Extended Prophylaxis With Nevirapine Does Not Affect Growth in HIV-Exposed Infants

Carolyne Onyango-Makumbi, MBChB, MS; Arthur H. Owora, MPH, DrPH; Ramadhani S. Mwiru, MD, MS, ScD; Anthony Mwatha, MS; Alicia M. Young, MS; Dhayendre Moodley, PhD; Hoosen M. Coovadia, MD; Lynda Stranix-Chibanda, MBChB, MMed (Paed); Karim Manji, MBBS, MMed, MPH, FRCPCH; Yvonne Maldonado, MD; Paul Richardson, MSc; Philip Andrew, RN; Kathleen George, MPH; Wafaie Fawzi, MBBS, DrPH; Mary Glenn Fowler, MD, MPH

Disclosures

J Acquir Immune Defic Syndr. 2019;82(4):377-385. 

In This Article

Abstract and Introduction

Abstract

Background: Effects of prolonged nevirapine prophylaxis exposure on growth among HIV-exposed uninfected (HEU) infants are unknown. This study examines the impact of extended nevirapine prophylaxis from 6 weeks to 6 months on the growth of HEU infants followed for 18 months and also identifies correlates of incident wasting, stunting, underweight, and low head circumference in the HPTN 046 trial.

Methods: Intention-to-treat analysis examined the effect of extended nevirapine exposure on: weight-for-age Z-score, length-for-age Z-score, weight-for-length Z-score, and head circumference-for-age Z-score. Multivariable linear mixed-effects and Cox proportional hazard models were used to compare growth outcomes between the study arms and identify correlates of incident adverse growth outcomes, respectively.

Results: Compared to placebo, extended prophylactic nevirapine given daily from 6 weeks to 6 months did not affect growth in HEU breastfeeding (BF) infants over time (treatment · time: P > 0.05). However, overall growth declined over time (time effect: P < 0.01) when compared with WHO general population norms. Male sex was associated with higher risk of all adverse growth outcomes (P < 0.05), whereas short BF duration was associated with wasting (P = 0.03). Maternal antiretroviral therapy exposure was protective against underweight (P = 0.02). Zimbabwe tended to have worse growth outcomes especially stunting, compared to South Africa, Uganda and Tanzania (P < 0.05).

Conclusions: It is reassuring that prolonged exposure to nevirapine for prevention-of-mother-to-child HIV transmission does not restrict growth. However, targeted interventions are needed to improve growth outcomes among at-risk HEU infants (i.e., male sex, short BF duration, lack of maternal antiretroviral therapy exposure, and resident in Zimbabwe).

Introduction

Progress has been made since 1999 in reducing mother-to-child transmission of HIV infection through expanded access to maternal–child health services and antiretrovirals (ARVs). Clinical trial findings motivated the World Health Organization (WHO) to implement rapidly evolving Prevention-of-Mother-to-Child-Transmission (PMTCT) and treatment guidelines for HIV-infected women in resource-limited settings who are encouraged and choose to breastfeed.[1]

Current WHO guidelines recommend antiretroviral therapy (ART) for all pregnant and breastfeeding women living with HIV regardless of WHO clinical stage, CD4 cell count, and to be continued for life.[2] Further guidance recommends breastfeeding for at least 12 months and up to 24 months or longer while on ART.[3]

Regarding infant prophylaxis, current guidelines recommend breastfeeding infants of ART-experienced mothers receive 6 weeks of daily nevirapine[2] and that breastfeeding infants at high risk of acquiring HIV, continue infant prophylaxis for an additional 6 weeks using nevirapine (once daily) or zidovudine (ZDV) (twice daily).[2] Here, high-risk infants are those born to HIV-infected women who have received <4 weeks of ART at the time of delivery, HIV-infected women with viral load >1000 copies/mL in the 4 weeks before delivery, women with incident HIV infection during pregnancy or breastfeeding, or those initially identified during the postpartum period, with previous negative HIV test prenatally.[2]

The widespread implementation of these guidelines especially in resource-limited settings is resulting in unprecedented numbers of children being exposed to ARV medications in utero over 1 million per year.[4] Infant ARV exposure likewise continues during the breastfeeding period, a critical period for infant/child growth and development. What is not clear is whether prolonged use of ARVs for PMTCT of HIV results in poor growth among HIV-exposed uninfected (HEU) infants compared with non-HIV non-ARV exposed infants. Because faltering growth is associated with increased risk of childhood morbidity and mortality,[5] further data regarding the impact of ART in this population are needed.

A randomized clinical trial (RCT) evaluating the effects of in utero ARV exposure (triple ARV regimens versus ZDV monotherapy) on longitudinal growth of HEU infants in Botswana found that length-for-age Z-scores and weight-for-age Z-scores at 24 months were significantly lower among triple ARV exposed HEU infants than among HEU infants in the ZDV monotherapy arm.[5] The higher incidence of growth faltering among infants of mothers unexposed to ART[6] underscores the need for initiation of lifetime maternal ART at the time of diagnosis that is now the standard of care worldwide for maternal treatment and PMTCT.

There is limited information on the effect of extended ARV exposure on growth among HEU infants in the postpartum period. With the lack of information on potential toxicities associated with ARV exposure and specifically infant ARV prophylaxis, HIV-infected women have expressed concerns regarding possible effects on infant/child growth and development.[7] There is inconsistent evidence regarding the growth benefits of breastfeeding among HEU infants; some studies suggest maternal micronutrients deficiencies among HIV-positive mothers may negatively affect breastmilk composition,[6] whereas others support WHO exclusive breastfeeding recommendations for the first 6 months of life in the context of HIV.[5,8] With these varying contexts it is unclear to what extent maternal ART and infant prophylaxis regimens may contribute to risk of adverse growth outcomes among HEU infants exposed to in-utero and postpartum ARVs.

This analysis evaluates the effect of an extended course of daily infant prophylactic nevirapine given from 6 weeks to 6 months on the growth of HEU breastfeeding infants, while adjusting for known risk factors of adverse growth outcomes. We also identify the correlates of incident wasting, stunting, underweight, and low head circumference. The potential effect of infant ARV prophylaxis on infant growth remains important, because increasing numbers of HIV-exposed infants will be exposed to prolonged prophylaxis postnatally during breastfeeding in situations where mothers are not able to adhere well to taking ART as evidenced by continued detectable viral load.

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