Three drug regimen superior for preventing vertical transmission in the PROMISE study

29 January 2015. Related: Pregnancy.

Polly Clayden, HIV i-Base

Taking three drug ART in pregnancy was more effective in preventing mother-to-child transmission than taking one drug during pregnancy, another in labour and two after delivery – according to interim data from the PROMISE (Promoting Maternal-Infant Survival Everywhere) study.

The findings were reported on 4 November 2014 during a scheduled interim review of PROMISE by an independent data and safety monitoring board (DSMB). The US National Institutes of Health issued a press release explaining the results on 17 November 2014. [1]

PROMISE is a multinational from the IMPAACT Network, [2] which has been ongoing since 2010, and is looking at the best way to reduce the risk of mother-to-child transmission during pregnancy and after delivery in asymptomatic women with CD4 >350 cells/mm3 (or national CD4 threshold for initiating treatment).

The study includes two years follow-up from after the last child is born to look at the safety and efficacy of antiretroviral regimens taken during the breastfeeding period. It is also looking at maternal health after the breastfeeding period in women who either stop or continue taking ART.

All infants receive a daily dose of nevirapine until 6 weeks of age, and those who are HIV-infected receive ART.

Women in the study were randomly assigned to receive: AZT from >14 weeks of pregnancy, and a single dose of nevirapine during labour, and two weeks of tenofovir and FTC after delivery (WHO Option A); or one of two triple ART regimens from >14 weeks (WHO Option B or Option B+). The ART regimens are lopinavir/ritonavir plus either 3TC/AZT or tenofovir/FTC.

At the time of the DSMB review, the study had enrolled >3,500 pregnant or post-partum women and >3,200 HIV-exposed infants of the women in India, Malawi, South Africa, Tanzania, Uganda, Zambia and Zimbabwe. HIV transmission data to 14 days post partum were evaluated.

The DSMB found that there was a significantly lower rate of transmission during pregnancy or delivery in the group who received an ART regimen than among those who received Option A.

Only 0.5% of infants whose mothers received the 3TC-containing regimen and 0.6% of infants whose mothers received the tenofovir-containing regimen were infected with HIV, compared to 1.8% of infants whose mothers received Option A.

The review also concluded that the 3TC-containing ART regimen appeared to be safer than the other strategies. Women who received 3TC experienced fewer severe adverse pregnancy outcomes including very low birth weight, very preterm delivery, stillbirth, spontaneous abortion or major birth defects. There were also fewer infant deaths within 14 days of birth those than in those in the tenofovir or Option A groups. Preterm delivery was the most common cause of death.

But, there were a greater number of less severe outcomes, including birth weight <2,500 grams and preterm delivery at < 37 weeks gestation, in infants whose mothers received ART than those whose mothers received Option A.

The DSMB recommended that these results be made public and the investigators, women in the study who remain pregnant, and their health care providers determine the best regimen with which to continue.

The other parts of the study will remain unchanged and continue.

Comment

Although Option A was still an option for women not yet eligible for treatment when this study was designed, several critics questioned the ethics of giving pregnant women a regimen below the standard of care in their country, as WHO and national guidelines abandoned it. [3]

It is also unclear why the 2012 review of PROMISE did not recommend stopping the suboptimal arm earlier.

Although transmission risk was very low across the trial arms, unsurprisingly three-drug ART does better at 14 days from delivery. However, the question of whether women should continue or stop ART after breastfeeding remains unanswered. Several national programmes now recommend lifelong ART for all pregnant women regardless of CD4 count (Option B+), largely to minimise the complexities of stopping and restarting treatment.

The more surprising finding was the greater frequency of adverse outcomes in the group receiving tenofovir-based ART. It is notable that the regimen used in PROMISE included lopinavir/ritonavir. Hill et al recently reported approximately 30% increases in tenofovir AUC in a literature search to determine the effects of boosted antiretrovirals on tenofovir plasma concentrations. The authors noted that tenofovir toxicity might be over estimated in clinical trails were it is only combined with boosted antiretrovirals.

The efficacy of tenofovir 300 mg once-daily was established in trials with EFV, which does not increase tenofovir drug levels. The WHO recommended first line regimen for pregnant women is EFV, 3TC and tenofovir.

The PROMISE interim findings have been submitted to CROI as a late breaker.

References:

1. National Institutes of Health press release. NIH-sponsored study identifies superior drug regimen for preventing mother-to-child HIV transmission. 17 November 2014.
   http://www.nih.gov/news/health/nov2014/niaid-17.htm
2. International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT)
   http://www.impaactnetwork.org/studies
3. Check Hayden E. HIV trial attacked. Nature 510, 324. 19 June 2014.
   http://www.nature.com/news/hiv-trial-attacked-1.15421
4. Hill A et al. Should the dose of tenofovir be reduced to 200-250 mg/day, when combined with protease inhibitors? HIV Drug Therapy Glasgow Congress, 2-6 November 2014. Poster abstract P-51. Journal of the International AIDS Society 2014, 17(Suppl 3):19583
.
   http://www.jiasociety.org/index.php/jias/article/view/19583