Introduction: There are a multitude of factors that impact the transmission of HIV from parent to child and the subsequent survival of infected children. Changing dynamics in HIV transmission have led to an increase in the number of children living with HIV in India. This review synthesizes the evidence related to transmission of HIV to children, survival and treatment provision among children living with HIV. Methods: A systematic search was conducted in MEDLINE, IndMed, Web of Science, Google Scholar and major journals related to HIV/AIDS to identify relevant studies published between 1992 and 2015. Inclusion criteria included studies related to parent to child transmission of HIV, treatment of children living with HIV and survival of children living with HIV. One of the authors reviewed the studies and extracted the data in a pre-coded extraction sheet. Results: Thirty-three studies were included in the review. HIV transmission rate from parent to Child who received nevirapine prophylaxis ranged from 2.1% to 27.3%. Extended dose regimen of nevirapine prophylaxis was found to be more effective than the single dose regimen. Adherence to ART ranged from 65% to 95%. Adherence varied depending upon the level of health care facility. Both social and medical factors were associated with non-adherence. CD 4 count at the time of diagnosis and delayed age at HIV diagnosis were important predictors of survival. Conclusion: Shift in policy to provide option B regimen is yielding better results. If the age at diagnosis could be reduced further, it would increase the survival of children living with HIV. The program needs to increase access to the health care facilities.
The HIV program in India has evolved dramatically over the last decade. Preventive and behavior change strategies, along with a scaled-up program for coverage of antiretroviral therapy (ART), have led to a nearly 50% decrease in the estimated number of new HIV infections in India―from 250,000 in 2001 to 120,000 in 2012 [
The HIV epidemic in India is concentrated in nature and heterogeneous in distribution [
Since 2012, the policy of single dose nevirapine prophylaxis has changed to a more effective multi-drug regimen [
In this paper we present findings from a systematic review of the literature published from India regarding parent to child transmission of HIV and treatment and survival of CLHIV.
We conducted a comprehensive search to identify all relevant studies related to parent to child transmission of HIV, treatment and survival of CLHIV (Box 1). We searched the following databases: Medline, Pubmed, IndMED, and used search engines like Web of Science and Google Scholar. To locate additional studies and reports, we screened the table of contents of journals that publish studies related to HIV/AIDS and scanned the websites of national and international organizations like National AIDS Control Organization (NACO), World Health Organization (WHO), United States Agency for International Development (USAID), and United Nations Program on HIV/AIDS(UNAIDS). We also searched the reference lists of articles included in the systematic review.
We conducted the search using three sets of key words. 1) Prevention of Parent to Child Transmission OR PPTCT, Parent to Child Transmission OR MTCT, Antenatal prophylaxis, Nevirapine prophylaxis, Option B regimen, Type of delivery, Delivery, Caesarean, Infant feeding, Mixed Feeding, Replacement feeding, Sero-dis- cordance, AND India; 2) Survival, Early Infant Diagnosis, Access to care, CD 4 count, Adherence, AND India AND HIV and Children OR Pediatric; 3) Anti-retro Viral Therapy OR ART, Adherence, Effectiveness, Efficacy, Survival, AND India AND Children OR Pediatric. The search was restricted to studies published between 1992 and 2015. All studies published in English or with a detailed summary in English were included in the review. The search was conducted in January 2015.
We screened the titles of all the search outputs, and excluded studies that were not found to be relevant. Abstracts of all the titles found to be relevant to the present review were screened, and those that met in the inclusion criteria, as given in Box 1, were included. We exported the search results to EndNote reference manager software. A structured data extraction sheet was used, based on the Cochrane data extraction sheet and the New Castle Ottawa scale. Quality assessment for randomized control trials was done using a five-point scale, namely the process of randomization, treatment allocation, baseline comparability, blinding and drop-out rate. However, we did not screen or exclude studies based on methodological quality as the purview of this review was exploration rather than estimation. Data extraction was done under the following heads: domain and sub-domain of the study, study identifier i.e. last name of author, year of study and publication, PubMed ID, study characteristics (study design, study setting, objective, sample size, and inclusion and exclusion criteria), participant characteristics for studies related to survival and treatment (sex wise, mean age, and age group), objective, exposure, outcome and important findings, drop-out rate and adjustment for confounders.
