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A meta-analysis assessing all-cause mortality in HIV-exposed uninfected compared with HIV-unexposed uninfected infants and children

Brennan, Alana T.; Bonawitz, Rachael; Gill, Christopher J.; Thea, Donald M.; Kleinman, Mary; Useem, Johanna; Garrison, Lindsey; Ceccarelli, Rachel; Udokwu, Chinenye; Long, Lawrence; Fox, Matthew P.

doi: 10.1097/QAD.0000000000001211
Epidemiology and Social

Objective: Conduct a meta-analysis examining differential all-cause mortality rates between HIV-exposed uninfected (HEU) infants and children as compared with their HIV-unexposed uninfected (HUU) counterparts.

Design: Meta-analysis summarizing the difference in mortality between HEU and HUU infants and children. Reviewed studies comparing children in the two groups for all-cause mortality, in any setting, from 1994 to 2016 from six databases.

Methods: Meta-analyses were done estimating overall mortality comparing the two groups, stratified by duration of follow-up time from birth (0–12, 12–24 and >24 months) and by year enrollment ended in each study: less than 2002 compared with at least 2002, when single-dose nevirapine for prevention of mother-to-child transmission (PMTCT) commenced in low-income and middle-income countries.

Results: Included 22 studies, for a total of 29 212 study participants [n = 8840 (30.3%) HEU; n = 20 372 (37.7%) HUU]. Random effects models showed HEU had a more than 70% increased risk of mortality vs. HUU. Stratifying by age showed that HEU vs. HUU had a significant 60–70% increased risk of death at every age strata. There was a significant 70% increase in the risk of mortality between groups before the implementation of PMTCT, which remained after 2002 [risk ratio: 1.46; 95% confidence interval (CI): 1.14–1.87], when the availability of PMTCT services was widespread, suggesting that prenatal antiretroviral therapy, and healthier mothers, does not fully eliminate this increased risk in mortality.

Conclusion: We show a consistent increase risk of mortality for HEU vs. HUU infants and children. Longitudinal research is needed to elucidate underlying mechanisms, such as maternal and infant health status and breast feeding practices, which may help explain these differences in mortality.

aDepartment of Global Health, Boston University School of Public Health, Boston, Massachusetts, USA

bHealth Economics and Epidemiology Research Office, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

cDepartment of Epidemiology, Boston University School of Public Health

dDepartment of Pediatrics, Boston University School of Medicine, Boston, Massachusetts, USA.

Correspondence to Alana T. Brennan, Department of Global Health, Boston University School of Public Health, Crosstown Center, 3rd Floor, 801 Massachusetts Ave, Boston, MA 02118, USA. Tel: +1 617 414 1479; e-mail: abrennan@bu.edu

Received 12 May, 2016

Revised 23 June, 2016

Accepted 30 June, 2016

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com).

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Introduction

The successful global implementation of programs to prevent mother-to-child transmission (PMTCT) of HIV via maternal antiretroviral provision has reduced the risk of perinatal transmission of HIV from 25–30% to approximately 2–5% [1,2]. Currently, approximately 1 million children are born to HIV-positive mothers each year [3]; assuming high uptake of PMTCT under current WHO guidelines [4], HIV-exposed but uninfected infants and children are the predominant pediatric population affected by HIV.

Though HIV-infected infants and children experience higher rates of morbidity and mortality than either population, a growing number of researchers have reported that HIV-exposed but uninfected children experience morbidity and death at rates exceeding that for HIV-unexposed uninfected (HUU) children [5–16]. This increased morbidity and mortality for HIV-exposed uninfected (HEU) children has been noted in both the pre-PMTCT and post-PMTCT eras and across various study settings [17]. The implication is that although effective PMTCT programs have curtailed rates of HIV transmission, it has not completely removed the risk of death or morbidity in HEU children compared with HUU children. Precise reasons for this disparity remain unclear, though it is likely multifactorial in nature, encompassing immunological, biological, maternal, social, behavioral and health systems factors [5–16].

Given the large numbers of children perinatally exposed to HIV each year, further analysis and examination of these trends in morbidity and mortality are warranted. The public health success of PMTCT, especially in this era of Option B+ globally [3], is remarkable. Although the numbers of new pediatric HIV infections will continue to decline as the number of pregnant women and mothers having access to effective PMTCT interventions increase, a commensurate number of HEU children will be left at risk of this ill-defined increase in illness. To better understand the scope and scale of this problem, we conducted a meta-analysis examining differential all-cause mortality rates between HEU infants and children as compared with their HUU counterparts from the years 1994 to 2016.

