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Chief, Division of Infectious Diseases
Brigham and Women's Hospital
Harriet Ryan Albee Professor of Medicine
Harvard Medical School
Daniel R. Kuritzkes, MD, has disclosed that he has served on an advisory board or panel for Gilead Sciences, Merck, and ViiV Healthcare; has received consulting fees from GlaxoSmithKline; and has received funds for research support from Gilead Sciences and Merck.
Women currently make up approximately one half of the global HIV epidemic, and they represent a unique population due in part to sex-based differences in ART metabolism as well as their childbearing potential. Decisions related to ART during pregnancy affect both maternal and infant health, yet there remains a paucity of data on the safety of most ART regimens during pregnancy. In this commentary, I focus on the latest data presented at CROI 2020 on efficacy, safety, and weight gain outcomes with different ART regimens during and after pregnancy.
IMPAACT 2010: Viral Suppression Rates at Delivery Significantly Higher With DTG Plus FTC/TAF or DTG Plus FTC/TDF vs EFV/FTC/TDF Initiation During Pregnancy in ART-Naive Women
The IMPAACT 2010 study was a randomized, open-label phase III trial in which ART-naive, pregnant women with HIV initiated ART with dolutegravir (DTG) plus emtricitabine (FTC)/tenofovir alafenamide (TAF) (n = 217), DTG plus FTC/ tenofovir disoproxil fumarate (TDF) (n = 215), or efavirenz (EFV)/FTC/TDF (n = 211) at 14-28 weeks of gestation. Mothers and infants were followed for 50 weeks postpartum. The primary efficacy endpoint was maternal HIV-1 RNA < 200 copies/mL at delivery. The rate of viral suppression at delivery was significantly higher with DTG-based ART vs EFV/FTC/TDF (97.5% vs 91.0%, respectively; P = .005) and time to viral suppression was significantly shorter (P < .001). Average weekly maternal weight gain was significantly higher with DTG plus FTC/TAF at 0.378 kg vs 0.319 kg with DTG plus FTC/TDF (P = .011) and vs 0.291 kg with EFV/FTC/TDF (P < .001). However, this level of weight gain was still lower than the maternal weight gain level of 0.42 kg per week recommended by the Institute of Medicine during the second and third trimesters of pregnancy for women with prepregnancy BMI in the normal range.
Women receiving DTG-based ART in IMPAACT 2010 also had better pregnancy outcomes than women receiving EFV-based ART. A composite adverse pregnancy outcome (including preterm delivery, small for gestational age, stillbirth, and spontaneous abortion) was significantly less frequent with DTG plus FTC/TAF vs DTG plus FTC/TDF or EFV/FTC/TDF (P < .05). Although the association of DTG plus FTC/TAF with both increased weight gain and fewer adverse pregnancy outcomes presents a paradox because excess weight gain during pregnancy is associated with increased risk for gestational diabetes; hence one might expect worse pregnancy outcomes. In this regard, it is important to consider the fact noted above that the weight gain in all 3 study arms was lower than that recommended during pregnancy. Therefore, the higher weight gain in this setting may be beneficial to the overall health of the pregnancy.
These data come in the context of recent concerns regarding the safety of DTG use at the time of conception and in very early pregnancy based on the results of the Tsepamo study, demonstrating a small but statistically significant in increase in the risk of neural tube defects with use of DTG vs non-DTG ART during conception/early pregnancy. Taken together, the findings from IMPAACT 2010 and Tsepamo support current DHHS recommendations that include DTG as a preferred ART component during pregnancy and as an alternative option for women who are trying to conceive. The IMPAACT 2010 data also provide a first look at outcomes in women receiving TAF-containing regimens during pregnancy.
Postpartum Weight Changes in Women Initiating DTG vs EFV During Pregnancy
DolPHIN-2 was a randomized, open-label trial in which pregnant ART-naive women with HIV in Uganda and South Africa began ART with DTG plus 2 NRTIs (n = 125) or EFV plus 2 NRTIs (n = 125) at ≥ 28 weeks of gestation. As previously reported, the percentage of patients who reached the primary endpoint of HIV-1 RNA < 50 copies/mL at delivery was significantly higher with DTG vs EFV (73.8% vs 42.6%, respectively; P < .0001), owing to the faster decline in viremia associated with INSTI-based regimens. The analysis reported at CROI 2020 evaluated postpartum weight changes (6-72 weeks postpartum) among 232 women from DolPHIN-2 and showed that mean weight was 4.35 kg greater with DTG vs EFV by a mixed-effects linear regression model adjusted for duration of ART use.
In a separate CROI 2020 report, investigators examined weight changes from 1 to 18 months postpartum among pregnant women with HIV treated with DTG vs EFV and among women without HIV infection, all participating in the Botswana Tshilo Dikotla cohort study. In this study, postpartum weight through 18 months was significantly higher with DTG-based ART by an average of 5 kg vs with EFV-based ART (P < .01) but was similar to women without HIV. This association remained significant after adjusting for HIV-specific factors (P = .04).
The weight gain results of both studies are consistent with findings during pregnancy from the IMPAACT 2010 trial and in nonpregnant women in the ADVANCE trial. The findings from IMPAACT 2010 showed that none of the ART treatment groups gained as much weight as is recommended during the second and third trimesters of pregnancy; the Tshilo Dikotla cohort showed that postpartum weight among DTG-treated women (greater than observed with EFV) was similar to weight gain experienced by HIV-negative women. This finding suggests that weight gain during pregnancy on a DTG-based ART regimen may actually be beneficial, as compared to the excessive weight gain experienced by some DTG-treated nonpregnant women. Additional support for this hypothesis comes from a 2019 report on weight gain during the Tsepamo pregnancy study, showing that although weight gain was higher with DTG-based vs EFV-based ART, the gains in both ART groups were lower than that in women without HIV.
It is encouraging to see rigorous data being collected and presented on these important questions related to ART efficacy and safety during pregnancy. These studies also highlight the continued importance of including adequate numbers of women in studies of novel HIV therapies as we move forward and of collecting data on the use of those therapies in pregnancy.
How might these results affect your clinical care of pregnant women living with HIV? What additional data are needed for optimizing ART management during pregnancy? Join the discussion by posting a comment.