Dolutegravir-based regimens safe and effective in pregnancy and postpartum

Polly Clayden, HIV i-Base

Two presentations at CROI 2021, showed post-partum data from key studies of dolutegravir in pregnancy.

VESTED (IMPAACT 2010) compared safety and efficacy of dolutegravir (DTG) + emtricitabine (FTC)/tenofovir alafenamide fumarate (TAF) vs DTG + FTC/tenofovir disoproxil fumarate (TDF) vs efavirenz (EFV)/FTC/TDF in women starting ART in pregnancy. Results shown were from enrollment through week 50 postpartum (PP). [1]
DolPHIN-2 compared safety and efficacy of DTG- vs EFV-based regimens among women starting treatment in the third trimester to in South Africa and Uganda. Final results with follow-up of mothers and infants to 72 weeks PP were shown. [2]

Both studies have previously reported results through delivery [3, 4].

VESTED

ART-naive pregnant women with HIV in 9 countries (Botswana, Brazil, India, South Africa, Tanzania, Thailand, Uganda, US and Zimbabwe – the majority from Africa) were randomised 1:1:1 to start open-label DTG + FTC/TAF vs DTG + FTC/TDF vs EFV/FTC/TDF at 14–28 weeks’ gestation.

Safety outcomes included pairwise comparisons of grade 3 and higher maternal and infant adverse events, infant mortality and infant HIV infection. Efficacy analyses included comparison of maternal viral load <200 copies/mL at week 50 PP between the combined DTG arms and the EFV arm.

Six hundred and forty three women were randomised to DTG + FTC/TAF; DTG + FTC/TDF and EFV/FTC/TDF. At baseline median age was 26.6 years, gestational age 21.9 weeks, viral load 903 copies/mL and CD4 count 466 cells/mm3. Median baseline BMI was 24.7 – pre-pregnancy BMI was not available.

There were no apparent differences between arms at week 50 PP in the estimated probability of maternal or infant grade 3 and higher adverse events.

Six hundred and seven (94.4%) women and 566 (91.7%) of 617 liveborn infants completed the study. Three quarters of the infants 479/617 (77.6%) were breastfed for a median of 49.9 weeks.

There were 20 infant deaths, of which 15 were within 28 days of delivery. The estimated probability of infant death was higher in the EFV arm (6.9%) compared to DTG + FTC/ TAF (1.0%, p<0.001) and DTG + FTC/TDF (2.0%, p=0.008) arms. In post-hoc analysis, combining still births and infant deaths, this was highest in the EFV arm (8.5%) compared to DTG + FTC/ TAF (4.6%) and DTG + FTC/TDF (7.0%).

Major congenital anomalies occurred in 4 infants: 2 in DTG + FTC/TAF arm (atrial septal defect and talipes equinovarus in the right foot) and 2 in EFV/FTC/TDF arm (duodenal atresia/ileal stenosis and subgaleal cyst).

Either stillbirth (previously reported) or infant death (combined) occurred as follows: 10 in DTG + FTC/TAF, 15 in DTG + FTC/TDF, and 18 in EFV/FTC/TDF arms. Four infants were diagnosed with HIV: 2 in DTG + FTC/TAF, 1 in DTG + FTC/TDF, and 1 in EFV arm.

Week 50 PP maternal viral load results were available for 573 (89.1%). Another 30 women had results within an extended window (due to COVID-19).

Proportions of women with viral load <200 copies/mL were similar in the combined DTG arms (96.3%) and EFV arm (96.4%).

The average weight loss from enrolment through PP was: -0.027 kg/week in DTG + FTC/TAF, -0.050 kg/week in DTG + FTC/TDF, and -0.084 kg/week in EFV/FTC/TDF arms (p<0.001, DTG + FTC/TAF vs EFV/FTC/TDF). There were no statistical differences in obesity rates between arms at week 50 PP – although this was highest in the DTG + FTC/TAF (22.6%) and lowest in the EFV/FTC/TDF (15%) arms .

DOLPHIN-2

In this study, 268 ART-naive pregnant women at 28 weeks’ gestation or more (safety cohort) were enrolled and randomised to receive EFV- (n=133) or DTG-based ART (n=135). Of those women, 250 (125 EFV and 125 DTG intention-to-treat cohort) were evaluable for efficacy.

