Dolutegravir noninferior to low-dose efavirenz in HIV-1 suppression
Dolutegravir demonstrated noninferiority to low-dose efavirenz in antiretroviral (ART)-naïve patients with HIV-1 infection in a resource-limited setting, according to the NAMSAL ANRS 12313* study presented at IAS 2019.
“[T]his phase 3 trial showed the noninferiority of a dolutegravir-based regimen, which is associated with a low risk of acquiring drug-resistance mutations, to a low-dose efavirenz-based regimen with regard to viral suppression at week 48 … supporting the current WHO** recommendations to initiate ART with a dolutegravir-based regimen,” said the researchers.
A total of 613 ART-naïve adults (median age 37 years, 65.9 percent female) from Cameroon with HIV-1 infection (viral load ≥1,000 copies/mL) were randomized 1:1 to receive dolutegravir or low-dose (400 mg) efavirenz (EFV400) in addition to tenofovir disoproxil fumarate and lamivudine.
At week 48, dolutegravir demonstrated noninferiority to EFV400 with regard to the proportion of patients with viral suppression (viral load of <50 copies/mL; 74.5 percent vs 69.0 percent, difference, 5.5 percentage points, 95 percent confidence interval [CI], -1.6 to 12.7; pnoninferiority<0.001; psuperiority=0.13). [N Engl J Med 2019;doi:10.1056/NEJMoa1904340]
Among patients with a viral load of ≥100,000 copies/mL at baseline, viral suppression at 48 weeks occurred in a similar proportion of patients on dolutegravir and EFV400 (66.2 percent vs 61.5 percent, difference, 4.7 percentage points, 95 percent CI, -4.6 to 14.0). Less than 60 percent of patients in both groups with a viral load of ≥500,000 copies/mL at baseline had viral suppression.
Viral suppression in women was more common in dolutegravir than EFV400 recipients (difference, 8.7 percentage points).
Virologic failure, defined as a viral load of >1,000 copies/mL, affected fewer dolutegravir than EFV400 recipients (n=3 vs 16). None of the dolutegravir recipients had drug-resistance mutations compared with six EFV400 recipients who had drug-resistance mutations at baseline and eight who acquired them during the study.
These findings are “worrisome” given the high baseline viral loads in this population (66.4 and 30.7 percent had viral loads of ≥100,000 and ≥500,000 copies/mL), commented Drs Diane Havlir from the University of California, San Francisco, US, and Meg Doherty from the World Health Organization, Geneva, Switzerland, in an editorial. [N Engl J Med 2019;doi:10.1056/NEJMe1909363]
Genotypic analysis showed that 1.3 and 6.1 percent of participants had a primary resistance to NRTIs and NNRTIs***, respectively. Thirty-five patients had a mutation resulting in efavirenz resistance.
No major safety events were reported or led to discontinuation. A similar proportion of patients in both groups experienced depression, anxiety, and stress. None of the infants born to the 25 women who became pregnant during the trial showed congenital abnormalities.
A greater degree of weight gain was associated with dolutegravir than EFV400 (median 5.0 vs 3.0 kg; p<0.001). Weight gain of ≥10 percent affected more women than men (38.8 percent vs 22.9 percent; p<0.001). Among patients with a ≥10 percent weight gain, both dolutegravir and EFV400 recipients experienced significant increases in cholesterol levels, while dolutegravir recipients had a greater increase in glucose levels than those who did not experience ≥10 percent weight gain. More dolutegravir than EFV400 recipients experienced obesity (12.3 percent vs 5.4 percent; p=0.004).
Interpreting the findings in real-life settings
The proportion of dolutegravir recipients with viral suppression was lower in this trial compared with the SINGLE trial (eg, 88 percent of dolutegravir-abacavir-lamivudine recipients), as was the proportion of EFV400 recipients with viral suppression in this trial compared with the ENCORE1 trial (94.1 percent for viral load <200 copies/mL). [N Engl J Med 2013;369:1807-1818; Lancet 2014;383:1474-1482]
“[E]fficacy results were much better with the use of a viral load threshold of <200 copies/mL, with viral suppression occurring in 89.0 and 83.5 percent of the participants in the dolutegravir and EFV400 groups, respectively; these results indicate that participants had a low persistent viraemia,” said the researchers.
Among the reasons suggested for the reduced efficacy were high viral loads at baseline, and potentially, reduced treatment adherence or baseline drug resistance. However, validated questionnaires did not suggest poor adherence and analysis suggested low incidence of mutations to NRTIs, the researchers said.
“[I]t is important to continue long-term monitoring of the patients who initiated dolutegravir treatment to confirm the absence of resistance mutations to this drug; the trial will continue until 2021,” said study author Professor Eric Delaporte from the University of Montpellier-IRD-INSERM in Montpellier, France.
Despite the prevalence of neural-tube defects associated with dolutegravir in the Tsepamo Study, [N Engl J Med 2019;doi:10.1056/NEJMoa1905230] Havlir and Doherty cautioned against writing off dolutegravir in women of reproductive age or relegating it to an alternative treatment.
“This recent headwind caused by the imperfections of dolutegravir should not slow down the urgency to deliver lifesaving therapy to millions still in need. We need to accelerate (not slow) the transition to dolutegravir-based regimens for initial therapy, offer treatment as early as possible, make use of the best currently available treatment options, shore up pharmacovigilance, and [simultaneously] continue research,” they advised.