FDA Approves 2-Drug Combination of Dolutegravir + Lamivudine

In April 2019, the U.S. Food and Drug Administration approved a combination pill comprising the integrase inhibitor dolutegravir (DTG), 50 mg, and the NRTI lamivudine (3TC), 300 mg, for use as a complete ARV regimen for initial HIV treatment of patients. The approval specifies that DTG/3TC is intended only for adults who have never received ART and whose HIV has no resistance to either of the two components. It is to be taken once daily without food restrictions.

Approval was based largely on the results of the GEMINI-1 and GEMINI-2 studies that compared DTG/3TC with the 3-ARV regimen DTG + tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in 1,433 treatment-naive individuals (85% were men, 68% were white). In combined analysis of the two trials, HIV viral loads were <50 copies/mL in 91% and 93% among subjects in the two groups, respectively, after 48 weeks of treatment, demonstrating statistical noninferiority of the study regimen. In patients with baseline CD4 counts of <200 cells/µL, however, the rate of viral suppression was substantially lower in the DTG/3TC groups (79%) than in the 3-drug groups (93%); no such differences were seen in persons with baseline HIV RNA loads of ≤100,000 copies/mL or >100,000 copies/mL. No emergent DTG or 3TC resistance mutations were found in the few individuals who experienced virologic failure in either treatment group.

Given current concerns about possible fetal neural tube defects resulting from exposure to DTG at the time of conception or during the early weeks of pregnancy, DTG/3TC is not recommended for women who may become pregnant while taking it or for pregnant women in the first trimester. And, because it includes only one component with anti-hepatitis B activity (3TC), it should not be used for persons with hepatitis B coinfection; patients should be tested for hepatitis B before DTG/3TC is prescribed.

DTG/3TC will be marketed under the brand name Dovato. Full prescribing Information is available at [email protected].

Clinical Bottom Line

DTG/3TC (Dovato) is the first 2-drug regimen to be approved for initial treatment of HIV. In the GEMINI study population, it appeared to be effective overall, though several caveats should be noted:

  • DTG/3TC has not been studied in persons with pretreatment HIV RNA loads of >500,000 copies/mL; it probably should not be used in patients with very high viral loads until data for this group are available.
  • Lower rates of virologic suppression were seen in DTG + 3TC recipients with baseline CD4 counts of <200 cells/µL; the reasons for that are not completely clear, but this regimen probably should be avoided in this group of patients.
  • GEMINI-1 and GEMINI-2 (rightly) excluded persons whose HIV had baseline resistance to either DTG or 3TC; the 2-drug combination of DTG/3TC should not be given to anyone whose virus has any resistance to integrase inhibitors or 3TC/FTC, as this would result in functional monotherapy.
  • Given the preceding caveats, DTG/3TC should not be given to persons newly diagnosed with HIV for whom results of baseline HIV RNA, CD4, and genotype tests are not available; ie, it should not be given as immediate ("rapid") ART.
  • DTG/3TC has not been studied in the "real world," where challenges to daily adherence are common, and its resilience is not clear.
  • In the GEMINI studies, TDF in the 3-drug arm was responsible for a modestly worse profile of adverse effects and markers of renal and bone function. It is not known whether the 2-drug regimen of DTG/3TC would have lower toxicity than 3-drug regimens comprising tenofovir alafenamide (TAF) or abacavir (ABC) plus DTG and 3TC (or FTC).

Thus, we do not yet fully know whether the potential benefits of this 2-drug regimen regarding adverse effects (and cost) outweigh the potential disadvantages in terms of potency, durability, and risk of virologic failure. Longer-term data from the GEMINI studies and from other ongoing studies will be helpful in clarifying the potential role of DTG/3TC in HIV treatment. Current DHHS guidelines do not include 2-drug regimens among "Recommended Initial Regimens for Most People with HIV" but do include DTG/3TC as a regimen to "Consider When ABC, TAF, and TDF Cannot Be Used."