As we have commented in the past, initial ARV regimens consisting of 2 drugs tend to perform poorly in comparison with currently recommended 3-drug regimens. Yet, given toxicity concerns about some ARVs (particularly about tenofovir DF and abacavir) and cost concerns about 3-drug regimens, the search for a potent and tolerable 2-drug regimen has continued. At the recent International AIDS Conference in late July, data were presented from two parallel Phase 3 studies (GEMINI-1 and GEMINI-2) of dolutegravir (DTG) + 3TC in initial therapy. These studies were large multisite double-blind studies in which 1,433 subjects (15% women, median age 32 years) were randomized to receive either DTG + 3TC or DTG + TDF/FTC. Subjects were required to have baseline HIV RNA levels ≤500,000 copies/mL.
At 48 weeks, by FDA snapshot analysis of the pooled data from the two studies, rates of HIV RNA suppression to <50 copies/mL were 91% in the 2-drug arm and 93% in the 3-drug arm, indicating noninferiority of DTG + 3TC. Results were very similar between the two treatment arms for those with baseline HIV RNA ≤100,000 copies/mL and for those with baseline HIV RNA >100,000 copies/mL. However, patients with baseline CD4 ≤200 copies/µL had lower rates of HIV RNA suppression in the 2-drug arm (79%) than in the standard 3-drug arm. Six persons in the DTG + 3TC experienced confirmed virologic failure, compared with 4 in the 3-drug therapy group; no new NRTI or integrase inhibitor mutations were identified in any. Changes in renal and bone biomarkers were significantly worse in persons on the 3-drug regimen (which contained TDF), but otherwise rates and types of adverse effects were similar in the two treatment arms.
Clinical Bottom Line
The 48-week virologic results of the GEMINI studies are impressive, and particularly because they included a large number of patients, unlike many studies of 2-drug regimens in initial therapy. A few cautions should be noted:
- Rates of virologic failure were low in both treatment groups but were numerically higher in the dual-therapy arm (6 vs 4), though no treatment-emergent resistance mutations were seen in any of these patients
- Persons whose virus had resistance-associated mutations were excluded from enrollment. DTG + 3TC certainly should not be used for persons whose virus has any resistance to 3TC (or FTC), as this would result in DTG monotherapy, which has been shown to lead to a substantial risk of virologic failure (and integrase resistance mutations).
- Persons with HIV RNA >500,000 copies/mL were excluded from enrollment, and thus we have no data on the efficacy of this regimen in persons with very high viral loads.
- For persons with baseline CD4 counts ≤200 copies/µL, rates of viral suppression were notably lower in the DTG + 3TC treatment arm than in the 3-drug arm.
We need more and longer-term data on the durability of the DTG + 3TC regimen in order to know for what patient scenarios it might be appropriate. And, it will be important to consider the potential role of 2-drug therapy given the availability (at least in the United States and Europe) of tenofovir alafenamide (TAF), which has less renal and bone toxicity than TDF and potentially allows construction of safer 3-drug combinations.
Current DHHS guidelines do not recommend 2-drug regimens for initial treatment of HIV but list two 2-drug regimens as "Regimens to Consider When ABC, TAF, and TDF Cannot Be Used."
Cahn P, Sierra Madero J, 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. In: Program and abstracts of the 22nd International AIDS Conference; July 23-27, 2018; Amsterdam. Abstract TUAB0106LB.