As 2019 draws to a close, TheBodyPro takes stock of the year's most noteworthy developments in HIV. And not just any developments: We're looking specifically at those with the largest impact for people who provide HIV care and services in the U.S. In this series, veteran clinician-researcher David Alain Wohl, M.D., guides us through the new research and other important moments of 2019 that have the greatest potential to alter the HIV clinical landscape in the months and years to come.
The GEMINI trials earned respect for the combination of dolutegravir (DTG, Tivicay) plus lamivudine (3TC, Epivir). At 96 weeks, this dual-therapy regimen remained non-inferior to dolutegravir plus emtricitabine/tenofovir disoproxil fumarate (FTC/TDF, Truvada) when taken as a first-line regimen, with no emergent drug resistance detected during study follow-up. That's longer-term data that would normally be worthy of Top 10 status.
But in the U.S., the real potential for 3TC/DTG -- which was approved by the U.S. Food and Drug Administration in April under the brand name Dovato -- is in maintenance, not first-line treatment. That's because, although getting a person's viral load suppressed is a taller order than keeping it that way, a switch study is arguably more relevant to us clinically as new diagnoses drop.
The TANGO trial was as straightforward a switch study as there ever has ever been. (Incidentally, in my next life, I want to be Donald Glover, but in the one after that I'd like to be the person who makes up names for clinical trials.) People with suppressed viremia on a first regimen that included emtricitabine/tenofovir alafenamide (F/TAF, Descovy) plus either a non-dolutegravir integrase inbibitor (INSTI), PI, or NNRTI either continued their HIV therapy or switched to fixed-dose 3TC/DTG.
The trial is open-label. Participants are overwhelmingly white and male. Almost 80% entered the trial on an INSTI (mostly elvitegravir, a.k.a. Vitekta). Participants were required to not be chronically infected with hepatitis B, given the potential randomization to a tenofovir-free regimen.
At the 2019 International AIDS Society conference, the 48-week data efficacy data were presented. An impressive 93% in both the switch and the continued-therapy arms had suppressed viremia. No resistance was detected during the trial, and subgroup analyses presented later at the European AIDS Conference found no differences in virologic suppression by demographics, pre-switch regimen type, or CD4 cell count above vs. below 350/mm3.
Drug-related adverse events, including those leading to treatment discontinuation, were uncommon but slightly more likely in the 3TG/DTG arm. All lipid subsets fell in the switch arm, while they ticked up a bit in the continued therapy arm. (Relevant to our #1 Top 10 story this year on integrase inhibitors and weight gain, the mean weight change from baseline in each arm was identical at 0.8 kg.)
The Bottom Line on 3TC/DTG as a Two-Drug Maintenance Regimen
Whether 3TC/DTG is sufficient to achieve and maintain viral suppression was last year's question. That question was answered in 2019 with the 96-week GEMINI results and the findings from TANGO, at least for people with no drug resistance or hepatitis B infection. As we move to 2020, a new question could be asked: Are three-drug regimens still necessary?
We are becoming accustomed to using two-drug combinations, such as dolutegravir/rilpivirine (Juluca), for maintenance of viral suppression. The anticipated upcoming U.S. approval of injectable antiretroviral therapy for maintenance will also include only two antiretrovirals. Meanwhile, for many of our patients, we have long been OK with using three-agent regimens in which we expect only two of the drugs to be active (e.g., when the 184V mutation is present and emtricitabine or lamivudine is included). The TANGO results certainly make a strong case that 3TG/DTG is enough.
However, there is reluctance to completely embrace dual therapy. Most providers need a good reason to switch someone from an effective single-tablet, three-drug regimen to the 3TC/DTG pill. For those on a cobicistat-containing regimen, that reason could be to get rid of the booster baggage. Similarly, many patients on co-formulated abacavir/dolutegravir/lamivudine (Triumeq) could be freed of any abacavir angst.
A harder sell would be to swap out bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy) for 3TC/DTG. One could consider this switch in patients who are suffering big gains in weight on this triple-drug agent. (TANGO did not show that dropping the TAF led to a decrease in weight, although such an effect could have been masked by the addition of dolutegravir.)
Also, there is a sense -- whether it's completely valid or not -- that using three drugs adds some indemnification against failure compared to two. Lastly, many providers point out that patients themselves are unaware of the number of active medications in their combination tablets, and they are thus unlikely to be motivated to abandon well-tolerated, effective regimens if the benefits of a switch are theoretical.
This is an important and hot debate that will be stoked if and when 3TG/DTG is added as a recommended initial regimen to the official U.S. Department of Health and Human Services HIV treatment guidelines -- which it should be, if two-drug regimens are held to the same standards as three-plus drug regimens (with caveats reflecting the inclusion and exclusion criteria applied in the GEMINI trials). Cost may also fuel the fire, as dolutegravir and lamivudine -- whether they are co-formulated or prescribed separately -- are generally cheaper than triple-drug therapy. This alone can spur use of 3TC/DTG outside the U.S., and who knows: Maybe this will become a trend toward antiretroviral minimalism from Europe that actually catches on across the Atlantic.