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Methods

Search strategy and selection criteria

We searched the databases PubMed, Web of Science (including Medline), Excerpta Medica Abstract Journals (EMBASE), ProQuest Dissertation & Thesis Outline, International AIDS Society (IAS) abstract archives and AIDS Conference abstract archives for articles and abstracts published between 1 January 1994 and 1 April 2016. We reviewed the references in the included articles and added any studies that met our inclusion criterion. Our search keywords can be found in Supplementary Table 1, http://links.lww.com/QAD/A956. We limited the search to human studies and articles published in English. Two reviewers out of five (M.K., R.C., L.G., J.U. and C.U.) screened all titles and abstracts to capture potentially relevant studies, and two reviewers (A.T.B. and R.B.) resolved any discrepancies between them. We included studies from any geographic location that compared mortality amongst HEU infants or children to HUU infants or children. Additional data were not obtained from study authors.

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Data extraction

The primary objective of this study was to compare mortality among HEU children to that among HUU children in any setting. For each study when possible, we extracted year published, region, country, dates enrollment started and ended, date follow-up ended and total N in each cohort. For all-cause mortality, we extracted data on the number of deaths in individual studies, if available, and the total number of study participants to calculate simple proportions and corresponding 95% confidence intervals (CIs) for HEU and HUU children. When studies using Kaplan–Meier methods did not summarize the number of deaths and the number in the risk set, we estimated the number of deaths based on the mortality proportion identified using the Kaplan–Meier curve multiplied by the total number of study participants.

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Data analysis

Meta-analyses were performed to estimate overall all-cause mortality comparing HEU and HUU children and then stratified by duration of follow-up time from birth in 12-month intervals (0–12, 12–24 and >24 months). We also stratified by year enrollment ended in each study: pre-2002 vs. 2002 or after, when single-dose nevirapine for PMTCT commenced in most public sector clinics in resource-limited settings and region within the African continent (Southern, Eastern, Western and Central) [18]. Meta-regression was used to first assess the linear effect of time (1994–2015) on mortality by regressing the natural log of the ratio measures for mortality on the year study enrollment ended as a continuous variable (graphically displayed using a bubble plot) and then regressed the outcome on time as a dichotomous variable (pre-2002 vs. 2002 and after). As many countries included in the study did not revise their national policies and provide implementation training and support immediately following the publication of WHO PMTCT guidelines, we repeated the meta-regression with time stratified by pre-2004 and 2004 and after, allowing more follow-up time to potentially see an effect. This shift in time would also take into account the change in the guidelines to include possibility of triple therapy for PMTCT in low-income and middle-income countries (LMIC) [19]. Heterogeneity between the studies was examined using Cochran's Q and the I2 statistics [20]. Random effects models were used to estimate all combined mortality rates and corresponding 95% CIs using standard methods because there was evidence of high heterogeneity between studies [21].

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Sensitivity analysis

To determine what proportion of the summary results driven by Marinda et al. which had the largest study population, we conducted a sensitivity analysis excluding this study.

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Publication bias

An analysis of publication bias was also performed using a funnel plot and Egger's linear regression test [21]. We used a confidence level of 0.10 to accommodate the low power of the Egger's test to detect a departure from the null hypothesis of no bias (symmetrical funnel plot).

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Results

A total of 2800 potentially relevant citations were identified, and 2451 remained after de-duplication (Fig. 1). Of 2451 articles, 204 studies appeared relevant and merited full text review, of which 22 studies published between 1994 and 2015 reported on all-cause mortality and were included; 21 (95.5%) from sub-Saharan Africa and one (4.5%) from Haiti (Table 1) [3,5,10,14,29–39]. The total population size of our study was 29 212 study participants [n = 8840 (30.3%) HEU and n = 20 372 (37.7%) HUU]. Cohort size ranged from 17 to 12 645 children. Fourteen studies ended enrollment of children before the implementation of PMTCT in public sector in 2002, and eight ended enrollment of children between 2002 and 2015.

Fig. 1

Fig. 1

Table 1

Table 1

All estimates are summary pooled random effects estimates of mortality. The overall summary measure of association showed that HEU children had a 70% increase in all-cause mortality (risk ratio: 1.70; 95% CI: 1.30–2.22) compared with HUU children (Fig. 2). When stratifying by time since birth in 12 month intervals, results showed that HEU vs. HUU children had a statistically significant 60–70% increased risk of death at every age strata (birth to 12 months – risk ratio: 1.78, 95% CI: 1.14–2.78; 12–24 months – risk ratio: 1.58, 95% CI: 1.10–2.27 and >24 months – risk ratio: 1.70, 95% CI: 1.12–2.57) (Fig. 3).

