A dolutegravir-based regimen was found to be noninferior to a low-dose efavirenz (400-mg dose) regimen in terms of viral suppression at week 48 in treatment-naive adults with HIV-1 living in a resource-limited setting, according to study results recently published in The New England Journal of Medicine.
In this phase 3, open-label, multicenter trial (NAMSAL; ClinicalTrials.gov Identifier: NCT02777229), researchers randomly assigned adults with HIV-1 in a 1:1 ratio to receive either dolutegravir or efavirenz 400 mg (reference treatment), both combined with tenofovir disoproxil fumarate and lamivudine, as first-line antiretroviral therapy. Participants with an HIV-1 RNA level of at least 1000 copies/mL were enrolled at 3 hospitals in Yaoundé, Cameroon, between July 2016 and August 2017. The primary end point was the proportion of participants with a viral load <50 copies/mL at week 48. Noninferiority of dolutegravir to low-dose efavirenz was tested with a margin of 10 percentage points.
A total of 613 participants (median age, 37 years; 65.9% women) received ≥1 dose of the assigned regimen. The median baseline viral load was 5.3 log10 copies/mL, and 66.4% of the participants had a baseline viral load of ≥100,000 copies/mL.
At week 48, 231 of 310 participants (74.5%) in the dolutegravir group and 209 of 303 participants (69.0%) in the low-dose efavirenz group had a viral load <50 copies/mL. The difference between treatment groups was 5.5 percentage points (95% CI, −1.6 to 12.7), meeting the criterion for noninferiority (P <.001). Among those with a baseline viral load of ≥100,000 copies/mL, a viral load of <50 copies/mL was observed in 137 of 207 participants (66.2%) in the dolutegravir group and in 123 of 200 participants (61.5%) in the low-dose efavirenz group, with a difference of 4.7 percentage points (95% CI, −4.6 to 14.0), thus showing noninferiority.
When using a viral load threshold of <200 copies/mL, results met criteria for noninferiority and superiority. Results showed that 276 of 310 participants (89.0%) in the dolutegravir group and 253 of 303 participants (83.5%) in the low-dose efavirenz group had viral suppression, with a difference of 5.5 percentage points (95% CI, 0.1-11.0).
Of the 404 women exposed to trial drugs, 6.2% became pregnant during the trial (13 in the dolutegravir group and 12 in low-dose efavirenz group). All children were born alive without any reported congenital abnormalities.
A greater median increase in body weight was noted in the dolutegravir group vs the low-dose efavirenz group (5.0 kg vs 3.0 kg; P <.001). Similarly, obesity occurred more in the dolutegravir group vs the low-dose efavirenz group (12.3% vs 5.4%; P =.004).
The researchers recognized “the concerns related to dolutegravir use in women of childbearing potential, and [that] the risk of obesity needs to be explored further.”
Virologic failure (defined as a viral load of >1000 copies/mL) occurred more often in the low-dose efavirenz group vs the dolutegravir group (16 vs 3). However, none of the 3 participants in the dolutegravir group had drug-resistance mutations at baseline or acquired them during the trial. In the low-dose efavirenz group, 6 of 16 participants had drug-resistance mutations at baseline (5 had mutations conferring resistance to efavirenz and 1 to lamivudine, tenofovir, and efavirenz). Of the 10 remaining participants who did not have drug-resistance mutations at baseline, 8 acquired them (2 acquired mutations conferring resistance to efavirenz, 3 to lamivudine and efavirenz, and 3 to lamivudine, tenofovir, and efavirenz).
The researchers observed a high level of integrase polymorphism with mainly E157Q and T97A mutations (in 8% and 6%, respectively). “Although these mutations have been suspected to decrease the efficacy of integrase inhibitors, no effect on viral suppression was identified in the dolutegravir group,” noted the researchers. “However, long-term follow-up studies would help to further evaluate the effect of these mutations, especially those associated with the persistent low viremia observed in a subgroup of our trial population.”
NAMSAL ANRS 12313 Study Group. Dolutegravir-based or low-dose efavirenz-based regimen for the treatment of HIV-1 [published online July 24, 2019]. N Engl J Med. doi:10.1056/NEJMoa1904340