Dolutegravir/3TC noninferior to DTG/TDF/FTC at 48 weeks in big ART-naive group
22nd International AIDS Conference, Amsterdam, Netherlands, July 23-27, 2018


Mark Mascolini

Dual therapy with dolutegravir/lamivudine (DTG/3TC) proved virologically noninferior to DTG plus tenofovir/emtricitabine (TDF/FTC) in two identical double-blind trials, GEMINI-1 and GEMINI-2 [1]. Sub-50-copy 48-week response rates were 90% or higher in all treatment arms, and resistance to integrase inhibitors or nucleosides never emerged.

Lower risk of long-term toxicity and lower cost support trials comparing 2-drug antiretroviral regimens with standard 3-drug combos. Most such trials have been small, but the combined international GEMINI trials enrolled more than 1400 people. Participants could have no more than 10 days of antiretroviral experience, and no one could have any major resistance mutations, HBV infection, or a need for HCV therapy. Everyone had an HIV load between 1000 and 500,000 copies. In a double-blind design, GEMINI investigators randomized 1433 participants 1-to-1 to DTG/3TC or DTG/TDF/FTC. The primary endpoint was the proportion of participants with a viral load below 50 copies at week 48 in an FDA snapshot analysis.

Median ages in the DTG/3TC and triple-therapy arm were 32 and 33, about 10% of participants were 50 or older, and about 15% were women. Two thirds of participants were white, about 12% black, and 10% Asian. About 20% of participants had a pretreatment viral load above 100,000 copies, and about 8% had a CD4 count below 200.

Proportions of participants with a week-48 viral load below 50 copies in the DTG/3TC arms of GEMINI-1 and 2 were 90% and 93%, compared with response rates of 93% and 94% in the DTG/TDF/FTC arms. Adjusted response differences of -2.6 (95% confidence interval [CI] -6.7 to 1.5) in GEMINI-1 and -0.7 (95% CI -4.3 to 2.9) in GEMINI-2 indicated that DTG/3TC was virologically noninferior to DTG/TDF/FTC through 48 weeks in previously untreated people (based on a 10% noninferiority margin). 

In an analysis in which treatment-related discontinuations equaled failure, similar higher proportions in the pooled dual-therapy and triple-therapy arms had a week-48 viral load below 50 copies regardless of pretreatment viral load (above or below 100,000 copies) or CD4 count (above or below 200). In a pooled snapshot analysis, the 48-week response rate proved lower with DTG/3TC than with triple therapy in people with a pretreatment CD4 count below 200 (79% versus 93%), but results did not differ by pretreatment viral load in the snapshot analysis.

By week 48 there were 6 confirmed virologic failures in the DTG/3TC arms and 4 in the DTG/TDF/3TC arms. No mutations conferring resistance to integrase inhibitors or nucleoside reverse transcriptase inhibitors emerged in any of these 10 people. 

Serious adverse events were rare with dual and triple therapy (7% and 8%), as were adverse events leading to withdrawal from the study (2% and 2%). Drug-related adverse events were somewhat less frequent with DTG/3TC than with DTG/TDF/FTC (18% versus 24%). Analysis of kidney and bone markers significantly favored the dual-therapy arm. 

Reference
Cahn P, Madero JS, Arribas J, et al. Non-inferior efficacy of dolutegravir (DTG) plus lamivudine (3TC) versus DTG plus tenofovir/emtricitabine (TDF/FTC) fixed-dose combination in antiretroviral treatment-naive adults with HIV-1 infection: 48-week results from the GEMINI studies. AIDS 2018: 22nd International AIDS Conference, Amsterdam, Netherlands, July 23-27, 2018. Abstract TUAB0106LB.