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PERSPECTIVE article

Front. Pediatr., 30 May 2018 | https://doi.org/10.3389/fped.2018.00157

Surviving and Thriving—Shifting the Public Health Response to HIV-Exposed Uninfected Children: Report of the 3rd HIV-Exposed Uninfected Child Workshop

Amy L. Slogrove1, Renaud Becquet2, Ellen G. Chadwick3, Hélène C. F. Côté4, Shaffiq Essajee5, Rohan Hazra6, Valériane Leroy7, Mary Mahy8, Maurine Murenga9, Jacqueline Wambui Mwangi10, Laura Oyiengo11, Nigel Rollins12, Martina Penazzato12, George R. Seage III13, Lena Serghides14,15,16, Marissa Vicari17 and Kathleen M. Powis18,19*
  • 1Department of Paediatrics & Child Health, Stellenbosch University, Cape Town, South Africa
  • 2Bordeaux Population Health Research Center, Institut National de la Santé et de la Recherche Médicale, University of Bordeaux, Bordeaux, France
  • 3Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
  • 4Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada
  • 5Senior Advisor in HIV, UNICEF, New York, NY, United States
  • 6Maternal and Pediatric Infectious Disease Branch, Eunice Kennedy Shriver National Institute of Child Health and Health and Human Development, National Institute of Health, Bethesda, MD, United States
  • 7French Institute of Health and Medical Research, Institut National de la Santé et de la Recherche Médicale, Paris, France
  • 8Strategic Information Department, UNAIDS, Geneva, Switzerland
  • 9Lean on Me Foundation, Nairobi, Kenya
  • 10The National Empowerment Network of People Living with HIV in Kenya, Maragoli, Kenya
  • 11Ministry of Health, Nairobi, Kenya
  • 12HIV Department, World Health Organization, Geneva, Switzerland
  • 13Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States
  • 14Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
  • 15Department of Immunology and Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
  • 16Women's College Research Institute, Toronto, ON, Canada
  • 17Collaborative Initiative for Paediatric HIV Education and Research, International AIDS Society, Geneva, Switzerland
  • 18Departments of Internal Medicine and Pediatrics, Masschusetts General Hospital, Boston, MA, United States
  • 19Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, United States

Great gains were achieved with the introduction of the United Nations' Millennium Development Goals, including improved child survival. Transition to the Sustainable Development Goals (SDGs) focused on surviving, thriving, and transforming, representing an important shift to a broader public health goal, the achievement of which holds the promise of longer-term individual and societal benefits. A similar shift is needed with respect to outcomes for infants born to women living with HIV (WLHIV). Programming to prevent vertical HIV transmission has been successful in increasingly achieving a goal of HIV-free survival for infants born to WLHIV. Unfortunately, HIV-exposed uninfected (HEU) children are not achieving comparable health and developmental outcomes compared with children born to HIV-uninfected women under similar socioeconomic circumstances. The 3rd HEU Child Workshop, held as a satellite session of the International AIDS Society's 9th IAS Conference in Paris in July 2017, provided a venue to discuss HEU child health and development disparities. A summary of the Workshop proceedings follows, providing current scientific findings, emphasizing the gap in systems for long-term monitoring, and highlighting the public health need to establish a strategic plan to better quantify the short and longer-term health and developmental outcomes of HEU children.

Introduction

Scale up of antiretroviral treatment (ART) to pregnant and breastfeeding women living with HIV (WLHIV) has had a remarkable impact on reducing infant acquisition of HIV, yielding a 47% reduction between 2010 to 2016 (1). While this is a welcomed public health success, many observational studies have shown that HIV-exposed uninfected (HEU) children are not achieving equivalent health, developmental, and survival outcomes to that of similarly situated HIV-unexposed uninfected (HUU) children born to HIV-uninfected women (29). With the shift from the focus of the United Nations' Millennium Development Goals on child survival to the Sustainable Development Goals (SDGs) focused on surviving, thriving and transforming (10), the milestone for children born to WLHIV needs to extend beyond merely HIV-free survival to a framework that incorporates HIV-free survival with attainment of optimal health and developmental outcomes.

Following on the first two HEU Child Workshops that explored differences in immune development, infectious morbidity risks, neurodevelopment, and optimizing research methods for HEU research, the 3rd HEU Workshop considered the benefits and risks of maternal ART for the HEU child and how to establish long-term evaluation of these (11). The 3rd Workshop was conducted as a satellite session at the International AIDS Society's 9th IAS Conference on HIV Science held in Paris, France in July 2017, and was sponsored by the World Health Organization, the Collaborative Initiative for Paediatric HIV Education and Research, and the Pediatric HIV/AIDS Cohort Study. Herein, we present a summary of workshop proceedings, concluding with the need for a strategic plan to better quantify the short and longer-term health and developmental outcomes of HEU children through well-designed cohort studies as well as national and global monitoring systems.

