CROI 2021: Pregnancy outcomes and weight gain with dolutegravir and TAF
Polly Clayden, HIV i-Base
Dolutegravir (DTG) and tenofovir alafenamide (TAF) have been linked to excessive weight gain. Both low and high weight gain during pregnancy have been associated with adverse outcomes. Three studies, presented at CROI 2021 looked at these associations.
- A secondary analysis from VESTED found low (but not high) antepartum weight gain was associated with adverse pregnancy outcomes. Women starting DTG + emtricitabine (FTC)/TAF in pregnancy gained more weight than women starting DTG + FTC/tenofovir disoproxil fumarate (TDF) or efavirenz (EFV)/FTC/TDF. Women starting EFV/FTC/TDF had the lowest weight gain. 
- Data from the Tsepamo birth outcomes surveillance study showed gestational weight gain to have weaker associations with adverse outcomes than baseline weight among women on ART at conception. Time on pre-pregnancy ART was associated with higher baseline pregnancy weight for DTG but not for EFV. The risk of maternal hypertension by baseline weight was higher for DTG than EFV. 
- Using data from ADVANCE, modelling predicted 18 additional adverse outcomes for every 100 women becoming pregnant after three years of TAF/FTC + DTG. 
The VESTED study (IMPAACT 2010) evaluated three ART regimens started in pregnancy. (Primary results were presented last year at CROI 2020 and 50 week postpartum results were also presented at CROI 2021). [4, 5]
Women with HIV in nine countries were randomised 1:1:1 at 14 to 28 weeks gestational age (GA) to start DTG + FTC/ TAF vs DTG + FTC/TDF vs EFV/FTC/TDF. All women were followed up for 12–26 weeks antepartum and 50 weeks postpartum. There was significantly lower rate of adverse pregnancy outcomes in the DTG + FTC/TAF arm at 14 days follow up postpartum.
This secondary analysis focused on antepartum weight gain and evaluated associations between weight and adverse pregnancy outcomes. Low weight gain was defined as less than 0.18 kg/week and high weight gain as at least 0.59 kg/week.
Six hundred and forty three women were randomised: 217 to DTG + FTC/TAF, 215 to DTG + FTC/TDF and 211 to EFV/FTC/TDF arms. At baseline, maternal medians were: age 26. 6 years; GA 21.9 weeks; viral load 903 copies/mL; and CD4 count 466 cells/mm3. Mean enrollment weight was 66.2 kg.
Antepartum weight data were available for 632 (98.3%) women and median duration of antepartum follow up was 17.4 weeks.
Weekly average weight gain was highest with DTG + FTC/TAF (0.378 kg) vs DTG + FTC/TDF (0.319 kg, p=0.011) vs EFV/FTC/TDF (0.291 kg, p<0.001). Notably the recommended maternal weight gain for second/third trimesters is 0.42 kg/week – so none of the arms reached this.
Low weight gain was least common with DTG + FTC/TAF (15.0%) vs DTG + FTC/TDF (23.6%) vs EFV/FTC/TDF (30.0%). The opposite was true for high weight gain: DTG + FTC/TAF (12.7%) vs DTG + FTC/TDF (9.9%) vs EFV/FTC/TDF (6.3%).
Low weight gain was associated with higher risk of any adverse pregnancy outcome and slightly higher but not significant risk of SGA: HR 1.4 (95% CI: 1.02 to 1.96), p=0.037 and HR 1.5 (95% CI: 0.99 to 2.22), p=0.054, respectively. There was no interaction by treatment arm.
Across all treatment arms there was a significant association between higher average weekly weight gain and a lower risk of any adverse pregnancy outcome: HR 0.5 (95% CI 0.25 to 0.97), p=0.04.
And overall low weight gain appeared to be associated with higher risk of stillbirth and preterm delivery compared with normal weight gain. The investigators noted that these data should be interpreted with caution as the numbers in the subgroups are quite small.
The Tsepamo study is a birth outcomes surveillance study in Botswana – it is the largest dataset of DTG exposure in pregnancy. 
The purpose of this analysis was to better understand the implications of ART-associated weight gain using Tsepamo data to define the associations between baseline maternal weight and weight gain on adverse pregnancy outcomes (very preterm, very small for gestational age, perinatal death, macrosomia and maternal hypertension) among women receiving ART from conception.
Of 22,828 women on ART at conception with singleton deliveries between August 2014 and April 2020, 16,300 (71%) had a documented weight measured at <24 weeks gestation (baseline weight) and 4437 (19%) had documented weight measured both at 12 (+/-2) weeks and 24 (+/-2) weeks.
Of 16,300 women, median baseline weight was 60.3 kg: 13% with low weight (<50 kg) and 7% high weight. Among the 4437 women, median gestational weight gain was 0.33 kg/week: 21% had low weight gain (<0.15 kg/week) and 15% high weight gain (>0.55 kg/week).
There were no substantial differences between low, high and average gestational weight gain categories and adverse pregnancy outcomes except for high weight gain and increased risk of macrosomia (birthweight >4000 g): aRR 2.01 (95% CI: 1.8 to 2.32).
