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CROI 2022: Updates from the VESTED study

1 June 2022. Related: Conference reports, Treatment strategies, .

Polly Clayden, HIV i-Base

CROI 2022Four sub-studies from the VESTED trial were presented at virtual CROI 2022. [1, 2, 3, 4]

VESTED (IMPAACT 2010) enrolled 643 women with HIV at 14–28 weeks gestational age in nine countries. [5]

Participants were randomised to start ART with dolutegravir (DTG) plus emtricitabine (FTC)/tenofovir alafenamide (TAF); DTG/FTC/tenofovir disoproxil fumarate (TDF); or efavirenz (EFV)/FTC/TDF. Mothers and infants were followed until 50 weeks after delivery.

The trial found all three regimens to be safe and effective in pregnancy but DTG-containing regimens led to better viral suppression and DTG/FTC/TAF to lower adverse pregnancy outcomes. Infants were similar between arms but there was a higher proportion with low birth weight in the EFV arm.

Results shown at CROI 2022 were from substudies comparing the three regimens with respect to: infant growth, risk-benefit, subsequent pregnancies and glycated hemoglobin (HbA1c) and glucose in study participants.  

Infant growth

The evaluation comparing the effect of the three maternal regimens on growth among exposed infants found those in the EFV/FTC/TDF arm were smaller than in both the DTG arms. Growth was similar in the infants exposed to TDF or TAF with DTG/FTC.

A high proportion of infants in all arms had severe stunting. This was highest (and occurred in one in five) among EFV/FTC/TDF-exposed 1-year olds.

The investigators evaluated infant growth at  approximately 26 and 50 weeks of age by maternal regimen in a post hoc analysis. They calculated Z-scores for length-for-age (LAZ), weight-for-age (WAZ), and weight-for-length (WHZ) using WHO standards. They also estimated the proportion of infants in each arm with severe stunting (defined as LAZ below -2).

In this group of mostly breastfed infants (78%) exposed to maternal HIV and ART (4 infants aquired HIV; 0.6%) mean LAZ and WAZ were lower in the EFV/FTC/TDF arm than the DTG arms.

At week 26 and 50, mean LAZ differences between DTG/FTC/TDF and EFV/FTC/TDF arms were: 0.4 (95% CI 0.1 to 0.6), p=0.0056 and 0.3 (95% CI 0.1 to 0.6; p=0.01), respectively. For DTG/FTC/TAF vs EFV/FTC/TDF, these differences were: 0.4 (95% CI 0.1 to 0.7), p=0.0047 and 0.2 (95% CI -0.1 to 0.5; p=0.14).

All pairwise comparisons favoured DTG except for DTG/FTC/TAF at week 50. LAZ scores were similar in the TDF and TAF, DTG arms.

Notably mean LAZ scores for all arms tended to be below WHO norms with higher rates of stunting (LAZ below -2) in the EFV vs DTG arms at both timepoints: approx 15% vs 21%.

At the same time points, mean WAZ differences between DTG/FTC/TDF and EFV/FTC/TDF arms were: 0.3 (95% CI 0.0 to 0.5), p=0.035 and 0.3 (95% CI 0.1 and 0.6) p=0.0094, respectively. For DTG/FTC/TAF vs EFV/FTC/TDF these scores were: 0.2 (95% CI -0.0 to 0.5), p=0.077 and 0.3 (95% CI 0.1 and 0.6), p=0.019.

The EFV arm had the highest proportion of underweight infants (approximately 11%). There were also 3–4% obese infants across all arms with no evidence of a higher proportion in the TAF arm.

There were no mean differences between DTG/FTC/TAF and DTG/FTC/TDF arms in LAZ or WAZ at either week 26 or 50.

There were no differences between arms in WHZ.

The investigators recommended that infant growth should be factored into choice of optimal maternal ART regimen during pregnancy and breastfeeding.

Risk-benefit

In these analyses, DTG/FTC/TAF gave the best and clearest risk-benefit trade-off overall. DTG/FTC/TDF also had a better risk-benefit profile than EFV/FTC/TDF.

The investigators explained that understanding the risk-benefit trade-off for pregnancy and infant outcomes in clinical trials of pregnant women is complex due to multiple outcomes of interest. It can be misleading when risks and benefits are summarised in separate analyses.

