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 nevirapine2 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 ART6 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.
This is a secondary data analysis of data from the HIV prevention trials network (HPTN) 046 trial, a phase 3, randomized, double-blind, placebo-controlled trial conducted in 4 countries in east and southern Africa. This trial assessed the efficacy and safety of extending once-daily nevirapine from the age of 6 weeks to 6 months or until cessation of breastfeeding when compared with 6 weeks of neonatal prophylaxis, for PMTCT among HIV-exposed breastfeeding infants (all of whom had received nevirapine prophylaxis until the age of 6 weeks).9
The study was conducted at research sites in South Africa, Uganda, Tanzania, and Zimbabwe where HIV-infected women were provided infant feeding counseling and received the local standard of care for PMTCT at the time. A majority of the women in this study were not receiving ART either antepartum or postpartum as it was not the standard of care at the time. Informed consent was obtained from eligible women. Infants were eligible if they had an HIV DNA polymerase chain reaction negative result from a blood specimen within 7 days of birth, a birth weight ≥2000 g, were breastfeeding, and had no life-threatening conditions. Mother–infant pairs were recruited and followed between June 2008 and March 2010. Ethical clearance to conduct the study was granted by local and US institutional review boards affiliated with each site.
At enrollment, all infants received open label daily oral nevirapine for the first 6 weeks (42 days) of life. Between 6 and 8 weeks, eligible infants were randomized within strata of maternal ART use (ie, maternal ART for treatment of HIV or no maternal ART for treatment of HIV at time of randomization) to one of 2 arms, either extended nevirapine or placebo daily from 6 weeks to 6 months or through cessation of breastfeeding, whichever was earliest.9
Baseline sociodemographic data, medical and pregnancy history were collected from the women at screening and enrollment. Infant evaluations were conducted within 7 days post birth at 2, 5, 6, and 8 weeks, and at 3, 4, 5, 6, 9, 12, and 18 months. At each of the scheduled study visits, physical examinations were performed including record of anthropometric measurements done by trained nurses using standardized instruments. Length was measured using a measuring board to the nearest 0.1 cm. Weight readings were taken using a pediatric scale to the nearest 0.1 kg. Head circumference was measured using tape measures to the nearest 0.1 cm. Information regarding breastfeeding status and practices was assessed by interview. All infants received prophylactic co-trimoxazole treatment from the age of 6 weeks to the time of confirmed HIV uninfected status after breastfeeding cessation. Mothers were counseled to exclusively breastfeed for 6 months as per the contemporaneous WHO infant feeding guidelines;10 however, the mother determined the timing of breastfeeding cessation.
Study endpoints were standardized growth indicators or standardized normal deviates (Z-scores) computed from the measurements of weight, length, and head circumference for each infant based on the infant's sex and age in months using the WHO Child Growth Reference Standards.11
We used an intention-to-treat approach to examine study intervention effect on growth outcomes for weight, length, and head circumference. Descriptive statistics were used to summarize the distribution of study variables by intervention arm.
Linear mixed effects models compared the rate of change in infant growth outcomes [weight-for-age Z-score (WAZ), length-for-age Z-score (LAZ), weight-for-length Z-score (WLZ), and head circumference-for-age Z-score (HCZ)] between the 2 study arms. Each infant was modeled as a random effect nested within treatment group. Time was modeled as a continuous variable (months).
Using Poisson regression models the incidence of adverse growth outcomes (underweight, stunting, wasting, and low head circumference) were calculated as the ratio of the total number of infants with a first event (eg, wasting) to the total person time at risk, whereas 95 percent confidence intervals for the incidence estimates were calculated using methods described by Garwood.12
Covariates considered in our models were selected based on existing literature with a focus on factors affecting infant and young child growth. Univariable Cox proportional hazard regression models identified the maternal and infant correlates of adverse growth outcomes. The Cox regression models excluded infants who had already experienced the outcome of interest at randomization. For example, infants who were stunted at randomization were excluded in the models that examined correlates of stunting. At the time of the study, unlike the other countries, Zimbabwe was undergoing a severe socioeconomic decline that affected the health and nutrition of children;13 therefore Zimbabwe was selected as the reference geographical site for our analysis.