At baseline women had a median age of 28 years, viral load 4.5 log10 copies/mL and CD4 449 cells/mm3.

Safety outcomes included maternal and/or infant drug related serious adverse events (SAE). Primary efficacy included maternal viral load <50 copies/mL.

At week 72 PP, 21.3% of women experienced one or more SAE: DTG 24.4% vs EFV 18.0%. But only 3% were judged to be drug-related. DTG was well tolerated with a lower frequency of drug-related SAE: DTG 2.2% vs EFV 3.8%.

Among the infants, 56.2% experienced one or more SAE, with 24.8% grade 3 or higher. There were 11 infant deaths: DTG 8 vs EFV 3. None of the SAE were judged to be drug-related. The high frequency of SAE was driven primarily by umbilical hernia and birth marks.

There were 4 infant HIV infections: 3 in utero in the DTG arm and 1 transmission at week 72 PP in the EFV arm. The late transmission was despite optimal maternal suppression (viral load <50 copies/mL) at delivery and serial negative tests in the infant.

At week 72 PP, 116/125 mothers receiving DTG achieved viral load <50 copies/mL with a median time of 4.14 (IQR 4.00 to 5.14) weeks. This compared to the EFV arm in which 114/125 women achieved suppression at a median of 12.14 (IQR 10.71 to 13.29) weeks: adjusted HR 1.93 (95% CI 1.47 to 2.53), p<0.0001.

For time to viral suppression to <1000 copies/mL, these values were DTG 1 week (IQR 1 to 2.86) vs EFV 3.71 weeks (IQR 3 to 4): adjusted HR 1.83 (95% CI 1.83 to 2.44), p<0.0001.

There were very few protocol defined failures (failure to achieve <50 copies/mL by week 24 PP or suppression with subsequent rebound – 2 consecutive results with viral load >1000 copies/mL). There was a small difference by arm: DTG 2.4% (n=3) vs EFV 6.4% (n=8).

The mean change in maternal weight from delivery to 72 weeks PP was -1.2 kg, with nonsignificant differences by arm in weight loss: DTG -0.7 kg vs EFV -1.6 kg.

comment

These data are reassuring and support WHO and most national recommendations to use DTG-based ART first-line including for pregnant and lactating women.

The HIV transmission to one infant in the DolPHIN-2 EFV arm, detected at week 72, shows the potential for transmission during breastfeeding despite undetectable viral load. The investigators described the infant feeding as exclusive breastfeeding to 6 months and stopped at 12 months. Maternal adherence included a “slight blip at 24 weeks”.

It is not clear how much additional evidence is needed before the UK BHIVA pregnancy guidelines change from the recommendation to still use efavirenz/boosted PI-based combinations?

References

Chinula L et al. Safety/efficacy of DTG vs EFV, TDF vs TAF in pregnancy/ postpartum: IMPAACT 2010 trial.
CROI 2021 (virtual). 6–10 March 2021. Oral abstract 177.
https://www.croiconference.org/abstract/safety-efficacy-of-dtg-vs-efv-tdf-vs-taf-in-pregnancy-postpartum-impaact-2010-trial/ (abstract)
http://www.croiwebcasts.org/p/2021croi/croi/177 (webcast)
Malaba TR et al. DoLPHIN2 final results dolutegravir vs efavirenz in late pregnancy to 72w postpartum. CROI 2021 (virtual). 6–10 March 2021. Oral abstract 175.
https://www.croiconference.org/abstract/dolphin2-final-results-dolutegravir-vs-efavirenz-in-late-pregnancy-to-72w-postpartum/ (abstract)
http://www.croiwebcasts.org/p/2021croi/croi/175 (webcast)
Clayden P. Dolutegravir-based ART is safe and effective for pregnant women: first results from the VESTED trial. HTB. 17 April 2020.
https://i-base.info/htb/37534
Clayden P. Dolutegravir suppresses viral load faster than efavirenz in late pregnancy: results from DolPHIN-2. HTB. 12 March 2019.
https://i-base.info/htb/35794

This report was first posted on 21 May 2021.