Fig. 2

Fig. 2

Fig. 3

Fig. 3

When stratifying studies according to completion of participant enrollment in relation to the implementation of PMTCT in public sector (pre-2002 vs. 2002 or after), the relative risk of all-cause mortality was higher amongst HEU vs. HUU children before the implementation of PMTCT (pre-2002 risk ratio: 1.73; 95% CI: 1.22–2.46). This increased risk remained even after the widespread availability of PMTCT services, as shown when restricting the analysis to studies that completed study enrollment in 2002 or after (risk ratio: 1.46; 95% CI: 1.14–1.87) (Fig. 4), suggesting that PMTCT does not fully eliminate the risk of increased mortality. This finding was robust even when the cutoff was shifted to 2004 (pre-2004 risk ratio: 1.78; 95% CI: 1.30–2.44 vs. 2004 or after risk ratio: 1.37; 95% CI: 1.05–1.79), a time selected to account for delayed implementation of PMTCT in addition to potentially increased access to triple therapy for PMTCT in some situations. In meta-regression analyses, when regressing the log(risk ratio) against time as a continuous variable, there was a slight trend toward declining mortality among the HEU children vs. HIV-unexposed children, but this difference was not statistically significant (Supplementary Fig. 1, http://links.lww.com/QAD/A956).

Fig. 4

Fig. 4

When stratified by region within Africa, excluding Central Africa that had only one study, we found that estimates were comparable between southern (risk ratio: 1.55; 95% CI: 1.13–2.13) and western (risk ratio: 1.40; 95% CI: 0.93–2.10) regions of the continent. Although NS and strongly influenced by three studies with the largest effect sizes [24,26,36], summary estimate for Eastern Africa were substantially higher (risk ratio: 5.21; 95% CI: 0.71–38.5) (Supplementary Fig. 2, http://links.lww.com/QAD/A956).

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Sensitivity analysis

To determine what proportion of the summary results were driven by Marinda et al. which had the largest study population (n = 12 345; 44.7% of all the meta-analysis study participants), we conducted a sensitivity analysis. After omitting Marinda et al., the overall summary estimate was attenuated (risk ratio: 1.37; 95% CI: 1.03–1.83), compared with the original finding.

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Publication bias

The funnel plot and nonsignificant Egger's test (P = 0.187) show little evidence of asymmetry suggesting little to no publication bias (Supplementary Fig. 3, http://links.lww.com/QAD/A956).

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Discussion

To our knowledge, this is one of the first meta-analyses of the literature showing an increased risk of mortality in HEU children compared with HUU children in LMICs, spanning different contexts and eras of maternal antiretroviral therapy and PMTCT. The increased risks of mortality for perinatally HIV-infected infants and children has been well described compared with uninfected infants and children [40], but in the current era of worldwide Option B+ for PMTCT, HEU children are a critical population. Our results show that, overall, HEU children compared with HUU children had a 70% increase in the risk of mortality.

The impact of PMTCT programs over the last 14 years is a major public health success, and it is essential that the expansion of antiretroviral prevention and treatment programs remain a global health priority [3]. However, our results show that HEU children are at higher risk of death at least within the first 2 years of life, compared with HUU children. The precise reason for this difference in mortality is unknown, but is likely multifactorial, and may include unrecognized coinfections (e.g. pneumonia, diarrhea or malaria) in the HEU children, impact of HIV on maternal health status (e.g. high viral load, poor transplacental maternal IgG antibody transfer or other immunological phenomena) during pregnancy, increased risk of preterm and or low birth weight outcomes for HIV-positive women [41,42], poorer maternal health or maternal death postnatally impacting the quality of infant care, or corresponding lower socioeconomic status for children born into households with an HIV-infected mother [43]. Although decreased transplacental antibody transfer from HIV-infected mothers has been demonstrated [44], the fact that the increased risk of mortality for HEU children persists to 2 years postnatally suggests that this cannot be the sole explanation for the mortality difference observed, though it may contribute to a higher mortality risk for exposed uninfected infants in the first 6 months of life. In addition, a number of immunological effects in the children of HIV-infected mothers have been noted, including increased immune activation factors in infants associated with high maternal viral load [45–48]. Few studies describe immunological changes in HIV-exposed infected and HEU children demonstrating HIV-specific immune responses in setting of maternal HIV, though the number of these studies is small [49,50]. It remains to be shown whether HIV-specific immune responses are persistent in HEU infants in this current era of complete maternal viral suppression with combination antiretroviral therapy for PMTCT [38]. In addition, decreased adaptive immunity, in the form of decreased antibody response to standard childhood immunizations, has been found in HEU children, which may account for some differences in mortality [51,52]. The decreased vaccine responses in HEU children is consistent with possible persistent immunological effects that may differentially impact or skew immune responses in the long term for HEU children as result of in-utero HIV exposure [51,52].

No studies have reported on nonbiological risk factors, such as social or environmental conditions, that might contribute to this difference in mortality. One possibility is that HIV-infected mothers may be sicker or more likely to be deceased (along with their male partner), than non-HIV infected mothers and therefore may be less able to provide care. None of the studies reported here provided such data. Such differences in maternal health status could also account for differences in breastfeeding practices between HIV-positive and HIV-negative mothers. As breastfeeding occurs after in-utero HIV exposure it is an effect modifier of the relationship between HIV exposure and all-cause mortality. Previous research has established that breastfeeding is protective against all-cause mortality for all children, and is the recommended feeding modality for all mothers, including those with HIV, in LMICs [51,52]. Breast-feeding can result in mother-to-child transmission of HIV and subsequent HIV-associated mortality, but a shorter duration of breast-feeding (or no breast-feeding at all) by HIV-infected mothers increases mortality from common childhood illnesses [5,6,14,52–57]. However, previous research has shown that when breastfeeding patterns are similar, mortality in HEU infants is still higher than infants born to HIV-uninfected mothers [5,6,14,52].

In resource-rich settings, both monotherapy [58–60] and combination (two or more drugs) [51,61,62] antiretroviral therapy have been used since the mid-1990s to decrease the risk of transmission of the HIV virus from mother to infant (in utero, during labor and delivery, and while breastfeeding) and also improve maternal health status allowing women to live longer to care for their offspring [19]. Antiretroviral therapy in the form of single-dose nevirapine for PMTCT use was introduced in resource-limited settings in 2002 [18] and combination therapy in 2004 [19]. Our results show that HEU compared with HUU children are at higher risk of death before the implementation of single-dose nevirapine for PMTCT in most resource-limited settings since 2002. However, it is important to note that PMTCT scale-up across resource-limited settings (and even within the same country) was not instantaneous, and therefore this cutoff of 2002 is somewhat arbitrary. Even after we moved the cutoff to 2004 to allow time for the slow uptake of PMTCT at the national level and for the shift to the implementation of triple therapy, we saw similar all-cause mortality estimates.

Given that this meta-analysis reflects over a 20-year time span (1994–2015), it is important to note that there has been a substantial overall decrease in global child mortality over the same time period [63]. However, given the overall decrease in childhood mortality observed in the past 20 years, we would then expect to see an overall smaller effect size over time, with the assumption that childhood mortality would similarly decline in both HEU and HUU populations over the same time period.

Our results should be considered alongside their limitations. First, as with any systematic review, there is the possibility of incomplete retrieval or abstraction of data; due to either human error or those studies, primary outcome was not mortality. However, we used the most complete and comprehensive publically available literature in which most major and well conducted studies should be reported. We also used two independent reviewers for cross reference and error checking. Second, we did not obtain raw data from study investigators for pooled estimation of mortality; we used only those studies that reported appropriate simple proportions or included Kaplan–Meier curves in their data presentation. Third, there was also substantial heterogeneity among the studies. Despite this heterogeneity, we felt it was important to pool the existing data to estimate mortality probability as these data provide a more robust estimate than any single study alone. Fourth, given the smaller number of studies in the postantiretroviral therapy PMTCT era, it is not possible for us to know how much of this effect on child mortality is mediated by maternal antiretroviral therapy (and, subsequently, improved maternal or paternal health status). Fifth, the majority of studies included in our analysis were conducted in an era when antiretroviral therapy was not available for pregnant women. As such, our inability to account for differences in maternal health status and maternal mortality between HIV-positive and HIV-negative women could result in an overestimate of our results. Maternal health status, in relation to when HIV exposure in the infant occurs, could confound or modify the association, whereas maternal mortality is an effect modifier as it occurs after HIV exposure in the infant. Sixth, we were unable to account for breastfeeding practices as an effect modifier in our study. With the exception of Shapiro et al.[6], whose entire study population for the analysis was the arm of The Mashi Study randomized to 6 months exclusive breastfeeding, and Rollins et al.[37] who classified breastfeeding according to WHO definitions as exclusive, predominant, partial or never breastfed, no other study clearly defined breastfeeding practices. As such, our results could be overestimating the association between HIV-exposure and all-cause mortality. However, as the previous research has shown [5,6,14,52], even when controlling for breastfeeding HEU infants and children remain at higher risk of mortality compared with their HIV unexposed counterparts.

