HIV-Exposed Uninfected Infants in Zimbabwe: Insights into Health Outcomes in the Pre-Antiretroviral Therapy Era

Abstract

The ZVITAMBO trial recruited 14,110 mother–infant pairs to a randomized controlled trial of vitamin A between 1997 and 2000, before the availability of antiretroviral therapy for HIV prophylaxis or treatment in Zimbabwe. The HIV status of mothers and infants was well characterized through 1–2 years of follow-up, leading to the largest cohort to date of HIV-exposed uninfected (HEU) infants (n = 3135), with a suitable comparison group of HIV-unexposed infants (n = 9510). Here, we draw on 10 years of published findings from the ZVITAMBO trial. HEU infants had increased morbidity compared to HIV-unexposed infants, with 50% more hospitalizations in the neonatal period and 30% more sick clinic visits during infancy, particularly for skin infections, lower respiratory tract infections, and oral thrush. HEU children had 3.9-fold and 2.0-fold higher mortality than HIV-unexposed children during the first and second years of life, respectively, most commonly due to acute respiratory infections, diarrhea/dysentery, malnutrition, sepsis, and meningitis. Infant morbidity and mortality were strongly related to maternal HIV disease severity, and increased morbidity remained until maternal CD4 counts were >800 cells/μL. HEU infants were more likely to be premature and small-for-gestational age than HIV-unexposed infants, and had more postnatal growth failure. Here, we propose a conceptual framework to explain the increased risk of infectious morbidity, mortality, and growth failure among HEU infants, hypothesizing that immune activation and inflammation are key drivers of both infection susceptibility and growth failure. Future studies should further dissect the causes of infection susceptibility and growth failure and determine the impact of ART and cotrimoxazole on outcomes of this vulnerable group of infants in the current era.

Stunting Mediates the Association between Small-for-Gestational-Age and Postneonatal Mortality

“…Among the HIV-exposed children in ZVITAMBO, inflammatory markers (e.g., C-reactive protein and α-acid glycoprotein) were associated with stunting (26). Similarly, Evans et al (29) found that immune activation and inflammation are likely key drivers of postnatal growth failure among HEU compared with unexposed children. It is possible that stunting may play a stronger mediating role between SGA and postneonatal mortality among HIV-exposed immunocompromised children than among HIV-unexposed children.…”

Association of maternal HIV‐1 severity with dental caries: an observational study of uninfected 5‐ to 7‐yr‐old children of HIV‐1‐infected mothers without severe immune suppression

“…There is evidence suggesting that exposure to HIV‐1 in utero , intrapartum, and during breastfeeding may confer a high risk of mortality, morbidity, and growth retardation in children, even in the absence of HIV‐1 transmission . Evans et al suggested that the potential underlying causes of morbidity and mortality in HEU children centered around fetal immune activation and immunological abnormalities resulting from direct exposure to HIV‐1 in utero .…”

Birth size and early pneumonia predict linear growth among HIV‐exposed uninfected infants

“…In 2016 alone, more than one million HEU infants were born (Slogrove et al, 2018). HEU infants are born with lower birthweight and shorter length compared with HIV-unexposed uninfected infants (Bailey, Kamenga, Nsuami, Nieburg, & St Louis, 1999;Evans, Humphrey, Ntozini, & Prendergast, 2016;Kurewa et al, 2009;Marinda et al, 2007;Patel et al, 2010;Sofeu et al, 2014;Taha et al, 1995) and experience high rates of stunting within the first five years (Bailey et al, 1999;Bobat, Coovadia, Moodley, Coutsoudis, & Gouws, 2001;McGrath et al, 2012;Newell, Borja, & Peckham, 2003;Patel et al, 2010).…”