We retrieved a total of 842 titles from the search term alone or in various combinations. Of these, 686 were not found to be relevant to the present review or were duplicate searches―i.e. the same title retrieved from different
Box 1. Study selection criteria.
sets of keywords. The abstract and full texts of the remaining 156 studies were screened, of which 33 met the inclusion criteria. These 33 selected studies were thematically grouped into three categories: i.e. studies related to parent to child transmission of HIV (19 studies), treatment of children living with HIV (11 studies), and survival of children living with HIV (3 studies). The results of the literature search and thematic categorization of studies are presented in
All the studies included in the review were conducted after 2000, and were health facility-based studies. Most (88%) were conducted in urban public health facilities. While around half were conducted in the high HIV prevalence states of Andhra Pradesh, Tamil Nadu and Maharashtra, 20% were conducted in West Bengal and 10% in Gujarat. Only three studies were conducted in the states of north India. In all, 28 studies were interventional or observational follow-up studies, 2 were cross-sectional studies and 3 were retrospective cohort studies (
Most studies explored the effectiveness of single dose nevirapine prophylaxis, and were conducted in a public health facility in southern India. All except two studies had a sample size of between 30 and 1890 HIV infected pregnant women.
The HIV sero-positivity rate among antenatal women ranged from 0.17% to 0.56% [
S. No. | Author (Year) | Study site (setting) | Sample size | Key findings |
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Parent to child transmission of HIV | ||||
1 | Alvarez Uria G. (2012) [ | Andhra Pradesh (Rural) | 523 | The overall HIV transmission rate from parent to child was 3.7%. The cumulative 12-month mortality was 9.6% for formula-fed infants versus 0.68% for breastfed infants. |
2 | Arora et al. (2014) [ | Maharashtra (Urban) | 30 | The overall transmission rate to infant till six weeks of age was 20%. |
3 | Goswami et al. (2011) [ | West Bengal (Urban) | 248 | 248 women were detected positive for HIV. Only 46 live births were tested for HIV and the transmission rate was 2.1% (1/46). |
4 | Gupta et al. (2013) [ | Maharashtra (NM) | 217 | 18 women tested HIV positive, leading to a transmission rate of 8.3%. The transmission rate among HIV infected parents who followed the PPTCT protocol was 5.2% vs 17.5% among those who did not. |
5 | Gupta et al. (2007) [ | Maharashtra (Urban) | 41 | Of the 41 infants who received nevirapine prophylaxis, the overall transmission rate up to the age of one year was 8%. The transmission rate in exclusively formula fed infants was 3.1% (1/31) vs 30% (3/10) in the mixed feeding group. |
6 | Jain et al. (2011) [ | Gujarat (Urban) | 326 | The transmission rate among those who received ARV prophylaxis was 5.2% (14/270) vs 41.1% (23/56) among those who did not. |
7 | Joshi et al. (2010) [ | Gujarat (Urban) | 541 | The HIV transmission rate among infants delivered through cesarean section was 2.9% (1/35) and 4.1% (2/49) for vaginal delivery at 18 months of age. With respect to feeding practice the transmission rate was 25% for those in the mixed feeding group, 2.4% for those exclusively breast fed and 0% for those exclusively formula fed. |
8 | Joshi et al. (2011) [ | Gujarat (Urban) | 81 | Among infants who received single dose nevirapine prophylaxis and tested for HIV at age one year, the transmission rate was 3.1%. 1/32). |
9 | Mandal et al. (2010) [ | West Bengal (Rural) | 19794 | Among parent child pair who received nevirapine with exclusive formula feeding, and tested at at 18 months of age, the transmission rate was 15.0% versus 57.2% in absence of both the interventions. |
