HIV-exposed uninfected children – why the increased mortality risk?

HIV-exposed children account for more than half of 24-month mortality in Botswana.

Zash R, Souda S, Leidner J, Ribaudo H, Binda K, Moyo S, Powis KM, Petlo C, Mmalane M, Makhema J, Essex M, Lockman S, Shapiro R. BMC Pediatr. 2016 Jul 21;16:103. doi: 10.1186/s12887-016-0635-5.

Background: The contribution of HIV-exposure to childhood mortality in a setting with widespread antiretroviral treatment (ART) availability has not been determined.

Methods: From January 2012 to March 2013, mothers were enrolled within 48 h of delivery at 5 government postpartum wards in Botswana. Participants were followed by phone 1-3 monthly for 24 months. Risk factors for 24-month survival were assessed by Cox proportional hazards modeling.

Results: Three thousand mothers (1499 HIV-infected) and their 3033 children (1515 HIV-exposed) were enrolled. During pregnancy 58% received three-drug ART, 23% received zidovudine alone, 11% received no antiretrovirals (8% unknown); 2.1% of children were HIV-infected by 24 months. Vital status at 24 months was known for 3018 (99.5%) children; 106 (3.5%) died including 12 (38%) HIV-infected, 70 (4.7%) HIV-exposed uninfected, and 24 (1.6%) HIV-unexposed. Risk factors for mortality were child HIV-infection (aHR 22.6, 95% CI 10.7, 47.5), child HIV-exposure (aHR 2.7, 95% CI 1.7, 4.5) and maternal death (aHR 8.9, 95% CI 2.1, 37.1). Replacement feeding predicted mortality when modeled separately from HIV-exposure (aHR 2.3, 95% CI 1.5, 3.6), but colinearity with HIV-exposure status precluded investigation of its independent effect. Applied at the population level (26% maternal HIV prevalence), an estimated 52% of child mortality occurs among HIV-exposed or HIV-infected children.

Conclusions: In a programmatic setting with high maternal HIV prevalence and widespread maternal and child ART availability, HIV-exposed and HIV-infected children still account for most deaths at 24 months. Lack of breastfeeding was a likely contributor to excess mortality among HIV-exposed children.

Abstract  Full-text [free] access 

Editor’s notes: It has been known for some time that HIV-exposed but uninfected children have a higher risk of death than HIV-unexposed children. There is now a need for prospective studies to explore the mechanisms underlying this observation. In this study from Botswana, one of every 20 HIV-exposed but uninfected children had died by 24 months. Four in every five deaths in the HIV-exposed but uninfected children were attributed to infectious diseases, most commonly diarrhoeal illness and respiratory infections.

The analysis was unfortunately not able to unpick the effect of infant feeding on mortality in the HIV-exposed uninfected children. Only 16% of HIV-exposed children were breastfed. This is consistent with national guidelines at the time, where formula feeding was recommended for mothers living with HIV. It is reassuring that in recently updated national guidelines, exclusive breastfeeding for six months is now recommended for mothers living with HIV on ART with virologic suppression.

Mother-to-child HIV transmission at 24 months was still around 2%, and further infections may have been undiagnosed in children who died before being tested. More than one in three children living with HIV died within 24 months. This reminds us that while there is increasing interest in HIV-exposed uninfected children, our priority for now should still be achieving elimination of mother-to-child HIV transmission.

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