Antiretrovirals do not cause neurodevelopmental harm to uninfected infants

Many infants had prolonged exposure to antiretrovirals, including 18 months of breastfeeding

In the first five years of life the neurological development of HIV-exposed but uninfected infants, exposed to maternal antiretrovirals before and after birth and throughout breastfeeding, is comparable to that of HIV-unexposed uninfected infants from similar socio-economic backgrounds. These findings, from a prospective cohort study in Uganda and Malawi, are published in The Lancet HIV.

Background

As increasing numbers of women living with HIV take antiretrovirals on an ongoing basis, the number of infants exposed to HIV as well as prolonged ART (during pregnancy, throughout breastfeeding and infant prophylaxis with nevirapine for about six weeks) will continue to grow.

While protecting children exposed to HIV from infection, the effect of prolonged ART exposure on their neurological development is a major concern for parents and healthcare workers.

Initial findings from the randomised PROMISE-BF study showed that while triple antiretroviral regimens were significantly more effective in preventing transmission there was a greater risk of adverse pregnancy outcomes compared to zidovudine alone. These outcomes, including low birthweight and preterm delivery, could potentially affect growth development.

Glossary

neurological

Relating to the brain or nervous system.

Subsequent findings showed that infant exposure to ART during a prolonged breastfeeding period (up to 18 months) was safe with minimal transmission, minimal adverse health effects and high HIV-free survival at two years of age. However, neurodevelopmental outcomes throughout infancy and early childhood were not assessed.

For the new study, Professor Michael Boivin and colleagues compared neurodevelopmental outcomes of antiretroviral exposure before and after birth in HIV-exposed and uninfected children to HIV-unexposed and uninfected children at 12, 24, 48 and 60 months of age.

All children were HIV negative, but some were born to mothers living with HIV (“HIV exposed”) and some were not (“HIV unexposed”).

The cohort was identified from two research sites in Malawi and Uganda of the PROMISE-BF trial. These are resource-poor settings which have adopted Option B+ and where most HIV-exposed infants are breastfed for prolonged periods of time.

The two groups of infants were matched for age, sex and socioeconomic background.

Primary outcomes were the Mullen Scales of Early Learning (MSEL) cognitive composite score at age 12, 24 and 48 months and the mental processing index for the Kaufman Assessment Battery for Children (KABC-II) global score at 48 and 60 months.

The MSEL test is used for longitudinal development assessment (visual reception, gross and fine motor skills, receptive and expressive language). The KABC II assesses cognitive ability outcomes from a neuropsychological perspective (memory, visual-spatial processing and problem solving, learning (immediate and delayed memory), non-verbal index and mental processing index). Both have been validated in sub-Saharan Africa.

Prolonged exposure, comparable neurodevelopmental outcomes

A total of 861 children were enrolled.

"While protecting children exposed to HIV from infection, the effect of prolonged ART exposure on their neurological development is a major concern for parents and healthcare workers."

There were no differences in MSEL cognitive composite scores according to ART exposure at 12 and 24 months of age, (p=0.19 and p=0.24, respectively for comparisons of all groups). The groups were triple ART plus infant nevirapine, triple ART plus maternal triple ART, zidovudine plus infant nevirapine, zidovudine plus maternal triple ART and HIV-unexposed controls.

At 48 months, however, scores for children of mothers who did not remain on triple ART both before and after birth were not as good as those remaining on triple antiretrovirals throughout. Adjusted means were 80.6, 81.3 and 85.9, respectively (p=0.049 for the comparison of all groups).

The KABC-II composite scores (mental processing index) did not differ at 48 or 60 months of age according to exposure (p=0.81 and 0.89, respectively).

These findings, based on both longitudinal development and neuropsychological assessments are unique. This is the first time such outcomes are available for HIV-exposed and uninfected children with prolonged exposure to antiretrovirals, note the authors.

A longer-term follow-up PROMOTE cohort study (of former PROMISE children) at seven sites will assess their later neurocognitive performance during their early school years.

Public health implications

Dr Peter Kazembe, of the Baylor College of Medicine Children’s Foundation in Malawi, in an accompanying comment notes the significant public health importance of these findings.

Policymakers can be reassured that the antiretrovirals they advocate do no neurodevelopmental harm to the uninfected infant. These data further support lifelong ART: antiretrovirals are good for the mother’s health, prevent HIV transmission to the infant and cause no harm to the infant in the medium term. Healthcare workers can reassure mothers on ART that prolonged breastfeeding is scientifically sound and will not harm the infant.

References

Boivin MJ et al. Neurodevelopmental effects of ante-partum and post-partum antiretroviral exposure in HIV-exposed and uninfected children versus HIV-unexposed and uninfected children in Uganda and Malawi: a prospective cohort study. Lancet HIV, http://dx.doi.org/10.1016/S2352-3018(19)30083-9, 2019.

Kazembe, PN. Exposure of HIV-exposed uninfected infants to antiretrovirals. Lancet HIV, http://dx.doi.org/10.1016/S2352-3018(19)30161-4, 2019.