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Conclusion

We show that there is a consistently observed increased risk of all-cause mortality for HEU infants and children compared with HUU infants and children. The mechanisms for this difference will require carefully conceived prospective cohorts to determine which of the several potential biological or environmental factors is partly or wholly responsible. With the great success of PMTCT, change in breastfeeding practices and HIV-infected adults living longer because of antiretroviral therapy, the population of HEU infants is increasing, highlighting the importance and need to understand the long-term health outcomes in this population. Understanding the causes of increased mortality in HIV-exposed, but uninfected, children will help countries strengthen the capacity to provide quality long-term services for this population. These efforts should ideally be complementary to national and international efforts to improve overall child survival as HEU children are still at risk from major childhood diseases such as pneumonia, diarrhea and malnutrition.

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Acknowledgements

Source of support: Funding was provided by USAID under the terms of the Cooperative Agreement 674-A-00-08-0000-700 to Right to Care and INROADS USAID-674-A-12-00029. This study is made possible by the generous support of the American people through the United States Agency for International Development (USAID). The contents are the responsibility of the authors and do not necessarily reflect the views of USAID, the United States government or the Right to Care Clinics.

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Conflicts of interest

There are no conflicts of interest.

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References

1. Mandelbrot L, Landreau-Mascaro A, Rekacewicz C, Berrebi A, Benifla JL, Burgard M, et al. Agence Nationale de Recherches sur le SIDA (ANRS) 075 Study Group. Lamuvidine-zidovudine combination for prevention of maternal-infant transmission of HIV-1. JAMA 2001; 285:2083–2093.
2. European Collaborative Study. Mother to child transmission of HIV in the era of highly active antiretroviral therapy. Clin Infect Dis 2005; 40:458–465.
3. UNAIDS. Progress report on the global plan. 2014; Available at: http://www.unaids.org/sites/default/files/documents/JC2681_2014-Global-Plan-progress_en.pdf [Accessed 1 April 2016].
4. WHO. Programmatic update: use of antiretroviral drugs for treating pregnant women and preventing HIV infection in infants. 2012; Available at: http://www.who.int/hiv/PMTCT_update.pdf [Accessed 1 April 2016].
5. Marinda E, Humphrey JH, Iliff PJ, Mutasa K, Nathoo KJ, Piwoz EG, et al. ZVITAMBO Study Group. Child mortality according maternal and infant HIV status in Zimbabwe. Pediatric Infec Dis J 2006; 26:519–526.
6. Shapiro RL, Lockman S, Kim S, Smeaton L, Rahkola JT, Thior I, et al. Infant morbidity, mortality, and breast milk immunologic profiles among breast-feeding HIV-infected and uninfected women in Botswana. J Infect Dis 2007; 196:562–569.
7. Mussi-Pinhata MM, Freimanis L, Yamamoto AY, Korelitz J, Pinto JA, Cruz ML, et al. Infectious Disease Mortality among young HIV-1 exposed but uninfected infants in Latin America and Caribbean countries; the National Institute of Child Health and Human Development International Site Development Initiative Perinatal Study. Pediatrics 2007; 119:e694–e704.
8. Thorne C, Newell ML, Dunn D, Peckham C. for the European Collaborative Study. Hospitalization of children born to human immunodeficiency virus-infected women in Europe. Pediatric Infect Dis J 1997; 16:1151–1156.
9. Singh HK, Gupte N, Kinikar A, Bharadwaj R, Sastry J, Suryavanshi N, et al. SWEN India Study Team: high rates of all-cause and gastroenteritis-related hospitalization morbidity and mortality among HIV-exposed Indian infants. BMC Infect Dis 2011; 11:193.
10. Taha TE, Graham SM, Kumwenda NI, Broadhead RL, Hoover DR, Markakis D, et al. Morbidity among human immunodeficiency virus-1 infected and uninfected African children. Pediatrics 2000; 106:e77.
