The current prevention of parent to child transmission (PPTCT) guidelines by National AIDS Control Organization (NACO), recommend lifelong anti-retroviral therapy (ART) to all pregnant and breast-feeding women with HIV regardless of clinical or immunological stage, anti-retroviral (ARV) prophylaxis to the baby, and safe infant feeding practices. A well-defined protocol has also been developed for care of the HIV-exposed infants [6]. The objective of this work is to report outcome of HIV-exposed infants born at a tertiary-case pediatric hospital, and provided standardized care as per the current NACO protocol.

This retrospective cohort study was conducted in the Pediatric Centre of Excellence in HIV care located at a public teaching hospital in northern India. Infants born to women with HIV infection at the linked hospital and registered in the PPTCT program at our Center from January 2011 to March 2016 were included. We excluded infants born at other hospitals and subsequently referred to our Centre, those diagnosed with HIV after admission to our pediatric wards, or those who never attended the Centre after birth at the linked hospital.

In accordance with the National guidelines, the HIV- exposed infants are registered at birth in our Centre and given a protocol-based care till 18 months of age [6]. This includes provision for early HIV diagnosis, safe feeding counselling, and access to routine infant care practices. Prior to January 2014, all women with HIV and their newborns were given a single dose of nevirapine (SDNVP) during labor and immediately after birth, respectively, in accordance with the national guidelines at that time [7]. After January 2014, all pregnant women with HIV are initiated on ART during pregnancy soon after detection of their HIV status. Infants born to these women are started on daily nevirapine prophylaxis at birth and continued for a minimum of 6 weeks [6]. This study included subjects registered both before and after these changes in the National recommendations. Determination of HIV status was done through HIV-1 DNA-PCR by dried blood spot (DBS) at ages 6 weeks, 6 months, and six weeks after stopping breastfeeding. Infants testing positive on DBS testing were re-tested for DNA-PCR on whole blo　od sample. In infants older than 18 months, serological tests (3 rapid antibody tests) were done for HIV diagnosis.

For the current study, information on maternal and infant characteristics was obtained from the records of all eligible infants maintained at our Centre. The nutritional status of children was determined by calculating Z-scores for weight for age (WFA), weight for length (WFL), length for age (LFA) and head circumference for age (HFA) using WHO growth reference standards [8].

The infants were considered to be HIV-infected if they tested positive on DNA-PCR any time before 18 months, or were found reactive on HIV serology at 18 months or beyond. They were considered HIV-uninfected if they had a negative DNA-PCR test and were not breastfeeding or had stopped it 6 weeks prior to the test, or had a non-reactive HIV serological test at or after 18 months performed at least 6 weeks after cessation of breastfeeding. The study was approved by the Institutional Ethics Committee for Human Research.

Statistical analysis: The data were analyzed using the SPSS statistical software package, Version 23. Chi square test, unpaired t test and Mann-Whitney U test were used to compare maternal and infant variables among HIV- uninfected infants at 18 months and those who died.

During the study period, 165 HIV-exposed infants were born at the linked hospital. Among these, 155 mother-infant pairs who were followed up at our centre till 18 months were eligible for the study. The clinical characteristics of these mother infant dyads are shown in Table I.

TABLE I	Clinical Characteristics of Infants Born to Mothers with HIV Infection (N=155)

Of the 155 infants, 10 (6.5%) died before 18 months of age. Among the 145 surviving infants, two were confirmed HIV-positive. The rest 143 (92.3%) were surviving and HIV-free at 18 months. Of the 10 infants who died before 18 months, one had positive and three had negative HIV DNA-PCR at the age of 6 weeks (all 3 on exclusive replacement feeds), while the rest died before their HIV status could be ascertained (Fig. 1).

Fig. 1 Outcome of HIV-exposed infants enrolled in the study.

HIV infection was reliably excluded in 146/155 infants (143 of those alive and 3 of those who died) while it was diagnosed in 3 infants (2 of those alive and 1 among those who died). Thus, HIV infection rate in the infants for whom the HIV test reports were available was 2% (3/149). On analyzing the data before (n=93) and after (n=62) the change in PPTCT guidelines, no significant difference was found in terms of HIV-free survival (92.5% vs 91.9%; P=0.9); or HIV transmission rate (2.2 vs 1.7 %; P=0.82).

The outcome in terms of survival and status of HIV infection stratified as per various maternal and infant factors is presented in Table II. Details of the three infants who were diagnosed with HIV infection are presented Web Table I.

TABLE II Outcome  of Infants Stratified According to Maternal and Infant Characteristics (N=155)

At the age of 18 months, Z scores for WFL (n=108), LFA (n=108) and OFC (n=106) were -0.6 (1.2) , -1.2 (1.2), and -0.9 (1.2), respectively. At that time, 15 (14%) of uninfected infants were wasted, 30 (28%) infants were stunted, and 3 (3%) had microcephaly.

TABLE III Details of Infants Detected HIV-Infected

The present study has documented HIV infection rate and HIV-free survival among infants of women with HIV infection managed as per national PPTCT strategy. Parent to child transmission rate in the present study was 2%, with an overall ARV cover in HIV positive mothers of 94% (ART 79%, SDNVP 15%). We have previously reported a rate of 14.8% when the ARV cover in HIV-infected mothers was only 61.5% [5]. The current transmission rate is also much less when compared to studies from Africa [9,10], as well as few studies from India where the transmission rate has varied between 8-19% [11,12]. These studies were conducted during the time when most mothers received SDNVP, ART being limited only to those eligible as per their clinical/immunological criteria. In a recent study, where 37% of HIV-infected pregnant women received ART, and 63% SDNVP, Seenivasan, et al. [13] have reported a HIV transmission rate of 4%. Another study from this region, where 92% of enrolled women were getting either ARV prophylaxis or ART, a HIV transmission rate of 3.4% was reported [14]. The results of the current and these other recent studies from India show that with current robust PPTCT strategy, the HIV transmission rate in India is approaching the rate observed in developed countries (1-2%) [15,16].

We observed a 92.3% HIV-free survival at 18 months of age, similar to a recent study from Rwanda [17] that reported a 24-month HIV-free survival of 93.2% in breastfeeding infants of HIV-positive mothers on lifelong ART. A systematic review including 18 studies published between 2005 to 2015 provided a pooled estimate of 18-month HIV-free survival of 89.0% with 6 months ART and 96.1% with lifelong ART [18]. The authors found that the HIV-free survival, though higher in the breastfeeding group, did not significantly differ by feeding patterns. Similar findings were also observed in the present study. At 18 months, the prevalence of wasting and stunting among infants was no different from that reported among Indian children of this age group as per NFHS-4 [19].

Several reasons contribute towards better outcome of HIV-exposed infants in terms of survival, HIV transmission and nutritional status in the current as compared to our previous study [5]. Unlike the previous study, the present work excluded infants diagnosed as HIV-exposed/infected after birth. A much higher proportion of mothers were on ART (79%) as compared to the previous study (17.4%). Provision of a protocol-based care with focus on repeated counselling to optimize health of mother-infant dyad also contributed to the improved outcome.

Due to a small number of infants who acquired HIV infection or died, our results give limited information regarding predictors of HIV infection transmission/mortality in HIV-exposed infants. As routine viral load was not introduced in the national protocol during this study period, maternal viral load, that directly impacts upon the HIV transmission rate, could not be assessed.

We conclude that implementation of the current PPTCT strategy, which includes lifelong ART to all HIV-infected pregnant and breastfeeding women with ARV prophylaxis to their infants, and a structured follow up of HIV-exposed infants, has remarkably improved the outcome of these infants.

Contributors: NB: managed the cases, recorded the information and drafted the paper; AS: conceptualized the paper, drafted and edited the manuscript and was the consultant in patient management. She will be the corresponding author for this work; SS: contributed towards design of the work, data analysis and manuscript preparation; GS: provided clinical care to study subjects, and contributed towards record keeping and manuscript preparation; PK, JC: consultants in patient management and helped in drafting /editing the paper. All authors gave their final approval for the submitted manuscript.

Funding: None; Competing interest: None stated.