Efficacy and Safety of Dolutegravir With Emtricitabine and Tenofovir Alafenamide Fumarate or Tenofovir Disoproxil Fumarate, and Efavirenz, Emtricitabine, and Tenofovir Disoproxil Fumarate HIV Antiretroviral Therapy Regimens Started in Pregnancy (IMPAACT 2010/VESTED): A Multicentre, Open-label, Randomised, Controlled, Phase 3 Trial

Abstract

Over 1 million women with HIV-1 become pregnant yearly. The use of antiretroviral therapy (ART) during pregnancy is important for the reduction of perinatal HIV transmission from mother to child and to improve maternal health outcomes. There is limited high quality data on the safety and effectiveness of ART with the use of dolutegravir. Dolutegravir was named a first-line therapy in adults with HIV by the World Health Organization in 2018.This study is a phase 3, multicenter open-label randomized controlled study performed in pregnant women from 14 to 28 weeks' gestation (≥18 years of age) in 9 countries (including the United States, Brazil, South Africa, and India). Women with multiple fetuses, a known fetal anomaly, a known psychiatric illness in the mother, active tuberculosis in the mother, laboratory abnormalities (a Cr clearance <60 mL per minute or alanine aminotransferase or aspartate aminotransferase ≥2.5 the upper limit or normal) or >14 days of ART during the current pregnancy were excluded.Participants were split on the basis of gestational age (14–18 weeks, 19–23 weeks, and 24–28 weeks) and were randomly assigned to receive either: (1) once-daily oral dolutegravir 50 mg (integrase strand transfer inhibitors) plus once-daily oral fixed-dose combination emtricitabine 200 mg and tenofovir alafenamide fumarate 25 mg (nucleotide reverse-transcriptase inhibitors [NRTIs]); (2) once-daily oral dolutegravir 50 mg plus once-daily oral fixed-dose combination emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg [NRTIs]; or (3) once-daily oral fixed-dose combination of efavirenz 600 mg, emtricitabine 200 mg, and tenofovir disoproxil fumarate 300 mg (non-nucleoside reverse transcriptase inhibitors [NNRTIs] or NRTIs). The primary end point was the proportion of viral suppression (HIV-1 RNA concentration: <200 copies per mL) at or within 14 days of delivery. The primary safety outcomes included the occurrence of adverse pregnancy outcomes (preterm delivery, infant small for gestational age, stillbirth, or spontaneous abortion).A total of 617 pregnant women participated: 217 in group 1, 215 in group 2, and 211 in group 3. The median gestational age at enrollment was 21.9 weeks, and the median HIV-1 RNA copies were 902.5 copies/mL. At delivery, 98% of the participants in groups 1 and 2 (395 of 405) had viral suppression, in comparison with 91% (182 of 200) of the participants in group 3 (P = .052; in intention-to-treat analysis). In terms of adverse pregnancy outcomes, there were significantly fewer participants with an adverse pregnancy outcome in group 1 (52 of 216 [24%]) than there were in group 2 (70 of 213 [33%]) or group 3 (69 of 211 [33%]). Children born to mothers in group 3 had higher rates of preterm delivery and neonatal mortality. Of note, however, there was no significant difference in grade ≥3 adverse event outcomes in either mother or child between the 3 groups.The use of dolutegravir in adults including pregnant women as recommended by the World Health Organization is affirmed by this study. Additionally, the use of dolutegravir plus emtricitabine and tenofovir alafenamide fumarate may be favored to the regimen of dolutegravir plus emtricitabine and tenofovir disoproxil fumarate because of the lower incidence of adverse pregnancy outcomes that was seen in this group.Infection with HIV remains a global phenomenon and improving both maternal outcomes during pregnancy and reducing transmission of HIV from mother to child are essential. With this study conducted in many different countries, the authors provide evidence that ART started in pregnancy with dolutegravir induces viral suppression and is associated with better fetal outcomes.