21st International AIDS Conference (AIDS 2016)


PROMISE Results Support WHO Recommendations for Pregnant and Breastfeeding Women: More Needs to Be Done to Improve ART Acceptability and Adherence

August 4, 2016

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Continued antiretroviral treatment was safe in women with higher CD4 counts after delivery and associated with improved maternal health -- but virologic failure rates were high -- according to data from the PROMISE study, presented at AIDS2016.

The study also revealed that acceptance of ART was low in this population and women needed time to consider starting treatment. And it found that ART during breastfeeding essentially eliminates vertical transmission by breast milk.

PROMISE (Promoting Maternal-Infant Survival Everywhere) is a multi county, multicomponent study, that began in 2010 and included 5398 asymptomatic HIV positive pregnant women who were not eligible for antiretroviral treatment (ART) at the time of enrollment. The study included breast feeding (BF) and formula feeding (FF) women, depending on local guidelines. Participants were randomly assigned different antiretroviral strategies to look at vertical transmission during pregnancy and post-partum, infant safety, and maternal health.

Research questions include:

  • Antepartum (1077BF/FF) Among HIV positive women who do not meet criteria for starting ART for their own health, what is the best intervention to prevent in utero and intrapartum HIV transmission to infants? Maternal ART vs a single drug prophylaxis regimen.
  • Postpartum (1077BF) Among HIV positive women who do not meet criteria for starting ART for their own health, what is the best intervention to prevent transmission of HIV to infants during breastfeeding? Maternal ART vs single drug infant prophylaxis.
  • Maternal health What is the best intervention to preserve maternal health after delivery? Stopping vs continuing ART.

The first part of the study (finally) provided randomised controlled trial (RCT) data to show that taking three drug ART in pregnancy was more effective in preventing vertical transmission than taking one drug during pregnancy, another in labour and two after delivery.1-3

These 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 2014.4

Standard of care also changed during the course of the study: as PROMISE was ongoing, the START study showed ART in people with CD4 500 cells/mm3 or more reduces the risk of HIV disease progression.5 PROMISE participants were informed of these results by the study group and women not receiving ART were strongly recommended to start immediately for their own health.

World Health Organisation (WHO) guideline subsequently changed to recommend "Treat All" reflecting the START results.6

Several analyses from PROMISE were presented at AIDS 2016 -- this commentary summarises results from studies looking at stopping or continuing ART postpartum, ART acceptability among women with higher CD4 counts and transmission during breastfeeding. The results broadly support the recommendations in the WHO guidelines -- including lifelong ART for all pregnant and breastfeeding women -- but also show that work needs to be done to improve adherence support and acceptability of ART among asymptomatic women.

Continuing ART Postpartum Benefits Maternal Health

In 2008/2009 when PROMISE was designed the health benefits of postpartum ART for women with high CD4 counts had not been evaluated in RCT. Judith Currier presented results from the component of PROMISE (1077HS) designed to assess the risks and benefits of continuing vs stopping ART among non-breastfeeding women after delivery.7 She showed these findings in an oral late breaker presentation on behalf of the study team.

HIV positive, non-breastfeeding, postpartum women with no indication for ART based on local guidelines, and who had received ART during pregnancy for at least four weeks in the main study, were randomised to continue or stop ART within 42 days of delivery. Women were followed for 84 weeks after the last enrollment. Those who stopped were restarted when their CD4 count dropped below 350 cells/mm3 or otherwise clinically indicated.

ART was provided by the study. The majority of participants received a regimen of lopinavir/ritonavir (LPV/r) plus tenofovir DF and emtricitabine (TDF/FTC). Atazanavir/ritonavir and, in some settings, rilpivirine and raltegravir were also available. Overall 90% of women were on PI-based ART.

The primary composite endpoint included: death, time to AIDS event (WHO stage 4), and serious non-AIDS events (cardiovascular, renal or hepatic). The primary safety endpoint was time to first targeted grade 2, 3 or 4 event. Key secondary endpoints were: a composite of HIV/AIDS related or WHO 2/3 events; or time to WHO 2/3 events.

The planned study sample size of 2000 participants provided 90% power to detect a 50% reduction from an annual primary event rate of 2.07% (calculated from other clinical trials). But in November 2014 the DSMB approved stopping enrollment at 1630 participants due to longer than expected time to enrol (the longer follow up was expected to make up for smaller sample size). All analyses were intent to treat.

Participants were informed of the START results and all offered ART in June 2015.

There were1652 participants enrolled from 52 sites across eight countries: Argentina, Botswana, Brazil, China, Haiti, Peru, Thailand and the US between January 2010 and November 2014. The majority were from Brazil (31%), Botswana (28%) and Thailand (18%).

Of the total, 827 and 825 women continued and stopped ART for a median of 2.31 vs 2.35 years; 79 (9.6%) vs 70 (8.5%) respectively discontinued the study. Adherence to randomly assigned treatment was generally good: 15% of women stopped ART in the continue arm and 12% restarted ART before the study threshold in the stop arm.

Median age was 28 years and 28% were black African, 16% Thai (16%) and 15% white. Median CD4 count at study entry was 696 cells/mm3, median ART exposure before delivery was 19 weeks and 91% had entry viral load <1000 copies/mL. During follow up 31% of the stop arm started ART at a median CD4 of 372 cells/mm3.

For the primary efficacy outcome events were very rare and not significantly different between arms. The events included: two cases of cervical cancer, and two deaths (one homicide and one unknown); and two cases of extrapulmonary TB, one toxoplasmosis and four deaths (one hepatic encephalopathy and one unknown), in the continue and stop arms respectively. The rate of safety endpoints was higher in the continue arm compared to the stop arm but this was not statistically significant.

WHO Stage 2 and 3 events were almost halved (44% reduction) with continued ART. The key events were: 16 herpes zoster and four bacterial infections; and six pulmonary TB, 43 herpes zoster, four thrombocytopenia, 10 oral candidiasis and 11 bacterial infections, in the continue and stop arms respectively. See Table 1.

Table 1: PROMISE 1077HS Endpoints
Endpoint (time to first event) Continue ART Stop ART Hazard ratio(95% CI) p-value
n rate/100 py n rate/100 py
Primary efficacy outcome 4 0.21 6 0.31 0.68(0.19 to 2.40) 0.54
Primary safety endpoint 260 18.4(15.7 to 21.4) 232 15.4(13.1 to 18.2) 0.08
Secondary Endpoints
Composite endpoint 57 3.09 99 5.49 0.56(0.41 to 0.78) <0.001
WHO 2/3 events 39 2.02 80 4.36 0.47(0.32 to 0.68) <0.001

Toxicity rates were higher in the continue arm but the difference was not statistically significant.

Among participants randomised to continue ART, 189/827 (23%) had virologic failure at or after 24 weeks of treatment. Of the 155 (82%) with resistance testing, 103 (66%) failed with no evidence of resistance to their current regimen (suggesting non-adherence). Of the 52 with evidence of resistance: 22 had resistance to one of the drugs in the failing regimen; 14/25 (11%) failing a PI regimen and 8/27 (30%) failing an NNRTI regimen.

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This article was provided by HIV i-Base. It is a part of the publication HIV Treatment Bulletin. Visit HIV i-Base's website to find out more about their activities, publications and services.

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