PROMISE at AIDS 2016

The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network is delighted to announce the presentation of several important outcomes from the ongoing Promoting Maternal and Infant Survival Everywhere (PROMISE) study at the 21st International AIDS Conference and the preceding 8th International Workshop on HIV Pediatrics in Durban, South Africa. A NIAID news release related to the presentations is available at https://www.nih.gov/news-events/news-releases/hiv-therapy-breastfeeding-mothers-can-virtually-eliminate-transmission-babies.

PROMISE is a large, multi-protocol, multi-component, international clinical research study designed to evaluate antiretroviral interventions for HIV-infected pregnant and postpartum women in good immune health and their infants. Results from the Antepartum Component of the study were previously announced and presented at the Conference on Retroviruses and Opportunistic Infections in February 2015. Further results presented in Durban are described below and the associated presentations will be posted here in the near future.
 

Benefits of Antiretroviral Therapy for Breastfeeding Women and Their Infants

The Postpartum Component of PROMISE (1077BF) was conducted at 14 IMPAACT sites in India, Malawi, South Africa, Tanzania, Uganda, Zambia, and Zimbabwe among 2431 women with high CD4 cell counts and their 2444 infants. Mother-infant pairs were randomly assigned to receive either maternal ART or infant nevirapine for prevention of HIV transmission during breastfeeding.

Efficacy and safety: Primary analyses of the Postpartum Component, presented by Taha E Taha on behalf of the study team, highlighted that rates of HIV transmission were extremely low (less than 1% at 12 months of age) and rates of infant survival were extremely high (99% at 12 months of age). Both interventions — maternal ART and infant nevirapine — were safe and well tolerated, with no statistically significant differences in rates of adverse events, rates of HIV transmission, or rates of infant mortality between randomized study arms.
 

Reference: TE Taha et al. Comparing maternal triple antiretrovirals and infant nevirapine prophylaxis for the prevention of mother-to-child transmission of HIV during breastfeeding. Oral presentation at the 8th International Workshop on HIV Pediatrics and poster presentation at the 21st International AIDS Conference (AIDS 2016) Durban, South Africa. July 2016.

Infant growth: An analysis of somatic growth among infants in the Postpartum Component, presented by Lynda Stranix-Chibanda on behalf of the study team, demonstrated no statistically significant differences in Z-scores for length-for-age, weight-for-age, or head circumference at 26 weeks of age when comparing infants randomized to maternal ART to infants randomized to infant nevirapine.
 

Reference: L Stranix-Chibanda et al. Impact of maternal antiretroviral therapy (ART) versus infant nevirapine prophylaxis on somatic growth of breastfeeding infants in the PROMISE trial. Poster presentation at the 8th International Workshop on HIV Pediatrics. Durban, South Africa. July 2016.

Maternal bone mineral density: Also presented by Lynda Stranix-Chibanda, the Bone and Kidney Health Substudy of PROMISE (P1084s) was conducted among a subset of mother-infant pairs enrolled in PROMISE to further evaluate the effects of predominantly tenofovir-containing maternal ART regimens. Among 397 women with no exposure to tenofovir during pregnancy, who were randomly assigned to either maternal ART or infant nevirapine in the Postpartum Component, and who were enrolled in the substudy, bone mineral density (BMD) in the hip and lumbar spine declined significantly more through 74 weeks of follow-up among women randomized to maternal ART postpartum compared to women randomized to infant nevirapine postpartum. The mean differences between randomized arms for the percentage change from baseline were -2.33% for hip BMD and -3.16% for lumbar spine BMD.
 

Reference: L Stranix-Chibanda et al. Impact of tenofovir-containing triple antiretroviral therapy (ART) on bone mineral density in HIV-infected breastfeeding women in sub-Saharan Africa. Oral presentation at the 8th International Workshop on HIV Pediatrics. Durban, South Africa. July 2016.

Findings from the Postpartum Component provide further randomized clinical trial evidence of the benefits of ART. Maternal ART can virtually eliminate HIV transmission to infants while preserving the health advantages of breastfeeding. Infant nevirapine also offers a safe and effective alternative if mothers have difficulty adhering to or tolerating ART. Findings from the Bone and Kidney Health Substudy identify a potential concern for women who breastfeed while on ART. Further study is needed to determine if bone mineral density improves following cessation of breastfeeding, evaluate long-term implications for maternal bone health, and identify interventions that may optimize bone health for women on ART.
 

Benefits of Antiretroviral Therapy for Postpartum Women

The HAART Standard version of PROMISE (1077HS) enrolled 1652 non-breastfeeding women with high CD4 cell counts at 52 IMPAACT and AIDS Clinical Trials Group (ACTG) sites in Argentina, Botswana, Brazil, China, Haiti, Peru, Thailand, and the United States. Enrollment in the study occurred within six weeks postpartum (two weeks on average) and women were randomly assigned at enrollment to either continue ART postpartum or stop ART postpartum to assess impacts on maternal health. Women randomized to stop ART re-started if their CD4 cell counts declined to 350 cells/mm^3 or if clinically indicated.

Efficacy and safety: Primary analyses of this component, presented by Judith Currier on behalf of the study team, highlighted that rates of death, AIDS-defining events, and serious non-AIDS events were lower than expected and did not differ significantly by study arm. However, the rate of WHO Stage 2 and Stage 3 events was significantly lower among women randomized to continue ART, compared to women randomized to stop ART. Continued ART was well-tolerated and adverse event rates did not differ significantly by study arm.

These results provide randomized clinical trial evidence of the benefits of ART for maternal health and support Option B+ and Treat All policies and programs. It should be noted, however, that 90% virologic suppression was not achieved in this population of postpartum women, highlighting the importance of providing long term adherence support for this population, particularly after the period of risk of perinatal HIV transmission has passed.
 

Reference: J Currier et al. Randomized trial of stopping or continuing ART among postpartum women with pre-ART CD4 ≥400 cells/mm^3 (PROMISE 1077HS). Oral presentation at the at the 21st International AIDS Conference (AIDS 2016) Durban, South Africa. July 2016.

Importance of Supportive Information and Counseling for ART Uptake

Following release of the START study results, all women in the PROMISE study (1077BF, 1077FF, and 1077HS) were informed of the results, and women who were not on ART were advised to initiate ART. An analysis of acceptance of early antiretroviral therapy among 1483 women who were not on ART, as presented by Lynda Stranix-Chibanda on behalf of the study team, found that 66% overall agreed to initiate ART following one information and counseling session. Rates of immediate ART uptake varied by country, ranging from 37% to 100%.

Following the first information and counseling session:

• Women who accepted ART primarily did so for health concerns and because of the recommendation given by the protocol team.
• Women who declined ART primarily did so because they wanted more time to consider, felt well, or knew their CD4 count was high.

Subsequent to the first session, provision of information and counseling has continued, as has monitoring of ART uptake. Final outcomes will be analyzed based upon all available data after completion of follow-up in September 2016. These findings highlight the importance of repeated opportunities for supportive locally-tailored information and counseling in the context of Option B+ and Treat All program implementation.

Reference: L Stranix-Chibanda et al. Low acceptance of early antiretroviral therapy (ART) among postpartum women enrolled in IMPAACT PROMISE studies across the globe. Poster presentation at the 8th International Workshop on HIV Pediatrics and oral presentation at the 21st International AIDS Conference (AIDS 2016) Durban, South Africa. July 2016.