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Review
. 2016 Jun;21(6):720-34.
doi: 10.1111/tmi.12695. Epub 2016 Apr 19.

Mortality risk and associated factors in HIV-exposed, uninfected children

Shino Arikawa  1 , Nigel Rollins  2 , Marie-Louise Newell  3 , Renaud Becquet  1
Affiliations
Review

Mortality risk and associated factors in HIV-exposed, uninfected children

Shino Arikawa et al. Trop Med Int Health. 2016 Jun.

Abstract
in English, French, Spanish

Objective: With increasing maternal antiretroviral treatment (ART), the number of children newly infected with HIV has declined. However, the possible increased mortality in the large number of HIV-exposed, uninfected (HEU) children may be of concern. We quantified mortality risks among HEU children and reviewed associated factors.

Methods: Systematic search of electronic databases (PubMed, Scopus). We included all studies reporting mortality of HEU children to age 60 months and associated factors. Relative risk of mortality between HEU and HIV-unexposed, uninfected (HUU) children was extracted where relevant. Inverse variance methods were used to adjust for study size. Random-effects models were fitted to obtain pooled estimates.

Results: A total of 14 studies were included in the meta-analysis and 13 in the review of associated factors. The pooled cumulative mortality in HEU children was 5.5% (95% CI: 4.0-7.2; I(2) = 94%) at 12 months (11 studies) and 11.0% (95% CI: 7.6-15.0; I(2) = 93%) at 24 months (four studies). The pooled risk ratios for the mortality in HEU children compared to HUU children in the same setting were 1.9 (95% CI: 0.9-3.8; I(2) = 93%) at 12 months (four studies) and 2.4 (95% CI: 1.1-5.1; I(2) = 93%) at 24 months (three studies).

Conclusion: Compared to HUU children, mortality risk in HEU children was about double at both age points, although the association was not statistically significant at 12 months. Interpretation of the pooled estimates is confounded by considerable heterogeneity between studies. Further research is needed to characterise the impact of maternal death and breastfeeding on the survival of HEU infants in the context of maternal ART, where current evidence is limited.

Objectif: Avec l'augmentation du traitement antirétroviral (ART) maternel, le nombre d'enfants nouvellement infectés par le VIH a diminué. Cependant, la possible augmentation de la mortalité parmi le grand nombre d'enfants exposés au VIH, mais non infectés peut être préoccupante. Nous avons quantifié les risques de mortalité chez les enfants exposés, non infectés et examiné les facteurs associés.

Méthodes: Recherche systématique dans les bases de données électroniques (PubMed, Scopus). Nous avons inclus toutes les études faisant état de la mortalité des enfants exposés, non infectés jusqu’à l’âge de 60 mois et les facteurs associés. Le risque relatif de mortalité entre les enfants exposés non inecftés et les enfants non exposés, non infectés par le VIH a été extrait le cas échéant. Les méthodes de variance inverse ont été utilisées pour ajuster pour la taille de l’étude. Les modèles à effets aléatoires ont été appliqués pour obtenir des estimations poolées.

Résultats: 14 études ont été incluses dans la méta‐analyse et 13 dans l'analyse des facteurs associés. La mortalité poolée cumulative chez les enfants exposés non infectés était de 5,5% (IC95%: 4,0 à 7,2; I2 = 94%) à 12 mois (11 études) et 11,0% (IC95%: 7,6 à 15,0; I2 = 93%) à 24 mois (4 études). Les ratios de risque poolés pour la mortalité chez les enfants exposés, non infectés par rapport aux enfants non exposés, non infectés dans le même cadre étaient de 1,9 (IC95%: 0,9 à 3,8; I2 = 93%) à 12 mois (4 études) et 2,4 (IC95%: 1,1‐ 5,1; I2 = 93%) à 24 mois (3 études).

Conclusion: Par rapport aux enfants non exposés, non infectés, le risque de mortalité chez les enfants exposés, non infectés était environ deux fois aux deux points d’âge, bien que l'association ne soit pas statistiquement significative à 12 mois. L'interprétation des estimations poolées est confondue par une hétérogénéité considérable entre les études. Des recherches supplémentaires sont nécessaires pour caractériser l'impact de la mortalité maternelle et l'allaitement maternel sur la survie des nourrissons exposés, non infectés, dans le cadre de l’ART maternel, où les données actuelles sont limitées.

Objetivo: Con el aumento de la terapia antiretroviral (TAR) materna, el número de niños recién infectados con VIH ha disminuido. Sin embargo, el posible aumento en la mortalidad de un gran número de niños expuestos al VIH pero sin infección (EVSI) podría ser preocupante. Hemos cuantificado el riesgo de mortalidad de niños EVSI y revisado los factores asociados.