For this evaluation they compared risk and benefit by arm using a desirability of outcome ranking (DOOR) with weights to account for severity of the outcome.

Mother-infant pair adverse outcomes were grouped according to the most severe outcome experienced: 1. infant death through one year of life, 2. spontaneous abortion or stillbirth, 3. infant HIV infection, 4. very preterm delivery (<32 weeks), 5. major congenital anomaly, 6. preterm delivery (<37 weeks), 7. small for gestational age (<10th percentile), 8. infant hospitalisation, 9. infant grade 3 or 4 adverse event.

The comparisons revealed: 79/216 (37%), 93/213 (44%), and 101/211 (48%) mother-infant pairs experienced at least one of the ranked outcomes in the DTG/FTC/TAF, DTG/FTC/TDF, and EFV/FTC/TDF arms, respectively.

Using ordinal logistic regression, there was a better risk-benefit trade-off for DTG/FTC/TAF compared with EFV/FTC/TDF: OR 0.60 (95% CI 0.42 to 0.88).

In the severity-weighted analysis, DTG/FTC/TAF also had a better risk-benefit trade-off compared with DTG/FTC/TDF and EFV/FTC/TDF, repectively: OR 0.64 (95% CI 0.49 to 0.84) and OR 0.28 (95% CI 0.21 to 0.36). DTG/FTC/TDF had a better risk-benefit trade-off relative to EFV/FTC/TDF: OR 0.41 (95% CI 0.32 to 0.53).

Subsequent pregnancies

Adverse pregnancy outcomes were very common among women who conceived on ART in VESTED – 35% of pregnancies ended in stillbirth or spontaneous abortion. Women with recent prior pregnancy loss were most at risk (but numbers were small).

This sub study looked at adverse pregnancy outcomes in women who became pregnant during postpartum follow-up (subsequent pregnancy).

These outcomes were: spontaneous abortion (<20 weeks), stillbirth (<20 weeks), preterm delivery (<37 weeks), small for gestational age (<10th percentile) and neonatal death (<28 days).

Due to a protocol amendment – based on concerns about neural tube defects among infants born to women who conceive on DTG – women who did not wish to use contraception after delivery were switched to (mostly) EFV.    

Nineteen (3%) of 643 women had 20 subsequent pregnancies during follow up. They were taking the following regimens at conception: DTG/FTC/TAF (3), DTG/FTC/TDF (2), EFV/FTC/TDF (11, 1 woman with 2 pregnancies), non-study ART (2) and no ART (1).

Only 12/20 (60%) subsequent pregnancies resulted in live birth: 4/20 (20%) spontaneous abortions, 3/20 (15%) stillbirths, and 1/20 (5%) induced abortion. Three (25%) liveborn infants were preterm (24, 26 and 36 weeks’ gestation).

At least one adverse pregnancy outcome occurred in 11/20 (58%) subsequent pregnancies, more frequently with EFV/FTC/TDF at conception (8 of 12 pregnancies; 67%) than with DTG-ART at conception (1/4 women).

Four of seven women who experienced spontaneous abortion or still birth in the subsequent pregnancy had a stillbirth in the index pregnancy and one a neonatal death. 

The investigators rightly noted that the sample size was too small to formally test differences in outcomes of subsequent pregnancies by regimen.

They added that this finding should be considered in analyses of incident pregnancies occurring in trial participants.

HbA1c and glucose

This sub study did not find significant differences in maternal glycated hemoglobin (HbA1C) by ART regimen or clinically-important differences in maternal or infant random glucose. But only modest sample sizes of participants were assessed.

In VESTED, as observed elsewhere, DTG, particularly in combination with TAF, was associated with more weight gain than ART containing EFV or TDF (but better pregnancy outcomes were shown with DTG/FTC/TAF). The impact of this weight gain during pregnancy on gestational diabetes is unknown.

The investigators evaluated HbA1c and glucose in study participants. After a protocol amendment partway through the trial, maternal HbA1c and random glucose was sampled at study entry, 12 weeks after enrolment (antepartum) and delivery. Neonatal glucose was sampled within 48 hours of birth.

The evaluation compared the proportion of women with post-baseline HbA1c >5.7% (prediabetic) between arms and described the proportion with HbA1c >6.5% (diabetic).