10 | Merchant et al. (2001) [ | West Bengal (Urban) | 92 | Among children who received single dose nevirapine prophylaxis and tested at 18 months of age, the transmission rate was 5.9% (4/68) vs 24.0% (55/229) among those who did not receive prophylaxis. |
11 | Omen et al. (2011) [ | West Bengal (Urban) | 1890 | The HIV transmission rate in the single dose prophylaxis group (10.4%) was higher than in the extended dose regimen group (8.9%). But, the difference was not statistically significant [risk ratio: 0.87%, 95% confidence interval (CI): 0.65 - 1.15]. Cumulative mortality in the extended dose regimen group was also significantly less (risk ratio = 0.53, 95% CI 0.32, 0.85) than in the single dose regimen group |
12 | Read et al. (2010) [ | Tamil Nadu (Rural) | 780 | The parent to child HIV-1 transmission rate of was 6.5% (95% CI: 1.4% - 17.9%). |
13 | Seth A. et al. (2012) [ | North India (Urban) | 162 | The HIV transmission rate was 14.8%. |
14 | Shah et al. (2006) [ | Maharashtra (Urban) | 222 | The HIV transmission rate for infants delivered through cesarean section was 1.1% (2/174). And for vaginal delivery it was 2.1% (1/48). Thus, elective cesarean section was not statistically better as compared to vaginal delivery (p = 0.8696) in presence of ART during pregnancy and absolute formula feeding during first six months. |
15 | SWEN study team (2008) [ | Maharashtra (Urban) | 770 | The HIV transmission rate at 6 months of age among HIV exposed infant who received single dose nevirapine prophylaxis was 9.6 % (87/901) whereas it was 6.3% (62/986) among those who received extended dose regimen. relative risk of acquiring HIV in infants was 0.80 (RR = 0.80, 95% C.I. 0.58 - 1.10) when given extended dose regimen as compared to a single dose regimen |
16 | Chaudhary et al. (2010) [ | West Bengal (Urban) | 47506 | Of the 11 children who had received single dose nevirapine prophylaxis, three (27.3%) were HIV positive at 18 months of age. |
17 | Ahir et al. (2013) [ | Maharashtra (Urban) | 58 | At the end of 18 months two of 58 children (3.5%) were HIV positive whose parents were on nevirapine prophylaxis. |
18 | Gupta et al. (2011) [ | Maharashtra (Urban) | 783 | Of 33 parents with TB, 10 (30%) transmitted HIV to their infants compared to 87 of 750 parents without TB (12%) |
Treatment of children living with HIV |
1 | Alvarez Uria G. et al. (2013) [ | Andhra Pradesh (Rural) | 247 | The cumulative incidence of attrition was 12.6% (95% confidence interval, 8.7 - 17.3) after five years of follow-up. Children who belong to scheduled tribes had a higher risk of delayed ART initiation and LTFU. Orphan children had a higher risk of delayed ART initiation and mortality. |
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2 | Alvarez Uria G. et al. (2014) [ | Andhra Pradesh (Rural) | 282 | The cumulative incidence of attrition (mortality and LTFU) was 15.6% at five years, and the attrition rate was higher during the first year after enrolment in care. |
3 | Banerjee et al. (2010) [ | West Bengal (NM) | 180 | Median duration of survival from date of diagnosis was 15.1 years. Those who received HAART survived significantly longer. |
4 | Bhattacharya et al. (2011) [ | Delhi (Urban) | 90 | Mean adherence was 91.4%. Adherence was low (<95%) in 31 (34.4%) patients. On multivariate logistic regression analysis, increasing time since ART initiation, low caregiver educational status, orphan hood, efavirenz-based ART regimens and female gender were associated with lower adherence. |
5 | Bhattacharya et al. (2012) [ | NA | 87 | The outcome of ART in terms of survival was not affected by the orphan status. Improvement in nutritional parameters and CD4 count was comparable in both the groups. |
6 | Chaudhary et al. (2012) [ | Delhi (Urban) | 130 | Following ART, a reduction in wasting was noted in 75.0% of children ≤5 years of age, whereas only 44.4 % of underweight children >5 years of age showed an improvement after therapy. |
