HIV and ID Observations

Three-drug therapy has been the standard of care for HIV therapy for so long it’s difficult to shake the view that it must be more effective than two drugs. This is particularly the case for those with advanced, HIV-related immunosuppression or very high viral loads, as they provide an important stress test for all regimens.

Remember the pivotal GEMINI studies, comparing initial two-drug treatment with DTG/3TC with three-drug regimens of TDF/FTC plus DTG? Overall, they found that the two-drug arm was noninferior in virologic response. But because of concerns about inadequate activity of using fewer drugs, the trial excluded participants with HIV RNA >500,000. Plus, in the small number of those who started with CD4 <200, the results hinted at a suboptimal response in the DTG/3TC arm.

Now, along comes the DOLCE study, which had an entry criterion that required a CD4 <200, limiting the study population to people with advanced HIV disease — a bold move. Conducted in Argentina and Brazil, DOLCE enrolled treatment-naive participants who then were randomized 2:1 to receive open-label DTG/3TC (given as a single pill) or TDF/XTC plus dolutegravir (DTG). Concomitant chronic hepatitis B was exclusionary.

If you’re new to this HIV treatment business, allow me this geeky digression: “XTC” here doesn’t refer to the 1980s New Wave band, but to lamivudine (3TC) or emtricitabine (FTC), which are interchangeable from a safety and virologic perspective. The names come from their chemical structures — 3TC from one of the 3’s in 2′,3′-dideoxy-3′-thiacytidine, FTC from its fluoro group. And yes, confusingly, lamivudine is “L” in TLD, the abbreviation for tenofovir-lamivudine-dolutegravir. Got it? There will be a quiz.

Ok, back to the study. DOLCE enrolled 229 participants, 152 assigned to DTG/3TC, and 77 to TDF/XTC + DTG. At baseline, the median CD4 cell count was 116, and the viral load was 151,000. Fully a third of the participants would not have qualified for the GEMINI trials, as 23% had viral loads >500,000, and 10% greater than 1 million.

At week 48, 82% in the DTG/3TC arm and 81% in the triple-therapy group achieved viral suppression (<50 copies/mL). Time to virologic suppression and CD4 outcomes were similar, with no hint that three drugs performed better. Notably, responses remained comparable with both strategies even in the group with very high viral loads (>500,000). No treatment-emergent resistance occurred.

All studies have limitations, and this one is no exception — each acknowledged by the authors. The DOLCE trial was relatively small and not powered in its primary analysis to make specific claims about noninferiority (though a post-hoc analysis suggested it would meet standard noninferiority criteria). Plus, as an open-label trial, the DTG/3TC arm had the benefit of a single-pill formulation, which was not the case in the three-drug arm. With only two South American countries participating and the study being predominantly men, the results might not be applicable in other settings, though there is no obvious reason to doubt effectiveness in broader populations.

Limitations notwithstanding, credit to the investigators for filling this gap in knowledge about DTG/3TC with a challenging patient population. The astute (and always quite witty) Dr. Laura Waters wrote a fine accompanying editorial, appropriately stating that the data are reassuring from the virologic and safety perspective — and noting that the underperformance of DTG/3TC in GEMINI was likely unrelated to its antiviral activity.

But she also noted that still missing is a clear benefit of two drugs over a regimen that contains TAF (not TDF)/FTC plus either DTG or BIC — none of the studies to date have found evidence that “less is more” when it comes to this comparison, which was not done here. It may turn out that the true advantage of the three-drug regimens with DTG or BIC is not that they’re three drugs with greater anti-HIV activity — but that they contain tenofovir, which has a happy additional effect of being a highly effective treatment and preventive strategy for hepatitis B.

Now take it away, XTC! And this time I don’t mean 2′,3′-dideoxy-3′-thiacytidine.