Discussion

Provisional 2017 UNAIDS Spectrum estimates of the size of the HEU child population were shared for the first time by Dr. Mary Mahy (UNAIDS). Spectrum estimates indicate that globally in 2016 there were approximately 1.4 million infants born to WLHIV, 1.25 million of whom remained HIV-uninfected and more than 1 million exposed in utero or postnatally to antiretroviral drugs (ARVs). Cumulatively, as of 2016 approximately 18 million children under 15 years of age have been HIV-exposed in utero but are HIV-uninfected, about 50% of whom also have in utero and/or postnatal ARV exposure. While the benefits of treating maternal HIV disease are undeniable, in an HEU child population of this size it is essential to continuously and objectively evaluate the benefits and potential risks of early life exposure to both ARVs and HIV in order to identify the safest ARVs and to elucidate mechanisms for observed disparities for which potential interventions can be introduced.

Quantifying Benefits and Risks to HEU Children of Maternal ART

Dr. Renaud Becquet (Bordeaux University) presented results from a collaborative individual patient meta-analysis with the objective to assess mortality risk in HEU children as well as to estimate the contribution of identified risk factors in mediating poor HEU child outcomes. More than 19,000 HEU children were included in this analysis that pooled data from 21 clinical trials and observational studies in Africa and Asia (12). Seventy five percent of included children were born in sub-Saharan Africa and 70% were born prior to 2005. Mortality occurred early at a median (interquartile range) of 113 (38–244) days with cumulative incidence [95% confidence interval (CI)] for mortality at 6, 12, and 24 months of 3.1% (2.8–3.3), 4.4% (4.1–4.7), and 5.5% (5.1–5.9), respectively. Maternal mortality was most strongly associated with HEU child mortality [adjusted hazard ratio (aHR) 11.1, 95% CI 8.3–15.0]. Low birth weight (aHR 2.87, 95% CI 2.47–3.35) and never breastfeeding (aHR 2.51, 95% CI 1.96–3.20) more than doubled the mortality hazard. HEU children of mothers on maternally-indicated ART had a 49% lower hazard of mortality (aHR 0.51, 95% CI 0.28–0.94) compared to children of mothers receiving no ARVs during pregnancy. Breastfeeding in combination with maternally indicated ART reduced HEU child mortality by 96% (aHR 0.04, 95% CI 0.03–0.07), when compared to children of mothers not on maternally-indicated ART and not breastfeeding. At a population level, maternal mortality accounted for 4.3% (95% CI 2.3–9.2) of HEU child mortality, never initiating breastfeeding 10.8% (95% CI 4.7–17.9), low birth weight 16.2% (13.1–19.2), and mothers not on ART 45.6% (19.1–63.9). In combination, these four factors accounted for 63.6% (95% CI 45.7–76.6) of all HEU child mortality, leaving approximately one third of HEU child mortality still unexplained. This analysis confirms that prior to universal ART, maternally-indicated ART and breastfeeding were of substantial survival benefit to HEU children. New studies are needed to understand, whether in the era of universal ART and safer breastfeeding, HEU child survival will be comparable to HUU children.

Dr. Lena Serghides (Toronto General Hospital Research Institute), shared findings from Canadian and Ugandan cohorts of pregnant WLHIV, as well as laboratory models illustrating hormonal dysregulation associated with ARV use during pregnancy. In Canadian WLHIV, use of protease inhibitor (PI)-based regimens in pregnancy was associated with decreased progesterone and increased estradiol levels (13). In a Ugandan cohort of pregnant WLHIV, those randomized to a PI-based regimen had higher estradiol levels, while those randomized to an efavirenz-based regimen had lower estradiol levels compared to WLHIV not yet initiated on ART (14, 15). This demonstrates that ARV classes differentially influence two key hormones required to maintain a healthy pregnancy. Dr. Serghides presented her team's mouse experiments, demonstrating that decreased progesterone following PI-based ART in pregnancy was associated with lower fetal weight. This adverse effect was partially ameliorated with progesterone supplementation in pregnancy (13). Dr. Serghides shared experiments, using both human placental tissue and her lab's mouse model, elucidating mechanistic pathways responsible for this hormonal dysregulation (16).