8 | Seth A. et al. (2014) [ | Kolkata (Urban) | 106 | Median duration of ART was 25 (IQR 16 - 35) months. The desired adherence level of >95% during six months of review assessed by pill count was achieved in 95.3% children. The 3-day recall method yielded >95% adherence in 99% children (p ≤ 0.001). |
9 | Violari et al. (2012) [ | Tamil Nadu (NM) | 288 | The median percentage of CD4+ T cells was 15%. The percentage of children who reached the primary end point was significantly higher in the nevirapine group than in the ritonavir-boosted lopinavir group (40.8% vs. 19.3%; p < 0.001). The time to a protocol-defined toxicity end point was shorter in the nevirapine group (p = 0.04), as was the time to death (p = 0.06). |
10 | De et al. (2012) [ | West Bengal (Urban) | 94 | Fifty-six percent of respondent parents and 65.8% of respondent children showed good adherence to ART. |
11 | Rajashekharan et al. (2009) [ | Tamil Nadu (Urban) | NA | The cumulative survival probability at 6, 12, 18, 24 and 30 months was 93%, 90%, 89.7%, 89.7% and 89.7%, respectively. Of the children who died, about 50% died within the first month. Nearly 6% of the children had adherence less than 95%. The children who had a baseline CD4 % less than or equal to 14% had significantly (p < 0.05) higher mortality as compared to children who had 20% or more. |
Survival of children living with HIV | ||||
1 | Alvarez Uria G. et al. (2013) [ | Andhra Pradesh (Rural) | 523 | Predictors for delayed entry into care and survival were; diagnosed after knowing that parent is HIV positive, age less than 18 month, alive parent, female sex, diagnosed at earlier calendar years, distance at ART center >90 minutes . |
2 | Gupta et al. (2013) [ | Pune (Urban) | 32 | The delayed entry into care i.e. delay in diagnosis was associated with incidence of opportunistic infection and survival |
3 | Radhakrishnan et al. (2013) [ | Tamil Nadu (NM) | 26 | All 26 (13 female and 13 male) perinatally HIV infected children, born during 1991-1996 were healthy until 2006. But by 2011, 18 were placed in progressors group with antiretroviral therapy (ART), while six remained in non progressors group and two died. AIDS free median survival period (years) in long term progressors group (CD4 count) of the cohort was 10 ± 0.66 (<200; p ≤ 0.05); 11 ± 0.61 (200 - 350, p ≤ 0.05), 12 ± 0.18 (>350, p ≤ 0.05). Intercurrent and opportunistic infections (OIs) were observed in long term progressors only. The incidence of opportunistic infections in long term progressors was higher when compared to general pediatric population. |
27.3% [
Few studies compared the HIV transmission rate with respect to feeding patterns. A study in Maharashtra showed that infants who were exclusively formula fed had a lower transmission rate than the overall transmission rate (3.1% vs 8.0%) [
Most of the studies which compared the HIV transmission rate with respect to type of delivery showed that cesarean section was better than vaginal delivery in preventing HIV transmission. In a cohort study in Gujarat, the transmission rate in the vaginal delivery group was 4.1% as compared to 2.9% among mothers who underwent cesarean section [
The presence of concomitant chronic conditions was also found have an effect on transmission of HIV. The parent to child transmission rate among pregnant women co-infected with HIV-TB was 30%, which was significantly more than the transmission rate of 12% in the absence of tuberculosis (p value = 0.02) [
Of the 11 studies covering treatment of CLHIV, four explored levels of ART adherence, and factors associated with non-adherence to treatment; 2 examined the magnitude of loss to follow up among children on ART care, and 3 explored the effectiveness of different highly active anti-retroviral therapy (HAART) regimens in the treatment of HIV-infected children.