For the above linear mixed, Poisson, and survival analysis models, in the absence of significant pair-wise interaction terms (eg, treatment × time, treatment × maternal ART exposure and others), we examined and controlled for potential confounding effects. A likelihood ratio test P-value of less than 0.1 in the univariable models was used as the cut-off for including variables in the multivariable models (see Table 1, Supplemental Digital Content, https://links.lww.com/QAI/B364). Final multivariable Cox models included variables significant at 0.05 level. Children's data were censored from the analyses at the time they were confirmed as being HIV infected. All analyses were conducted using the R package nlme.14
Baseline Maternal and Infant Characteristics
In HPTN 046, 751 mother–infant dyads were randomized to the extended nevirapine group and 753 to the placebo group. Sociodemographic characteristics, distribution of WHO clinical stage of disease, mode of delivery, maternal ART status, and infant birth weight were similar between the 2 groups (Table 1). The overall median maternal age was 27 years (range: 23–31). Parity of the women in both groups was a median of 3 pregnancies and median of one live birth. Most of the women (95%) were in immune category 1 and 2 of the CDC Classification System for HIV Infection15 showing normal immune function to moderate suppression as evidenced by absolute CD4 cell counts. The median duration of breastfeeding was 6 months with 94% of infants breastfed for more than 3 months. On further stratification by sex, the median duration of breastfeeding was 6 months in the 2 study groups.
Mean Trajectories of Child Growth Outcomes
Overall, the mean trajectories of WAZ, LAZ, and WLZ did not differ between infants assigned to extended nevirapine versus placebo (treatment × time interaction: P > 0.05; Fig. 1), but declined over time in both groups (time effect: P < 0.01). However, significant group differences in mean HCZ were observed between the extended nevirapine and placebo groups (Fig. 1). Mean HCZ was significantly higher among the infants randomized to extended nevirapine when compared with infants randomized to placebo particularly at 6 months (group effect: P < 0.01) and 18 months (group effect: P < 0.01). Maternal ART exposure did not modify treatment effects on growth outcomes (ie, maternal ART × treatment: P > 0.05).
Prevalence and Incidence Rate of Adverse Growth Outcomes
Adverse growth outcomes analyzed included underweight (WAZ < −2SD), stunting (LAZ < 2SD), wasting (WLZ < −2SD), and low head circumference (HCZ < −2SD). At baseline (6 weeks postdelivery randomization), there were no differences in growth outcome measures between the study arms (Table 2). Overall, prevalence of stunting, underweight, wasting, and low head circumference at randomization were 14.8%, 5.4%, 3.9%, and 1.0%, respectively and by 18 months the prevalence of stunting, underweight, wasting, and low head circumference were 58.1%, 27.7%, 20.3%, and 5.7% respectively (Table 2). The incidence rates of the adverse growth outcomes increased substantially over the study period from 6 weeks to 18 months. The highest incidence rate among the different types of adverse growth outcomes was observed for stunting and it was similar between the 2 treatment arms (47.9/100 years in the extended nevirapine (NVP) arm versus 48.3/100 years in the placebo arm).The incidence rates for underweight, wasting, and low head circumference did not differ between study arms (P > 0.05; Table 3).
Predictors of Risk of Adverse Growth Outcomes
Correlates of Underweight
Multivariable Cox proportional hazard models (Table 4) showed that site, infant sex, and maternal ART were associated with risk of WAZ falling <−2SD. Compared to infants born in Zimbabwe, infants born in South Africa and Uganda had 84% [hazard ratio (HR): 0.16; 95% confidence interval (CI): 0.09 to 0.27; P < 0.01] and 31% (HR: 0.69; 95% CI: 0.53 to 0.92; P = 0.01) lower risk of dropping below WAZ < −2SD, whereas those born in Tanzania were not different (P = 0.59). Male infants had 77% (HR: 1.77; 95% CI: 1.38 to 2.28; P < 0.01) higher risk of being underweight than female infants. Infants of mothers on ART at the time of randomization had 27% lower risk of being underweight (HR: 0.73; 95% CI: 0.56 to 0.95; P = 0.02) than those born to mothers not on ART.