Dr. Hélène Côté (University of British Columbia) presented findings from the pan-Canadian “Children and Women: Antiretrovirals and Markers of Aging” (CARMA) cohort and on behalf of the CARMA study team. She started with a focus on autism spectrum disorder (ASD). The Canadian population prevalence of ASD averages 1.5%, yet a Canadian cohort of HEU children was found to have an ASD prevalence of 5.7%. Dr. Côté and colleagues compared plasma mitochondrial DNA (mtDNA) levels between HEU children enrolled in CARMA and matched HUU children. HEU children diagnosed with ASD had the highest mtDNA content, followed by HEU children without ASD, HUU children with ASD, and HUU children without ASD. Higher mtDNA content was significantly associated with both HEU status and ASD status (17). In this analysis, perinatal ARV exposure was not a significant predictor of mtDNA content, although the study was not powered or designed to detect such a difference.

Dr. Côté also shared a CARMA study of neurodevelopmental outcomes, comparing results from HEU and matched (1:3) HUU children born between 1990 and 2012 (18). In multivariable analysis, controlling for time to follow-up, infant sex, and maternal smoking and/or substance use, the odds of an HEU child having one or more neurodevelopmental disorders (including ASD, emotional disturbances, hyperkinetic syndrome, developmental delay, intellectual disability, or epilepsy) was 1.5 (95% CI 1.2–2.5) times greater than an HUU child. Additional adjustment for preterm birth reduced the risk of having one or more neurodevelopment disorders by 20%, highlighting the strong association between preterm birth and neurodevelopmental outcomes, and the additional risk this adverse birth outcome places on HEU children (1922). The work from the CARMA cohort further suggest that HEU children with in utero exposure to triple ARV regimens may have a lower risk of adverse neurodevelopmental outcomes, a trend requiring validation in larger cohorts and in high HIV burden settings.

The benefits of maternal ART undeniably outweigh the potential risks of in utero ARV exposure for HEU children. However, as in the examples presented at the Workshop, laboratory studies and small cohort studies have raised concerns about potential long-term implications of ARV and HIV exposure. These concerns and risks are still not well-defined and will remain so without investment in systems for long-term evaluation of HEU child outcomes.

Establishing Systems for Long-Term Evaluation of HEU Child Outcomes

The Workshop audience heard presentations from Dr. Ellen Chadwick (Northwestern University) providing an overview of the highly-resourced United States (US)-based Surveillance Monitoring of ART Toxicities (SMARTT) cohort study structure and from Dr. Mary Mahy (UNAIDS) on challenges of and opportunities for establishing national and global HEU child monitoring.

The SMARTT cohort includes over 3,000 HEU infants, children, and adolescents in active follow-up, along with their caregivers, from 22 sites in the United States, including Puerto Rico. The novel trigger-based design employed by the SMARTT study provides an efficient way to identify associations between in utero exposures to specific ARV drugs and adverse events, after controlling for social, maternal, and infant characteristics (23). Under the trigger-based design, study-wide adverse events represent signals that “trigger” in depth epidemiologic and clinical investigations in select cases. Event domains monitored in the SMARTT study include growth, metabolic outcomes, mitochondrial function, neurologic outcomes including microcephaly and seizures, neurodevelopmental outcomes, chemistry, hematological and other laboratory adverse events, and hearing impairment. SMARTT visits are conducted throughout infancy, childhood, and adolescence. Dr. Chadwick shared some of the challenges with the SMARTT cohort, issues germane across all settings regardless of resources, including the difficulty in enrolling truly “matched” HUU infant, child and adolescent comparator groups, and the fact that HUU comparator groups need to be sufficiently large to achieve adequate power to detect rare adverse events, an expensive proposition.

While monitoring of the HEU child population is warranted, Dr. Mahy identified national and global challenges to this. Ideally designed monitoring systems measure progress toward targets over time or while implementing interventions expected to change outcomes. Monitoring systems for children living with HIV have matured over time. However, similar systems do not yet exist for HEU children. Some, but not all national programs, have sufficiently robust health systems with child health and/or immunization visit data that could be disaggregated, including by maternal HIV status, maternal ARV use in pregnancy and during breastfeeding, and child HIV exposure and infection status, facilitating monitoring of HEU child outcomes. However, even where health systems could support disaggregation of data to facilitate HEU child health outcome monitoring, longer term monitoring through health information systems is challenging as children get older and are no longer in regular contact with the healthcare system. Additionally, child well-being measures change over time and while it will be essential to compare HEU to HUU child outcomes, this will require integration of HEU child outcome monitoring within the broader child health monitoring systems. In the current era of universal ART, if maternal ART, maternal survival, and breastfeeding represent the major protective factors against HEU child mortality, we would expect to see HEU child mortality declining over the coming years as universal ART and uptake of safer breastfeeding continue to expand in countries experiencing generalized HIV epidemics. Monitoring of HEU child mortality trends at a national level in selected high HIV burden countries can provide evidence of whether maternal ART and safer breastfeeding are sufficient to ameliorate excess mortality risk in HEU children at a population level.