The attrition rate for ART among children (14 years or less) living with HIV on ART was 12.6% and 15.6% in two studies conducted in Andhra Pradesh [
Appropriate adherence to ART (more than 95% of doses) varied from 65.8% to 95.5% across studies [
Of the three studies that assessed the survival pattern of CLHIV, one study each reported time to infant diagnosis, time of entry into care and CD 4 count at the time of diagnosis as factors related to survival. CD 4 count at the time of diagnosis was an important predictor of progression of HIV [
In a cohort study in South India, 13% of the children were lost to follow up in the one year after diagnosis. Most of the children who were not eligible for treatment during the first year were lost to follow up [
We found that the majority of research in India has focused on the effectiveness of interventions related to nevirapine prophylaxis. However, the Government of India has decided to roll-out and scale-up the Option B plus regimen, a conclusively effective regimen [
The provision of exclusive formula feeding during the first six months of life is beneficial in reducing parent to child transmission of HIV. However, due to the socio-economic context in the Indian setting, consensus has been built to continue with exclusive breast-feeding during the first six months of life [
Most of the studies that explored issues around the treatment of CLHIV explored ART adherence and loss to follow up, and only a few studied the effectiveness of HAART. After initiating a child on ART, frequent monitoring is critical for assessing well-being as well as side effects and adherence. Monitoring should also focus on the general growth, development, immunization status as well as nutritional status. Visits should also be used as an opportunity to educate and counsel parents and care-givers on adverse drug reactions, opportunistic infections and adherence. Local evidence and operational challenges in this regard are lacking and call for adequately sampled prospective cohort studies.
Increase in accessibility to HIV treatment for the pediatric population has led to an increase in long-term survival [
Assessments are needed of the knowledge gap among the cadre of health care workers in light of new HIV treatment guidelines, implementation challenges and training needs. Evidence is also needed to improve prevention and treatment of malnutrition among HIV-exposed and HIV-infected children. Presently there is little information available on the effectiveness of nutritional interventions among HIV-infected children.
Disclosing the diagnosis of HIV to an HIV-infected child is an emotionally charged issue for parents and health care providers. The present status of research on HIV among children in India is completely missing in this regard. There have been many studies on disclosure related to patients with cancer, and lessons may be drawn for HIV [
Most of the studies included in this systematic review have been small unplanned studies, conducted as a part of routine health care delivery related to HIV. Shift in policy to provide option B regimen is yielding better results. Various factors identified as the determinants of transmission of HIV from parent to child need to be targeted. If the age at diagnosis could be reduced further, it would increase the survival of children living with HIV. The program needs to increase access to the health care facilities to improve adherence rate and reduce attrition.
Universalization and increased uptake of the newer and more effective Option B plus regimen is recommended. There is need to conduct operational research to document the effectiveness of life-long ART in pregnant women in preventing parent to child transmission of HIV in the Indian setting. Tracking of children exposed with HIV should be done as parent-child pairs, with strict follow-up. A more robust follow-up strategy should be implemented under the program. There is a need to target various modifiable programmatic factors associated with poor treatment adherence, including type of treatment setting and late initiation of ART after diagnosis. There is a need to conduct more scientifically robust studies to facilitate programmatic recommendations.
This paper (NACO/SIMU/NDAP/2015/07) was written as part of the National Data Analysis Plan (NDAP), an initiative of the Strategic Information Management Unit of National AIDS Control Organization (NACO), Ministry of Health and Family Welfare, Government of India. This project was supported by NACO’s other development partners, which include Center for Diseases Control (CDC), World Health Organization-India, FHI-360, and John Snow India. This paper was conceptualized, developed and finalized by the author, under the guidance of mentors (senior public health experts) and the NDAP Unit, NACO. The Knowledge Network project of the Population Council, which is a grantee of the Bill & Melinda Gates Foundation though Avahan, the India AIDS Initiative, has supported the scientific writing, reviewing, editing and finalization of this paper. The views expressed in this paper are those of the authors, and do not necessarily reflect the views of NACO.
Conceived and designed the experiment: S.K., P.H., S.K.R., A.K.S. Performed the experiment: A.K.S. Wrote the paper: A.K.S., P.H. Data interpretation: S.K., P.H., S.K.R., A.K.S. Critical revision to the manuscript: S.K., P.H., S.K.R. Read and approved final manuscript: S.K., P.H., S.K.R., A.K.S. Guarantor of the paper: P.H., A.K.S.
Arvind KumarSingh,ParthaHaldar,Sanjay KumarRai,ShashiKant, (2015) A Systematic Review to Explore the Factors Related to Parent to Child Transmission of HIV, Survival and Treatment Provision of Children with HIV in India. World Journal of AIDS,05,245-255. doi: 10.4236/wja.2015.53028