Correlates of Stunting
Study site and infant sex were associated with stunting in the multivariable model (Table 4). There was a lower risk of stunting among infants in South Africa (HR: 0.27; 95% CI: 0.19 to 0.37; P < 0.01), Uganda (HR: 0.81; 95% CI: 0.65 to 1.00; P = 0.05), and Tanzania (HR: 0.63; 95% CI: 0.47 to 0.86; P < 0.01) than in Zimbabwe. The risk of stunting was 2-fold (HR: 2.10; 95% CI: 1.77 to 2.60; P < 0.01) higher among male than female infants.
Correlates of Wasting
Study site, infant sex, and duration of breastfeeding were associated with wasting (Table 4). Infants born in Uganda had 71% (HR: 0.29; 95% CI: 0.19 to 0.43; P < 0.01) lower risk of wasting than those born in Zimbabwe. However, the risk of wasting was not different between infants born in Zimbabwe versus South Africa or Tanzania. Male infants had 55% (HR: 1.55; 95% CI: 1.18 to 2.05; P < 0.01) higher risk of wasting than female infants. The risk of wasting was lower among children who were breastfed for 3 or more months than infants who were breastfed for a shorter duration (HR: 0.56; 95% CI: 0.34 to 0.94; P = 0.03).
Correlates of Low Head Circumference
Similar to stunting and wasting, study site and infant sex were associated with risk of low head circumference (Table 4). Specifically, infants born in South Africa (but not Uganda or Tanzania) had 67% (HR: 0.33; 95% CI: 0.12 to 0.88; P = 0.03) lower risk of low head circumference than those born in Zimbabwe. The risk of low head circumference was 72% (HR: 1.72; 95% CI: 1.01 to 2.93; P = 0.05) with higher risk among male than female infants.
Our results show that an extended course of prophylactic nevirapine given daily from 6 weeks to 6 months does not adversely affect growth (WAZ, LAZ, WLZ, and HCZ) in HEU breastfeeding infants when compared with infants who only received infant NVP in the first 6 weeks of life. Independent of treatment effect, standardized growth measures declined over time when compared with WHO general population norms. Almost half of all HEU exposed infants in HPTN 046 experienced stunting by age 18 months.
Shorter NVP exposure (6 weeks versus 6 months) was associated with lower mean HCZ, particularly at 6 and 18 months. The differences were observed from baseline and thus not attributable to the placebo. The observed difference could be due to chance that the placebo group may have had low head circumference from the start compared with the extended nevirapine group and with time just paralleled the decline seen in both. The finding regarding low HCZ among HEU infants in the placebo group (versus extended NVP) is a new finding contradicting previous findings reported in a 5-year follow-up of HIVNET 012 HEU children randomized to NVP or ZDV that showed HCZ was comparable to WHO norms.16 Owor et al, however, did not examine HCZ differences between HEU randomized to NVP versus ZDV, but focused on comparing HEU and HIV-infected children (who had lower HCZ than HEU).
The prevalence and incidence rate of adverse growth outcomes did not differ between the randomized study arms (extended NVP versus placebo) but was associated with other variables. Male sex was associated with a higher risk of all adverse growth outcomes, short duration of breastfeeding was predictive of wasting and lack of maternal ART exposure was associated with higher risk of underweight among infants. The risk of adverse growth outcomes differed between study sites; Zimbabwe tended to have worse outcomes compared to South Africa, Uganda, and Tanzania.
Our findings suggest that extended prophylaxis with nevirapine does not affect growth when compared with the standard 6 weeks of nevirapine prophylaxis; this is reassuring given evidence of its added advantage in preventing HIV infection risk among HEU infants.9 The general decline in standardized growth measures into the second year of life, independent of duration of nevirapine exposure (ie, study treatment assignment), emphasizes need for early identification, regular monitoring, and intervention among HEU infants (characterized by male sex, short duration of breastfeeding, lack of maternal ART exposure, and site location).