11. Epalza C, Goetghebuer T, Hainaut M, Prayez F, Barlow P, Dediste A, et al. High incidence of Group B Streptococcal infections in HIV-exposed uninfected infants. Pediatrics 2010; 126:e631–e638.
12. McNally LM, Jeena PM, Gajee K, Thula SA, Sturm AW, Cassol S, et al. Effect of age, polymicrobial disease, and maternal HIV status on treatment response and cause of severe pneumonia in South African children: a prospective descriptive study. Lancet 2007; 369:1440–1451.
13. Slogrove A, Reije B, Nadoo S, De Beer C, Ho K, Cotton M, et al. HIV-exposed uninfected infants are at increased risk of severe infections in the first year of life. J Trop Pediatr 2012; 58:505–508.
14. Brahmbhatt H, Kigozi G, Wabwire-Mangen F, Serwadda D, Lutalo T, Nalugoda F, et al. Mortality in HIV-infected and uninfected children of HIV-infected and uninfected mothers in rural Uganda. J Acquir Immune Defic Syndr 2006; 41:504–508.
15. Landes M, van Lettow M, Chan AK, Mayuni I, Chan AK, Tenthani L, et al. Mortality and health outcomes of HIV-exposed and unexposed children in a PMTCT cohort in Malawi. PLoS One 2012; 7:e47338.
16. Kelly MS, Wirth KE, Steenhoff AP, Cunningham CK, Arscott-Mills T, Boidistswe SC, et al. Treatment failures and excess mortality among HIV-exposed, uninfected children with pneumonia. J Ped Infect Dis 2015; 4:e117–e126.
17. Schouten EJ, Jahn A, Midiani D, Makombe SD, Mnthambala A, Chirwa Z, et al. Prevention of mother-to-child transmission of HIV and the health-related Millennium Development Goals: time for a public health approach. Lancet 2011; 378:282–284.
18. Prevention of mother-to-child transmission of HIV: use of Nevirapine among women of unknown serostatus. Report of a technical consultation | 5-6 December 2001, Geneva. Available at: http://www.who.int/hiv/pub/mtct/nevirapine_meeting/en/ [Accessed 1 April 2016].
19. Strategic Approaches to the Prevention of HIV Infection in Infants. Report of a WHO meeting, Morges Switzerland, 20–22 March 2002. Available at: http://www.who.int/hiv/pub/mtct/en/StrategicApproachesE.pdf?ua=1. [Accessed 1 April 2016].
20. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7:177–188.
21. Sterne JA, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ 2011; 343:d4002.
22. Ryder RW, Nsuami M, Nsa W, Kamenga M, Badi N, Utshudi M, et al. Mortality in HIV-1-seropositive women, their spouses and their newly born children during 36 months of follow-up in Kinshasa, Zaïre. AIDS 1994; 8:667–672.
    23. Taha TE, Dallabetta GA, Canner JK, Chiphangwi JD, Liomba G, Hoover DR, et al. The effect of human immunodeficiency virus infection on birthweight, and infant and child mortality in urban Malawi. Int J Epidemiol 1995; 24:1022–1029.
      24. Berhane R, Bagenda D, Marum L, Aceng E, Ndugwa C, Bosch RJ, et al. Growth failure as a prognostic indicator of mortality in pediatric HIV infection. Pediatrics 1997; 100:E7.
      25. Zijenah L, Mbizvo MT, Kasule J, Nathoo K, Munjoma M, Mahomed K, et al. Mortality in the first 2 years among infants born to human immunodeficiency virus-infected women in Harare, Zimbabwe. J Infect Dis 1998; 178:109–113.
        26. Spira R, Lepage P, Msellati P, Van De Perre P, Leroy V, SImonon A, et al. Natural history of human immunodeficiency virus type 1 infection in children: a five-year prospective study in Rwanda. Mother-to-Child HIV-1 Transmission Study Group. Pediatrics 1999; 104:e56.
        27. Jean SS, Pape JW, Verdier RI, Reed GW, Hutto C, Johnson WD Jr, Wright PF. The natural history of human immunodeficiency virus 1 infection in Haitian infants. Pediatr Infect Dis J 1999; 18:58–63.
          28. Taha TE, Kumwenda NI, Broadhead RL, Hoover DR, Graham SM, Van Der Hoven L, et al. Mortality after the first year of life among human immunodeficiency virus type 1-infected and uninfected children. Pediatr Infect Dis J 1999; 18:689–694.
            29. Ota MOC, O’Donovan D, Alabi AS, Milligan P, Yamuah LK, N’Gom PT, et al. Maternal HIV-1 and HIV-2 infection and child survival in The Gambia. AIDS 2000; 14:435–439.
            30. Schim van der Loeff MF, Hansmann A, Awasana AA, Ota MO, O’Donovan D, Arge-Njie R, et al. Survival of HIV-1 and HIV-2 perinatally infected children in The Gambia. AIDS 2003; 17:2389–2394.
