Friday, December 20, 2013

Prevention of mother-to-child HIV transmission in Botswana

Kathleen Powis, MD, MPH, Assistant Pediatrician and Assistant Physician, Massachusetts General Hospital, Instructor in Medicine, Harvard Medical School, Research Assistant, Harvard School of Public Health.

Kathleen (Kate) Powis, a Med-Peds trained physician, began her clinical research efforts focusing on the prevention of mother-to-child HIV transmission in Botswana. In Botswana, nearly 1 in 3 pregnant women are HIV-infected, one of the highest HIV-infection rates among pregnant women in the world.  In 2008, when Kate first began working in Botswana, the World Health Organization’s (WHO) policy for prevention of mother-to-child transmission of HIV (PMTCT) called for use of triple antiretroviral (ARVs) regimens for women with CD4+ cell counts < 200 cells/mm3, and the use of twice-daily zidovudine beginning on or after the 28th week of pregnancy for those with CD4+ cell counts ≥ 200 cells/mm3. With regard to infant feeding practices, the WHO promoted formula feeding for HIV-infected women if deemed to be acceptable, feasible, affordable, sustainable and safe according to local conditions and standards, but deferred to the Ministries of Health to provide guidance for their own countries.

Kate began her work with Dr. Roger Shapiro, the Principal Investigator of the Botswana-based MmaBana study (Setswana for Mother-Child),  a combined randomized controlled trial (RCT) and observational study, investigating the safety and efficacy of maternal triple ARV regimens initiated during pregnancy and continued throughout breastfeeding, up to six months postpartum.  The RCT portion of the study randomized HIV-infected treatment-naïve women, with CD4+ cell counts ≥ 200 cells/mm3,to one of two triple ART regimens.Whereas the observational arm followed HIV-infected treatment naïve women with CD4+ cell counts < 200 cell/mm3 as they initiated the national ARV regimen.Kate spent two years providing direct clinical care and supervising others in the treatment of women and infants enrolled in the MmaBana study.  The study demonstrated that use of triple ARVs during pregnancy and breastfeeding was highly efficacious and safe, with only8 of 709 live-born infants acquiring HIV, 6 of them infectedin utero.  The MmaBanastudywas published in the New England Journal of Medicine1 and was one of the studies cited by WHO when it changed its policy in 2010 to recommend that all HIV-infected women initiate triple ARVs in pregnancy and continue throughout breastfeedingfor PMTCT.  The latest WHO recommendations have led to optimism that mother-to-child HIV transmission can be virtually eliminated by 2015 with a global commitment to scale-up access to triple ARVs for all HIV-infected pregnant women.

The latest WHO recommendations will result in more prolonged in utero and breastfeeding exposure for infants to ARVs.  While the benefits of maternal ARVs during pregnancy and breastfeedingappear to outweigh risks to the fetus and infant, identifying any risks, as well as maternal regimens most likely to optimize the health and survival of the HIV-exposed uninfected infant represents and important public health challenge.   Because of this, Kate has shifted her research focus from PMTCT to optimizing the health and survival of HIV-exposed uninfected infants.   She has been funded by Harvard Center for AIDS Research and an NIH K23 Mentored Career Development award.  Initially utilizingdata from theMmaBana trial, Kate studied the association of in utero exposure to maternal triple ARVs and the growth among HIV-exposed uninfected infants. She compared these outcomesto those from a subset of HIV-exposed uninfected infants born to women participating in an earlier PMTCT trial in Botswana where mothers received only zidovudine in pregnancy.  Infants exposed to triple ARV regimens were found to have significantly lower weight-for-age and length-for-age z-scores at birth compared with infants exposed to zidovudine only in utero.2While mean weight-for-age z-scores showed no statistical difference by three months of life between groups, length-for-age remained significantly lower through six months of life (Figure 1).  

Figure 1: Mean Weight-for-Age and Length for Age Z-scores by Infant in utero exposure group

Figure 1: Mean Weight-for-Age and Length for Age Z-scores by Infant in utero exposure group

In the global health setting, both lower birth weight and stunting, defined as a length-for-age z-score of greater than 2 standard deviations below the norm, are associated with increased morbidity and mortality.  This is important, as various studies have demonstrated that HIV-exposed uninfected infants in low- and middle-income countries face 2-4 times higher morbidity/mortality in the first two years of life compared with infants born to HIV-infected infants.3,4   The higher morbidity and mortality is predominantly from infectious causes, specifically pneumonia and diarrheal disease, and this trend has not changed, despite the scale-up ofPMTCT programs.

Kate is continuing to work with Dr. Shapiro and others in Botswana through Botswana-Harvard School of Public Health AIDS Initiative Partnership to conduct clinical trials investigating methods to optimize the health and survival of HIV-exposed uninfected infants.  She is a co-investigator on a clinical trial exploring survival benefits and safety of treating HIV-exposed uninfected infants with Cotrimoxazole versus placebo from 14 days of life through 15 months of life.  Over 2,000 HIV-exposed infants have been enrolled to date, with a total planned accrual of nearly 3,800 infants.


  1. Shapiro R, Hughes M, Ogwu A, Kitch D, Lockman, S, Moffat C, Makhema J, Moyo S, Thior I, McIntosh K, van Widenfelt E, Leidner J, Powis K, Asmelash A, Tumbare E, Zwerski S, Sharma U, Handelsman E, Mburu K, Jayeoba O, Moko E, Souda S, Lubega E, Akhtar M, Wester C, Snowden W, Martinez-Tristani M, Mazhani L, Essex, M. Antiretroviral Regimens in Pregnancy and Breast-Feeding in Botswana. N Engl J Med. 2010;362:2282-2294
  2. Powis KM, Smeaton L, Ogwu A, Lockman S, Dryden-Peterson S, van Widenfelt E,  Leidner J, Makhema J, Essex M, Shapiro RL. Effects of in utero antiretroviral exposure on longitudinal growth of HIV-exposed uninfected infants in Botswana.  JAIDS 2011;56(2):131-138
  3. Marinda E, Humphrey JH, Iliff PJ, et al. Child mortality according to maternal and infant HIV status in Zimbabwe. Pediatric Infectious Disease Journal 2007;26:519-526.
  4. Chilongozi D, Wang L, Brown L, et al. Morbidity and mortality among a cohort of human immunodeficiency virus type 1-infected and uninfected pregnant women and their infants from Malawi, Zambia and Tanzania. Pediatric Infectious Disease Journal 2008;27(9): 808-814.

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