A dolutegravir-based two-drug regimen was non-inferior to the standard three-drug therapy among treatment-naive participants, the principal investigator of the two GEMINI trials, Pedro Cahn, M.D., Ph.D., of Fundación Huésped in Buenos Aires, Argentina, announced at the recent 22nd International AIDS Conference (AIDS 2018) in Amsterdam, the Netherlands. The trials are separate but identical Phase III studies conducted in a variety of countries around the world.
A total of 1,433 antiretroviral-naive participants were randomized 1:1 to take either dolutegravir (Tivicay, DTG) and lamivudine (3TC, Epivir) or dolutegravir and emtricitabine/tenofovir disoproxil fumarate (Truvada). The primary endpoint of both trials was week 48 data on the proportion of virally suppressed participants in each study arm. Viral suppression was defined as plasma HIV-1 RNA less than 50 copies/mL. That endpoint was met by 91% in the two-drug arm versus 93% in the three-drug arm. Applying a 10% non-inferiority margin, the two-drug combination was just as successful as the conventional three-drug therapy in achieving undetectable viral loads. CD4 cell counts improved by a mean of 224 cells/μL in the two-drug arm versus 218 cells/μL in the three-drug group.
The double-blind portion of the studies will continue through week 96, followed by a comparative phase through week 144. "The last year of the study is open label, but people remain on their randomized study regimen," Kimberly Smith, M.D., M.P.H., the head of global research and vice president of global medical strategy at ViiV Healthcare, the manufacturer of dolutegravir, explained. This next phase will show whether the early viral suppression rates can be sustained in the long term, Cahn said.
A two-drug regimen would reduce the drug burden on people who must continue to take antiretrovirals for the rest of their lives, decrease drug toxicity, and lower treatment costs, Cahn explained at a press conference prior to his presentation at AIDS 2018. This strategy is not a one-size-fits-all approach but serves as an option for people living with HIV who fit the studies' inclusion criteria, he added. These criteria were: baseline viral load less than or equal to 500,000 copies/mL, no hepatitis B infection, and no baseline genotypic resistance.
Because of concern over dolutegravir's potential harm to the developing fetus if taken early in pregnancy, women (14%-16% of participants, depending on study arm) were required not to be pregnant or lactating and had to use one of the birth control methods defined in the study protocol while participating in the trial. While the studies drew on people from Africa, Asia, Europe, and North and South America, most participants (67-69%, depending on arm) were white. Latinos made up the next largest demographic group (30-32%), followed by African Americans/Africans (11-14%) and Asians (10%).
Adverse events (AEs) were common in both arms (76% and 81% in the two-drug and three-drug arms, respectively), but there were fewer drug-related AEs in the two-drug compared with the three-drug group (18% versus 24%). The most common complaint was headache (10% of participants in each arm). Other AEs included diarrhea, nasopharyngitis, upper respiratory tract infection, nausea, insomnia, pharyngitis, and back pain. Rates of serious events were similar in both groups (7% and 8%, respectively), as were withdrawal rates due to AEs (15 and 16 participants, respectively). Slightly more people left the two-drug arm than left the three-drug arm (six versus four participants) due to neuropsychiatric issues. Overall safety and tolerability was thus comparable between groups.
No mutations that would confer resistance to either integrase inhibitors (such as dolutegravir) or nucleoside reverse transcriptase inhibitors (such as lamivudine) were found in any participant who withdrew from the study due to confirmed virologic failure. There were six such withdrawals in the two-drug arm and four in the three-drug arm, representing less than 1% of participants in either case. Whether any of these failures were related to not taking the study drugs as prescribed is unclear at this point because adherence data are not yet available. Adherence was measured by pill count, according to Smith.
Biomarkers for renal and bone health improved significantly more on the two-drug regimen compared with the three-drug one. Tenofovir disproxil fumarate (TDF) -- only included in the three-drug arm -- is known to worsen kidney and bone problems. However, total mean cholesterol rose by 0.32 mmol/L from baseline in the two-drug group while it dropped by 0.15 mmol/L in the three-drug group. TDF has cholesterol-lowering properties, which could explain the decrease. Smith attributed an increase in HDL cholesterol in the two-drug group to people getting healthier from HIV treatment.
"The GEMINI studies show that we can get the efficacy of three drugs in a two-drug regimen with the tolerability and drug interaction profile of DTG and 3TC,"Cahn concluded in a press release about his presentation. The release also announced that the two drugs' manufacturer, ViiV Healthcare, is planning to apply for regulatory approval for a fixed-dose combination of dolutegravir and lamivudine later this year.