The SMARTT cohort study team has found that some WLHIV are hesitant to disclose their HIV status to their HEU child/adolescent. To address this, the study's caregiver and young adult Community Advisory Board, in collaboration with SMARTT investigators, developed disclosure materials specifically designed for use by caregivers, with separate materials for study staff. These tools assess caregiver readiness for disclosure and provide caregiver support for disclosure. Without disclosure to the HEU adolescent, long-term follow-up of adult health and survival consequences following in utero exposure to HIV and ARVs is precluded, a point of tension that was raised again during the panel discussion. From the individual perspective, WLHIV expressed the critical need to engage with communities in a process of learning together how to track long term HEU child outcomes, using an approach that affords confidentiality, prevents stigma, and ensures children enjoy their childhood. Parents considering disclosure of HEU status to their adolescent children require time to prepare both themselves and their children for the process. The issue of “stigma by association” for HEU children was expressed by panel members, who highlighted the importance of “mainstreaming” any programs to optimize and track HEU child outcomes into health programming for all children.

Conclusion

The scale up of ART to pregnant and breastfeeding women living with HIV is one of the most remarkable public health achievements of the past decade, resulting in substantial reductions globally in infant perinatal and breastfeeding acquisition of HIV. This effort was driven, in part, by the impetus of the Global Plan toward the elimination of new HIV infections among children by 2015 and keeping their mothers alive (24). This program has now evolved into the “Start Free, Stay Free, AIDS Free” framework which promotes acceleration of action to prevent and treat HIV in children and adolescents within a life cycle approach (25). The value of this framework for action, particularly in setting public health goals, is imperative for strategically mapping out health infrastructure focus and investments. Furthermore, the framework implemented in response to the HIV/AIDS epidemic has demonstrated that access to high-quality data permits the establishment of ambitious, measurable, and time-bound targets that have been used to track progress and foster accountability. Yet no framework currently exists to support the rapidly expanding HEU child population. HEU children, having evaded HIV infection, no longer fall clearly within HIV programming and opportunities to support the HEU child population in the broader early childhood development framework are still being explored.

There is clearly a need to achieve consensus and develop a strategic plan for a new set of long-term cohort evaluation systems to identify subtle but possibly significant effects of HIV and ARV exposure on HEU children that individual studies are not able to identify or evaluate confidently. With the current emphasis on SDG number 17.18, calling for enhanced capacity building in developing countries to increase the availability of high-quality, timely, and reliable data disaggregated by characteristics relevant in national contexts, an opportunity exists to upgrade routine monitoring in child health and incorporate HEU children into the existing child health and SDG monitoring agenda in HIV high burden countries.

Author Contributions

AS and KP jointly prepared the initial manuscript with RB, EC, HC, SE, RH, VL, MarM, MauM, JW, LO, NR, MP, GS, LS, and MV all critically reviewing the manuscript and providing important intellectual edits.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We wish to acknowledge the contributions of the CARMA and mother-child pairs who participated in the CARMA study. CARMA co-investigators included: Ariane Alimenti (The University of British Columbia [UBC]), Ari Bitnun (University of Toronto), Jason Brophy (University of Ottawa), Matthew Budd (UBC), Jennifer Bowes (Children Hospital of Eastern Ontario [CHEO]), Kristina Calli (UBC), John C. Forbes (UBC), Carole Gentile (University of Ottawa), Anthony Y. Y. Hsieh (UBC), Patricia Janssen (UBC), Fatima Kakkar (CHU Sainte-Justine and Université de Montréal), M. E. Suzanne Lewis (UBC), Evelyn Maan (Oak Tree Clinic), Micah Piske (UBC), Annie A. Qiu (Oak Tree Clinic), Laura J. Sauve (UBC), Lindy Samson (University of Ottawa), Joel Singer (UBC), Hugo Soudeyns (CHU Sainte-Justine and Université de Montréal). The CARMA studies were funded by the Canadian Institutes of Health Research (CIHR) grants # HET-85515 and TCO-125269.

The meeting was co-sponsored with funding from the Collaborative Initiative for Paediatric HIV Education and Research, the World Health Organization and the Pediatric HIV/AIDS Cohort Study (U01 HD52102, Principal Investigator: GS DSc., MPH).

Abbreviations

aHR, adjusted hazard ratio; ART, antiretroviral treatment; ARV, antiretroviral; ASD, autism spectrum disorder; CARMA, Children and Women: Antiretrovirals and Markers of Aging; CI, confidence interval; HEU, HIV-exposed uninfected; mtDNA, mitochondrial DNA; HUU, HIV-unexposed uninfected; PI, Protease Inhibitor; SDG, