, and change in antiretroviral treatment. Most of these seem to be unrelated to efficacy, but the FDA snapshot algorithm cares not for excuses, and while one could fully understand the motivation to explain the lower rate of success for DTG+3TC in the less than 200 cells/mm³ stratum, traditionally in clinical trials, there has been little attempt to do so.
The Bottom Line
Living as we are in an all-bets-are-off world in which the previously unimaginable (not to say, the unacceptable) are commonplace, it has become difficult to be genuinely surprised. Yet, in the small corner of the universe that we call the field of HIV therapeutics, only the arrogant or the visionary could believably claim to not be blown away by the success of DTG+3TC.
We have been flirting with pared-down HIV treatment, currently life-long in duration, for years. But what started as a bit of starry-eyed chit chat over drinks has now bloomed into a full-on affair. While some caution against complete commitment to DTG+3TC as a first-line therapy option until longer-term data are gathered and this strategy is stress-tested in more diverse populations of people living with HIV, we have to accept that we do clinical trials for a reason, and the GEMINI results are striking.
Understandably, it is hard to part from the tried and true, and absent a clear signal of longer-term toxicity of current triple therapies, many will cling to the perceived or (perhaps) very real security of more rather than less antiretroviral therapy. Current triple-drug regimens are far from burdensome, toxic, or otherwise so different from DTG+3TC that patients will notice.
An exception to this thinking, of course, is the potential differential effect of a two- versus three-drug regimen on the pocketbooks of insurers. Less medicine could mean lower costs, and that may be an attractive attribute for bottom-line watchers -- including health care administrators in nations that are so advanced as to provide their populace universal access to medications.
So, we end the year knowing DTG+3TC as initial therapy works. Will HIV providers and patients be motivated to adopt it without being forced to? That is a question for another year.
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-director of HIV services for the North Carolina state prison system. In 2014, he became co-director of the UNC-Duke Clinical RM Ebola Response Consortium.
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