The prevalence and incidence of adverse growth outcomes in this study is consistent with existing literature from general population studies.17–20 Stunting was the most prevalent adverse growth outcome followed by underweight, wasting, and low head circumference. Among HEU infants, deficits in growth may be attributable to a combination of dietary inadequacy, intestinal damage, and chronic inflammation resulting from HIV exposure in utero or during the breastfeeding period in addition to other infections that may have occurred during the study period.21–23 In our analyses, because we did not account for potential effects of maternal or infant diet/nutrition and infection, it remains unclear how much of the variation in adverse growth outcomes is explained by prolonged maternal and/or infant ART exposure.
In this study, male sex was associated with worse growth outcomes: underweight, stunting, wasting, and low head circumference. This is consistent with previous results related to stunting reported from other sub-Saharan African countries;24,25 however, the sex disparity regarding risk of underweight, wasting, and low head circumference is less established. Moreover, the reasons for the observed sex differences related to growth are not well understood and need more research. These differences could be purely biological as male (versus female) children are generally more severely affected by environmental stresses.26 Both morbidity and mortality have been found to be higher in males than females early in life suggesting that boys generally are more vulnerable to adverse growth.27
Duration of breastfeeding influences the health benefits to infants/children.28–31 There were no observable differences in median duration of breastfeeding between the study arms for exclusive and any breastfeeding. Children who were breastfed for a longer duration (>3 months) were at lower risk of wasting than children who were breastfed for a shorter duration. The protective effect of breastfeeding on wasting could be explained by immunologic activity via secretory IgA antibodies, or by other antimicrobial properties against gastrointestinal and respiratory infections.29,30,32 Future research needs to examine the effects of prolonged ARV exposure through breast milk beyond 6 months (examined in this study) to at least 12 or 24 months as per current guidelines for breastfeeding among HIV-infected mothers.3
Our findings show that infants in Zimbabwe had more compromised growth especially stunting when compared with other study sites. During the RCT, Zimbabwe experienced severe socioeconomic decline affecting Zimbabwean children with stunting levels of over 40% among children aged less than 5 years.33 It is plausible that worse socioeconomic status and poor healthcare access in Zimbabwe (compared with other study sites) may explain our findings.13
Maternal ART reduces mortality and morbidity rates among HIV-infected women, and improves their quality of life.34 Our findings suggest that these benefits may be extended to infants in lower risk of underweight (but not other growth outcomes) and do not modify effect of infant prophylaxis duration. These findings are supported by studies that show that women not on ART, particularly those with advanced disease, could have impeded maternal to child transfer of antibodies (needed to curtail morbidity linked to lower weight among infants) that occurs during pregnancy and/or through breastfeeding.35–39 Our results are reassuring given the scale up of maternal ART, particularly Option B plus, and infant prophylaxis in resource-limited settings. It is important to note that in this study, a low proportion of women were on ART; ART was only given to women who had a CD4 of ≤350 cells/mm3 at the start of treatment.40 Maternal ART exposure may therefore serve as a proxy for disease severity making it difficult to know whether the ARV or underlying health status of the women was driving the results. Our results, however, suggest that maternal ART did not modify the relationship between treatment group and growth outcomes.
There were limitations to this study. In the original RCT, we did not collect nutrition data; therefore we were unable to assess specific effects of nutrition on the outcome variables.41,42 We did not examine potential moderation or confounding effects of infant concurrent illnesses and/or neurodevelopmental disorders on the relationship between treatment and growth outcomes. All infants received co-trimoxazole prophylaxis against opportunistic infections from 6 weeks to 6 months after breastfeeding cessation; making it difficult to separate treatment intervention and antibiotic effects on growth. The randomization of infants to treatment intervention to some extent controls for potential confounding by other treatments/medications.
In summary, extended prophylactic nevirapine given daily from 6 weeks to 6 months does not adversely affect growth (WAZ, LAZ, WLZ, and HCZ) in HEU breastfeeding infants. Targeted interventions may curtail the incidence of adverse growth outcomes among at-risk HEU infants characterized by male sex, short breastfeeding duration, lack of maternal ART exposure and resident in Zimbabwe.
The authors sincerely thank the mothers and children who volunteered and participated in the HPTN 046 trial and all the site staff for their participation in and support of the trial.
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