In contrast, compared to women with baseline weight 60 to 70 kg, low baseline weight was associated with any severe birth outcomes: aRR 1.63 (95% CI: 1.45 to 1.83). Specifically low baseline weight was associated with increased risk of very preterm delivery and very small for gestational age: aRR 1.30 (95% CI 1.03 to 1.65) and aRR 1.96 (95% CI 1.69 to 2.28), respectively.
High baseline weight was associated with increased risk of macrosomia and maternal hypertension: aRR 3.24 (95% CI 2.36 to 4.44) and aRR 1.79 (95% CI 1.62,1.97), respectively. Baseline weight was not associated with perinatal death.
Baseline weight was similar for women on DTG vs EFV: 62.9 kg vs 62.3 kg, respectively. This differed by length of time on ART before conception for DTG (62.5 kg <1 year, 63.3 kg 1–2 years and 64.4 kg 2–3 years, p=0.11) but not EFV.
The investigators noted that maternal hypertension was higher among women on DTG compared with EFV across all baseline weight categories and in adjusted analyses, ART regimen was a significant effect modifier (p<0.001) for the relationship between baseline weight and this outcome.
The ADVANCE study is an ongoing three arm, 192 week, phase 3, study comparing first-line ART with: TAF/emtricitabine (FTC) + DTG, tenofovir disoproxil fumarate (TDF)/FTC + DTG or TDF/FTC/EFV. Week 96 results, as well as an earlier version of this pregnancy outcomes analysis, were presented at AIDS 2020. [7, 8].
This study predicted long-term risks of adverse outcomes in pregnancy and child health from treatment-associated clinical obesity among pregnant women, using data from the ADVANCE trial.
After 144 weeks of treatment in the ADVANCE trial, the percentage of women with normal baseline BMI becoming clinically obese was 19% for TAF/ FTC + DTG, 5% for TDF/FTC + DTG, and 0% for TDF/FTC/EFV.
From baseline to week 144, the predicted increase of adverse maternal outcomes was 15% with TAF/ FTC + DTG vs 4% with TDF/FTC + DTG. Risk predictions for adverse infant outcomes were 12% and 3% in these two groups, respectively.
The predicted risk of adverse outcomes in child health was 28% and 7% for TAF/FTC + DTG and TDF/FTC + DTG, respectively. No additional adverse events were predicted for pregnant women treated with TDF/FTC/EFV.
This model predicted that for every 100 women becoming pregnant after three years of TAF/FTC + DTG treatment, there would be 18 additional adverse outcomes.
The authors suggested that new stopping rules may be required to switch women off TAF/FTC + DTG and similar combination treatments, to lessen these risks.
Tsepamo investigators noted that ART-associated weight gain with newer antiretrovirals may have both a positive and negative impact on maternal and child health depending on the mother’s weight at the start of pregnancy.
Tsepamo only looked at DTG-based ART with TDF so the greater weight gain in ADVANCE and VESTED with TAF and DTG-based ART was not evaluated.
In VESTED all women started ART in pre-pregnancy and the data did not include pre-pregnancy weight.
ADVANCE pregnancy outcomes were modelled compared with clinical data in VESTED and Tsepamo.
All groups plan further analyses – for VESTED this will include postpartum weight through 50 weeks.
- Hoffman RM et al. Antepartum weight gain and adverse pregnancy outcomes in IMPAACT 2010. CROI 2021 (virtual). 6–10 March 2021. Oral abstract 176.
https://www.croiconference.org/abstract/antepartum-weight-gain-and-adverse-pregnancy-outcomes-in-impaact-2010/ (abstract and webcast)
- Zash R et al. Maternal weight and adverse pregnancy outcomes among women on ART at conception. CROI 2021 (virtual). 6–10 March 2021. Poster abstract 571.
https://www.croiconference.org/abstract/maternal-weight-and-adverse-pregnancy-outcomes-among-women-on-art-at-conception/ (abstract and webcast)
- Baxevanidi EE et al. Predicted long-term adverse birth and child health outcomes in the ADVANCE trial.CROI 2021 (virtual). 6–10 March 2021. Poster abstract 572.
https://www.croiconference.org/abstract/predicted-long-term-adverse-birth-and-child-health-outcomes-in-the-advance-trial/ (abstract and webcast)
- Clayden P. Dolutegravir-based ART is safe and effective for pregnant women: first results from the VESTED trial. HTB. 17 April 2020.
- 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.
- Clayden P. Neural tube defects in two of 1000 conception exposures with dolutegravir: reassuring update from Tsepamo study. HTB. 22 July 2020.
- Clayden P. ADVANCE 96-week results: dolutegravir weight gain continues, especially in women and when used with TAF – no evidence of a plateau. HTB. 16 July 2020.
- Clayden P. Obesity linked to dolutegravir, especially with TAF, could increase risk of adverse pregnancy outcomes. HTB. 22 July 2020.