HbA1c and/or glucose results were available for 348 mothers and 65 infants: 114 in the DTG/FTC/TAF; 116 in the DTG/FTC/TDF and 118 in the EFV/FTC/TDF arms.

Maternal medians at enrolment were: age 25.9 years, gestational age 21.5 weeks, BMI 24.1 kg/cm2, HIV-1 RNA 3.1 log10, and CD4 466 cells/mm3.

Maternal mean HbA1c levels and mean time-averaged HbA1c AUC did not differ significantly between arms.

Seven per cent of women in the DTG/FTC/TAF arm, 6.0% in the DTG/FTC/TDF arm, and 3.4% in the EFV/FTC/TDF arm had at least one post-baseline HbA1c >5.7%, p=0.21 for between-arm comparisons.

No woman had diabetes at baseline. One woman in the DTG/FTC/TAF arm developed HbA1c >6.5% post-baseline.

The DTG/FTC/TDF arm had slightly higher mean time-averaged AUC glucose (4.8 mmoL/L) vs the EFV/FTC/TDF arm (4.63 mmoL/L): mean difference 0.17 mmol/L (95% CI 0.00 to 0.34).

Mean infant glucose levels within approximately 48 hours birth were similar by arm.

comment

Information about the impact of specific maternal ART regimens during pregnancy and breastfeeding on mothers and infants is limited.

Although modest sample size is almost always a limitation sub studies such as these, the value of large randomised trials to make many randomised comparisons looking at important issues such as these, over and above the primary outcomes cannot be underestimated.

Along with other trials such as START and ADVANCE, VESTED has been a goldmine. 

References

Unless stated otherwise, references are to the 29th Conference on Retroviruses and Opportunistic Infections, 12–16 and 22–24 February 2022, virtual meeting.

  1. Stranix-Chibanda L et al. Growth of infants with perinatal exposure to maternal DTG vs EFV and TDF vs TAF. CROI 2022.12–16 February. Virtual. Oral abstract 30.
    https://www.croiconference.org/abstract/growth-of-infants-with-perinatal-exposure-to-maternal-dtg-vs-efv-and-tdf-vs-taf/ (abstract)
    http://www.croiwebcasts.org/console/player/50290 (webcast)
  2. Brummel S et al. Risk-benefit trade-off for pregnancy and infant outcomes: DTG, EFV, TAF, AND TDF. CROI 2022. 12–16 February. Virtual. Poster abstract 679.
    https://www.croiconference.org/abstract/risk-benefit-trade-off-for-pregnancy-and-infant-outcomes-dtg-efv-taf-and-tdf/ (abstract)
    https://2jg4quetidw2blbbq2ixwziw-wpengine.netdna-ssl.com/wp-content/uploads/sites/2/posters/2022/CROI2022_Poster_679.pdf  (poster)
  3. Fairlie L et al. Adverse outcomes in subsequent pregnancies in the IMPAACT 2010 trial. CROI 2022. 12–16 February. Virtual. Poster abstract 680.
    https://www.croiconference.org/abstract/adverse-outcomes-in-subsequent-pregnancies-in-the-impaact-2010-trial/ (abstract)
    https://2jg4quetidw2blbbq2ixwziw-wpengine.netdna-ssl.com/wp-content/uploads/sites/2/posters/2022/CROI2022_Poster_680.pdf (poster)
  4. Chinula L et al. Pregnancy hemoglobin A1c and glucose with DTG vs EFV, TDF vs TAF: IMPAACT 2010. CROI 2022. 12–16 February. Virtual. Poster abstract 687.
    https://www.croiconference.org/abstract/pregnancy-hemoglobin-a1c-and-glucose-with-dtg-vs-efv-tdf-vs-taf-impaact-2010/ (abstract)
    https://2jg4quetidw2blbbq2ixwziw-wpengine.netdna-ssl.com/wp-content/uploads/sites/2/posters/2022/CROI2022_Poster_687.pdf (poster)
  5. Lockman S et al. 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. The Lancet. Volume 397. Number 10281 p1237-1324. 3 April 2021.
    https://www.thelancet.com/journals/lancet/issue/vol397no10281/PIIS0140-6736(21)X0014-1

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