Human Immunodeficiency Virus–exposed Uninfected Infants: Surviving and Thriving or Overlooked by Success?

To the Editor—Globally, 1.4 million women who live with human immunodeficiency virus (HIV) give birth annually, and 1.25 million of their HIV-exposed infants remain HIV uninfected. The public health success of peri- and post-natal HIV transmission prevention is tempered by the realization that HIV-exposed uninfected (HEU) infants and children survive and thrive less well than HIV-unexposed (HU) children in comparable settings. Across all settings, compared to HU infants, HEU infants are vulnerable to higher rates and greater severity of infectious morbidity [1–3], and in low- and middle-income countries (LMICs) specifically, they experience a 20%–30% increased risk for preterm birth and 80%–90% increased risk for mortality [4, 5].

Therefore, we applaud the seminal work of Goetghebuer and colleagues who established in a Belgian HEU infant cohort that initiation of maternal antiretroviral therapy (ART) before pregnancy reduced the risk of infant infection-related hospitalizations [6]. In this cohort of 132 HEU infants and 123 HU infants, risk for infection-related hospitalization was highest in HEU infants of mothers who initiated ART during pregnancy (adjusted hazard ration [aHR], 3.84; 95% confidence interval [CI], 1.69–8.71). However, rates in HEU infants whose mothers were already on ART at conception (aHR, 1.42; 95% CI, 0.58–3.48) were similar to those in HU infants. Furthermore, this is the first study to demonstrate an association between increased infectious morbidity risk and the well-described altered HEU infant immune phenotype [7, 8]. Goetghebuer and colleagues found that maternal and newborn monocyte activation and reduced transfer of maternal antibodies were most pronounced when maternal ART was initiated during pregnancy as opposed to before conception. These immune alterations, which occur in utero and are measurable at birth, predicted risk for infection-related hospitalization. That maternal ART from conception appeared to normalize this altered immune phenotype and largely eliminate infectious morbidity risk in HEU infants is extremely promising.

As the authors recognize, this study was conducted in a high-income country with a low HIV prevalence where women living with HIV are not encouraged to breastfeed, and these findings cannot be generalized to eastern and southern Africa where 85% of all HEU infants are born. In LMICs, but not in high-income countries, women who live with HIV and conceive while on ART are at a 40% (meta-analysis risk ratio, 1.41; 95% CI, 1.22–1.63) higher risk of preterm delivery than those who initiate ART during pregnancy [9]. Preterm birth places infants at substantially higher risk for morbidity and mortality during infancy [10]. Therefore, the immunological benefits for HEU infants that are derived from a mother being on ART from conception may be offset in LMICs by adverse consequences of preterm birth. This is just one example of the complexities in the pathways to HEU infant vulnerability. Although it is reasonably expected that in the universal test and treat era where improved maternal health and safer prolonged breastfeeding will benefit all HEU children, we need to provide definitive evidence of this benefit to HEU infants who comprise up to 25% of the infant population in the highest HIV-burden countries. Investment is urgently needed to support carefully designed, appropriately sized cohort studies in settings with the highest prevalence of HEU infants and children.

Notes

Financial support.A.L.S receives salary support through early career development awards from the NIH Fogarty International Center (grant number 1K43TW010683) and the International AIDS Society (grant number 2017/518-SLO).

Potential conflicts of interest.All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.