Métodos: Búsqueda sistemática de bases de datos electrónicas (PubMed, Scopus). Hemos incluido todos los estudios que reportan mortalidad en niños EVSI de hasta 60 meses de edad y los factores asociados. El riesgo relativo de mortalidad de niños no infectados ‐ EVSI y niños sin exponer al VIH (NSE) – se extrajo de donde era relevante. Se utilizaron métodos de varianza inversa para ajustar según el tamaño del estudio. Se utilizaron modelos de efectos aleatorios ajustados para obtener estimaciones agrupadas.

Resultados: Se incluyeron 14 estudios dentro del meta‐análisis y 13 en la revisión de factores asociados. La mortalidad acumulada conjunta de niños EVSI era del 5.5% (IC 95%: 4.0–7.2; I2 = 94%) a los 12 meses (11 estudios) y del 11.0% (IC 95%: 7.6–15.0; I2 = 93%) a los 24 meses (4 estudios). El cociente de riesgo agrupado para mortalidad en niños EVSI comparado con niños NSE en el mismo emplazamiento era de 1.9 (IC 95%: 0.9–3.8; I2 = 93%) a los 12 meses (4 estudios) y de 2.4 (IC 95%: 1.1–5.1; I2 = 93%) a los 24 meses (3 estudios).

Conclusión: Comparados con NSE, el riesgo de mortalidad en niños EVSI era casi del doble en ambos puntos de corte, aunque la asociación no era estadísticamente significativa a los 12 meses. Hay un efecto de confusión en la interpretación de los cálculos agrupados debido a la gran heterogeneidad entre los estudios. Se requieren más estudios que caractericen el impacto de la muerte materna y de la lactancia en la supervivencia de niños EVSI dentro del contexto del TAR materno, áreas en las cuales la evidencia actualmente es limitada.

Keywords: HIV; Mortalidad; Mortalité; VIH; child; enfant; facteur de risque; factores de riesgo; infant; lactantes; meta-analysis; meta-análisis; mortality; méta-analyse; niños; nourrisson; risk factor.

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Figures

Figure 1
Figure 1
Flow diagram of study selection.
Figure 2
Figure 2
(a) Pooled 3‐month cumulative mortality in HEU infants. Note: (a) 50% short‐term breastfed group (median of 4 months), with support for replacement feeding. (b) Predominantly long‐term breastfeeding (median of 8 months). (c) Breastfeeding cessation by 6 months, with support for replacement feeding. Infant cotrimoxazole. (d) Prolonged breastfeeding (>12 months). (e) Infants receiving ARV post‐exposure prophylaxis. Mortality at 100 days. Subsidized formula. (f) Majority of women ever breastfed. ART arm receiving three ARVs from 28 to 36 weeks of pregnancy up to 6.5 months post‐partum or breastfeeding cessation whichever first occurs. (b) Pooled 6‐month cumulative mortality in HEU infants. Note: (a) 50% short‐term breastfed group (median of 4 months), with support for replacement feeding. (b) Predominantly long‐term breastfeeding (median of 8 months). (c) All infants were breastfed (median of 6 months). Maternal ART introduced during study. (d) Breastfeeding cessation by 6 months, with support for replacement feeding. Infant cotrimoxazole. (e) Prolonged breastfeeding (>12 months). (f) Majority of women ever breastfed. ART arm receiving three ARVs from 28–36 weeks of pregnancy up to 6.5 months post‐partum or breastfeeding cessation whichever first occurs. (c) Pooled 12‐month cumulative mortality in HEU infants. Note: (a) 50% short‐term breastfed group (median of 4 months), with support for replacement feeding. (b) Predominantly long‐term breastfeeding (median of 8 months). (c) Cotrimoxazole given to all infants. (d) Breastfeeding cessation by 6 months, with support for replacement feeding. Infant cotrimoxazole. (e) Prolonged breastfeeding (> 12 months). (f) All women breastfeeding with a half weaning at 4 months. Infants received weaning supplement and cotrimoxazole. (g) 8% of mothers with maternal ART. (h) Women randomized to receive triple ARVs until cessation of breastfeeding. Majority weaned at 6 months. Cotrimoxazole given to all infants. (i) Majority of infants received some type of breastfeeding (median of 7 months). (d) Pooled 24‐month cumulative mortality in HEU children. Note: (a) All infants were breastfed (median of 6 months). Maternal ART introduced during study. (b) All women breastfeeding with a half weaning at 4 months. Children received cotrimoxazole.
Figure 3
Figure 3
(a) Mortality risk ratio at 12 months between HEU and HUU infants. (b) Mortality risk ratio at 12 months between HEU and HUU infants (excluding Marinda 4). (c) Mortality risk ratio at 24 months between HEU and HUU children. (d) Mortality risk ratio at 24 months between HEU and HUU children (excluding Marinda 4).
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