Two-Drug HIV Regimen Non-Inferior to Three-Drug Regimen

When it comes to antiretroviral therapy for HIV, less is often more. To that end, the medical community has been working on ways to reduce the number of drugs patients must take in order to stay virally suppressed. Fortunately, the days of the multidrug cocktail have given way to fewer and fewer pills, making it easier to stay on antiretroviral therapy and lessening the chance of adverse events.

A team of investigators based at Buenos Aires University in Argentina decided to test whether a 2-drug regimen would work as well as a 3-drug regimen in people with HIV. They designed 2 identical trials, called GEMINI-1 and GEMINI-2, to run concurrently at 192 different health centers in 21 countries. The team recruited adults with HIV whose HIV RNA levels were no higher than 500,000 copies/mL and who had never taken antiretroviral therapy.

The 1441 subjects ultimately chosen for the trials were randomly assigned in a 1:1 ratio to either the 2-drug arms or the 3-drug arms. The 2-drug regimen consisted of dolutegravir plus lamivudine, while the 3-drug regimen was comprised of dolutegravir plus tenofovir disoproxil fumarate and emtricitabine. The participants were seen at regular intervals from July 2016 to March 2017, and the main outcome of the study was the proportion of participants in each arm who were able to get their HIV RNA levels down to less than 50 copies/mL by week 48.

The results? As of week 48, 90% of subjects in the 2-drug arm of the GEMINI-1 trial had achieved viral suppression, defined as plasma viral loads of less than 50 copies/mL. In the 3-drug arm of the trial, 93% of subjects had achieved viral suppression. In the GEMINI-2 trial, the results were at least as good: 93% of those taking the 2-drug regimen achieved viral suppression, and 94% of the subjects taking the 3-drug regimen did so.

Although most subjects reported experiencing side effects from the drug regimens, they typically reported non-serious issues such as headache, diarrhea, nausea, and the common cold. A greater percentage of those on the 3-drug regimen experienced adverse events (24%) than those taking 2 drugs (18%), but the investigators determined that was chiefly due to more in the former group reporting low-grade nausea, which typically passes. Serious adverse effects were reported by 7% on the 2-drug regimen and 8% on the 3-drug regimen.

In general, the 2-drug regimen did not disappoint. Not only did it enable viral suppression, but it proved safe and tolerable for the majority of participants.

“Changes in renal and bone biomarkers favored the 2-drug regimen and might be attributed to the inclusion of tenofovir disoproxil fumarate in the 3-drug regimen group, which is associated with impaired renal function and bone health,” the authors wrote in their report, which was published in The Lancet. Although the overall cholesterol profile was better in the subjects on the 3-drug regimen—likely due to the known cholesterol-lowering properties of tenofovir disoproxil fumarate—the HDL levels of the subjects on the 2-drug regimen were higher, on average, than those in the 3-drug regimen.

Will an HIV treatment plan consisting of just 2 drugs become standard? Some experts think so.

“These results show that modern 2-drug regimens, such as previously shown for lamivudine in combination with ritonavir-boosted darunavir or lopinavir over 48 weeks, might in fact become reliable drug sparing treatment options for HIV-infected patients,” wrote Arne Kroidl and Joseph Eberle, infectious disease researchers at the University of Munich, in a commentary also published in The Lancet.

They noted, however, that such a determination is country-specific: “The GEMINI trials involved few participants from low-resource countries (eg, South Africa and those in southeast Asia). The feasibility of a 2-drug regimen in these countries is, however, limited because of high numbers of hepatitis B virus coinfection[s], which are insufficiently covered with lamivudine monotherapy.”