            31. Jeena PM, Minkara AK, Corr P, Bassa F, McNally LM, Coovadia HM, et al. Impact of HIV-1 status on the radiological presentation and clinical outcome of children with WHO defined community-acquired severe pneumonia. Arch Dis Child 2007; 92:976–979.[Epub ahead of print].
            32. Luabeya KK, Mpontshane N, Mackay M, Ward H, Elson I, Chhagan M, et al. Zinc or multiple micronutrient supplementation to reduce diarrhea and respiratory disease in South African children: a randomized controlled trial. PLoS One 2007; 2:e541.
            33. Sutcliffe CG, Scott S, Mugala N, Ndhlovu Z, Monze M, Quinn TC, et al. Survival from 9 months of age among HIV-infected and uninfected Zambian children prior to the availability of antiretroviral therapy. Clin Infect Dis 2008; 47:837–844.
            34. Chilongozi D, Wang L, Brown L, Taha T, Valentine M, Emel L, et al. Morbidity and mortality among a cohort of human immunodeficiency virus type 1-infected and uninfected pregnant women and their infants from Malawi, Zambia, and Tanzania. Pediatr Infect Dis J 2008; 27:808–814.
            35. Kurewa EN, Kandawasvika GQ, Mhlanga F, Munjoma M, Mapingure MP, Chandiwana P, et al. Realities and challenges of a five year follow up of mother and child pairs on a PMTCT program in Zimbabwe. Open AIDS J 2011; 5:51–58.
            36. Arinaitwe E, Gasasira A, Verret W, Homsy J, Wanzira H, Kakuru A, et al. The association between malnutrition and the incidence of malaria among young HIV-infected and -uninfected Ugandan children: a prospective study. Malar J 2012; 11:90.
            37. Rollins NC, Ndirangu J, Bland RM, Coutsoudis A, Coovadia HM, Newell ML, et al. Exclusive breastfeeding, diarrhoeal morbidity and all-cause mortality in infants of HIV-infected and HIV uninfected mothers: an intervention cohort study in KwaZulu Natal, South Africa. PLoS One 2013; 8:e81307.
            38. Dimitriades K, Morrow BM, Jeena P. A retrospective study on the effects of colistin therapy in children with multidrug-resistant Gram-negative bacterial pathogens: impact of HIV status on outcome. Arch Dis Child 2014; 99:262–266.
            39. von Mollendorf C, von Gottberg A, Tempia S, Meiring S, de Gouveia L, Quan V, et al. Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa. Increased risk for and mortality from invasive pneumococcal disease in HIV-exposed but uninfected infants aged <1 year in South Africa, 2009–2013. Clin Infect Dis 2015; 60:1346–1356.[Epub ahead of print].
            40. Newell ML, Coovadia H, Cortina-Borja M, Rollins N, Gaillard P, Dabis F. Ghent International AIDS Society (IAS) Working Group on HIV Infection in Women and Children. Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis. Lancet 2004; 364:1236–1243.
            41. Tuomala RE, Shapiro DE, Mofenson LM, Bryson Y, Culnane M, Hughes MD, et al. Antiretroviral therapy during pregnancy and the risk of an adverse outcome. N Engl J Med 2002; 346:1863–1870.
            42. Slyker JA, Patterson J, Ambler G, Richardson BA, Maleche-Obimbo E, Bosire R, et al. Correlates and outcomes of preterm birth, low birth weight, and small for gestational age in HIV-exposed uninfected infants. BMC Pregnancy Childbirth 2014; 14:7.
            43. Afran L, Garcia Knight M, Nduati E, Urban BC, Heyderman RS, Rowland-Jones SL. HIV-exposed uninfected children: a growing population with a vulnerable immune system?. Clin Exp Immunol 2014; 176:11–22.
            44. de Moraes-Pinto MI, Almeida AC, Kenj G, Filgueiras TE, Tobias W, Santos AM, et al. Placental transfer and maternally acquired neonatal IgG immunity in human immunodeficiency virus infection. J Infect Dis 1996; 173:1077–1084.
            45. Brown CC, Poli G, Lubaki N, St Louis M, Davachi F, Musey L, et al. Elevated levels of tumor necrosis factor-alpha in Zairian neonate plasmas: implications for perinatal infection with the human immunodeficiency virus. JID 1994; 169:975–980.
            46. Hygino J, Lima PG, Filho RGS, Silva AA, Saramago CS, Andrade RM, et al. Altered immunological reactivity in HIV-1-exposed uninfected neonates. Clin Immunol 2008; 127:340–347.
            47. Clerici M, Sarasella M, Colombo F, Fossati S, Sala N, Bricalli D, et al. T-lymphocyte maturation abnormalities in uninfected newborns and children with vertical exposure to HIV. Blood 2000; 96:3866–3871.
