In Reply: Investment long overdue in primary studies of HIV exposed uninfected infant infectious morbidity

In Reply,

We thank Slogrove and Powis for their comments on our study,¹ and we strongly agree that original research in this population is urgently needed. However, that does not discount the potential value of secondary analyses, so long as the limitations of this approach are clearly stated and accounted for. Much is still not understood about infectious morbidity in the HEU population, nor for how long infectious morbidity risks continue.^2,3 As Slogrove and Powis point out, HEU status has well known effect on infectious illness within the first 6 months, and this alone may have implications later in life. Slogrove et al’s systematic review of infectious morbidity in HEU children identified 22 studies, of which three studies evaluated children 6 months and older.⁴ Furthermore, the consequences of recurrent infectious illness on growth (especially linear growth) is an area that has received little attention within HEU research, despite established evidence of its importance in the HIV-unexposed population.

As stated in Slogrove et al’s review, studies ‘have not consistently considered confounding by universal infant risk factors of infectious morbidity and mortality; therefore, the role of direct HIV-exposure on infectious disease susceptibility is unclear.’⁴ We considered clinical markers of severity as universal risk factors for infectious morbidity and mortality, not specifically associated with either HIV exposure, pneumonia related to HIV exposure, or on the causal pathway. Using that reasoning we did adjust for clinical markers of severity in our study. We have now repeated the multivariable analysis, omitting Blantyre Coma Score and oxygen saturation; the results are not materially changed (OR for death for HEU = 1.02 [95% CI 0.41, 2.50]). In addition, HEU children may have factors independent of illness severity at presentation that predispose them to poor outcome. It is also worth pointing out that on univariate analysis, none of the clinical parameters obtained on admission were significantly associated with HEU status. What we also controlled for, and would regard one of the strengths of our secondary analysis, were important social and environmental issues that could be confounders, such as number of household members and maternal education, and we continued to find a consistent effect across anthropometric parameters when we did so.

On the final point by Slogrove and Powis we are in agreement; that further studies designed specifically for the HEU population need to be considered and conducted, if we are to advance the science. Investment in studies primarily designed and appropriately powered to elucidate the HEU population however depends on funding. We hope the study we have conducted has improved understanding but also increased awareness that many questions still remain unanswered. It remains imperative that we understand how the clinical presentation, risk factors, and trajectory of HEU children are distinct from HIV-unexposed individuals, so that we can target this growing population for specific interventions.