Polly Clayden, HIV i-Base
Taking a three-drug ART combination in pregnancy was more effective in preventing mother-to-child transmission than taking one drug during pregnancy, another in labour and two after delivery.
This was reported from the PROMISE (Promoting Maternal-Infant Survival Everywhere) study presented at CROI 2015. 
These initial findings were reported in a US National Institutes of Health press release on 17 November 2014 after a scheduled interim review by the data and safety monitoring board (DSMB). 
PROMISE is a multinational trial conducted by the IMPAACT Network , which has been ongoing since 2010. Mary Glenn Fowler presented the data on behalf of the trial investigators. She summarised the goals of PROMISE:
- Maximise prevention of mother-to-child HIV transmission (PMTCT) and optimise maternal/child health and survival.
- Assess the relative safety and efficacy of triple antiretroviral treatment compared to other PMTCT regimens in women who did not require antiretroviral treatment, and their infants.
- Conduct the study in the context of standard of care (SOC) for adult HIV treatment and infant feeding – Breastfeeding (BF) and Formula Feeding (FF).
PROMISE is multinational and includes sites in the following resource-limited countries: India, Malawi, South Africa, Tanzania, Uganda, Zambia and Zimbabwe.
Asymptomatic women with >350 cells/mm3 (or above local threshold for starting treatment) were enrolled. The trial has three randomisations:
Antepartum (14 weeks term) Arm A – AZT plus single-dose nevirapine (NVP) at delivery plus tenofovir (TDF)/emtricitabine (FTC) tail vs Arm B – AZT-lamivudine (3TC) plus lopinavir/ritonavir (LPV/r) vs Arm C – TDF/FTC plus LPV/r.
Postpartum (duration of breastfeeding) uninfected infant, triple antiretroviral prophylaxis vs nevirapine prophylaxis.
Maternal health mothers receiving ART, after stopping BF, continue vs stop ART.
At the interim review, the DSMB reported that the pre-specified efficacy boundary for the antepartum part of the trial was crossed and there were safety differences between arms. The DSMB recommended: dissemination of the antepartum results to 14 days postpartum; continue follow-up for protocol-specified duration to obtain longer term efficacy/safety data and achieve the postpartum and maternal health objectives; and women who were still pregnant were advised to switch to ART arm.
Antepartum data to 14 days postpartum were presented at the conference.
Efficacy analyses compared vertical transmission in Arm A to the pooled triple ART arms. Safety analyses compared all three arms. Dr Fowler noted that Arm C was only open to all women in a later version of the protocol (V3) because of concerns about the safety of TDF in pregnancy. So comparisons of Arms A and B included all women, but comparisons with Arm C only included those randomised under V3, when there was more TDF safety data available.
Data from 3523 pregnant women were available for analysis. At baseline, the women were a median age of 26 years; 97% were black African; median enrolment gestational age was 26 weeks; median CD4 was 530 cells/mm3; and 97% of women had not previously received antiretrovirals for PMTCT.
The rate of vertical transmission at 14 days postpartum was significantly lower in the pooled triple ART arms: 0.56% (9/710) vs 1.8% (25/1,326). This gave a difference in transmission risk of -1.28% (95% CI: -2.11 to -0.44).
There were no maternal deaths. There were significantly higher rates of Grade 2-4 adverse events (mostly LFTs) in both triple ART arms. Moderate but not severe adverse pregnancy outcomes were also higher with triple ART. Severe pregnancy outcomes were greater in Arm C: any, 4 vs 9%, p=0.02; preterm delivery < 34 weeks, 3 vs 6%, p=0.04, respectively B vs C.
There were no significant differences in infant signs/symptoms and laboratory adverse events across arms for all infants and for V3 only infants. There were 60 early infant deaths by 14 days; 28 occurred in V3 infants. In V3, there was a significantly lower risk of infant death for Arm B vs C: –0.6%(2/346) vs 4.4% (15/341), p=0.001. The difference was mostly in deaths in preterm infants <34 weeks gestation.
There was significantly higher HIV-free survival in Arm B vs C at 14 days, p=0.002.
Dr Fowler concluded that the results support the 2013 WHO recommendations for use of triple maternal ART regimens in pregnancy (Option B or B+). She noted that antepartum triple ART regimens were associated with higher risk of moderate but not severe adverse maternal and pregnancy outcomes, including preterm birth and low birth weight, and that this will require follow up of 12 month infant mortality.
She also added that the difference in risk of early infant deaths in the FTC/TDF triple ART arm compared to the 3TC/AZT one was unexpected and requires further investigation.
The other parts of the study will remain unchanged and continue.
We previously reviewed these findings after the NIH press release in January. 
We wrote then that the regimen used in PROMISE included lopinavir/ritonavir. And that a recent report found approximately 30% increases in tenofovir AUC in a literature search to determine the effects of boosted antiretrovirals on tenofovir plasma concentrations.
The authors of the report noted that tenofovir toxicity might be overestimated in clinical trials where it is only combined with boosted antiretrovirals. Andrew Hill, the lead author, made the same observation in questions after the PROMISE presentation. He suggested that a reduced dose of TDF might be appropriate with lopinavir/ritonavir.
The PROMISE investigators plan to look at drug levels.
- Fowler MG et al. PROMISE: Efficacy and safety of 2 strategies to prevent perinatal HIV transmission. CROI 2015. 2015 Conference on Retroviruses and Opportunistic Infections (CROI 2015), 23-26 February 2015, Seattle. Oral abstract 31LB.
- National Institutes of Health press release. NIH-sponsored study identifies superior drug regimen for preventing mother-to-child HIV transmission. 17 November 2014.
- International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT)
- Clayden P. Three drug regimen superior for preventing vertical transmission in the PROMISE study. HTB, January/February 2015.
- 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