            48. Legrand FA, Nixon DF, Loo CP, Ono E, Chapman JM, Miyamoto M, et al. Strong HIV-1 specific T cell responses in HIV-1 exposed uninfected infants and neonates revealed after regulatory T cell removal. PLoS One 2006; 1:e102.
            49. Levy JA, Hsueh F, Blackbourn DJ, Wara D, Weintraub PS. CD8 cell noncytotoxic antiviral activity in human immunodeficiency virus-infected and -uninfected children. J Infect Dis 1998; 177:470–472.
            50. Ono E, Nunes dos Santos AM, de Menezes Succi RC, Machado DM, de Angelis DS, Salomao R, et al. Imbalance of naive and memory T lymphocytes with sustained high cellular activation during the first year of life from uninfected children born to HIV-1-infected mothers on HAART. Braz J Med Biol Res 2008; 41:700–708.
            51. Simani OE, Adrian PV, Violari A, Kuwanda L, Otwombe K, Nunes MC, et al. Effect of in-utero HIV exposure and antiretroviral treatment strategies on measles susceptibilities and immunogenicity of measles vaccine. AIDS 2013; 27:1583–1591.
            52. Reikie BA, Naidoo S, Ruck CE, Slogrove AL, de Beer C, la Grange H, et al. Antibody responses to vaccination among South African HIV-exposed and unexposed uninfected infants during the first 2 years of life. Clin Vaccine Immunol 2013; 20:33–38.
            53. WHO. Guidelines on HIV and infant feeding 2010: principles and recommendations for infant feeding in the context of HIV and summary of evidence. 2010; Available at: http://apps.who.int/iris/bitstream/10665/44345/1/9789241599535_eng.pdf [Accessed 1 April 2016].
            54. Kuhn L, Aldrovandi GM, Sinkala M, Kankasa C, Semrau K, Mwiya M, et al. Effects of early, abrupt weaning for HIV-free survival of children in Zambia. N Engl J Med 2008; 359:130–141.
            55. Thior I, Lockman S, Smeaton LM, Shapiro RL, Wester C, Heymann SJ, et al. Breastfeeding plus infant zidovudine prophylaxis for 6 months vs formula feeding plus in-fant zidovudine for 1 month to reduce mother-to-child HIV transmission in Botswana: a randomized trial: the Mashi Study. JAMA 2006; 296:794–805.
            56. Kuhn L, Sinkala M, Semrau K, Kankasa C, Kasonde P, Mwiya M, et al. Elevations in mortality associated with weaning persist into the second year of life among uninfected children born to HIV-infected mothers. Clin Infect Dis 2010; 50:437–444.
            57. Fawzy A, Arpadi S, Kankasa C, Sinkala M, Mwiya M, Thea DM, et al. Early weaning increases diarrhea morbidity and mortality among uninfected children born to HIV-infected mothers in Zambia. J Infect Dis 2011; 203:1222–1230.
            58. Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O'Sullivan MJ, et al. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 1994; 331:1173–1180.
            59. European Collaborative Study. HIV-infected pregnant women and vertical transmission in Europe since 1986. AIDS 2001; 15:761–770.
            60. Dorenbaum A, Cunningham CK, Gelber RD, Culnane M, Mofenson L, Britto P, et al. International PACTG 316 Team. Two-dose intrapartum/newborn nevirapine and standard antiretroviral therapy to reduce perinatal HIV transmission: a randomized trial. JAMA 2002; 288:189–198.
            61. The Petra Study Team. Efficacy of short-course regimens of zidovudine and lamivudine in preventing early and late transmission of HIV-1 from mother-to-child in Tanzania, South Africa and Uganda (Petra study): a randomised double-blind, placebo controlled trial. Lancet 2002; 359:1178–1186.
            62. Ray M, Logan R, Sterne JA, Hernandez-Diaz S, Robins JM, Sabin C, et al. HIV-CAUSAL Collaboration. The effect of combined antiretroviral therapy on the overall mortality of HIV-infected individuals. AIDS 2010; 24:123–137.
            63. Liu L, Oza S, Hogan D, Perin J, Rudan I, Lawn JE, et al. Global, regional, and national causes of child mortality in 2000–2013, with projections to inform post2015 priorities: an updated systematic analysis. Lancet 2015; 385:430–440.
            Keywords:

            HIV-exposed uninfected; HIV-unexposed uninfected; meta-analysis; mortality

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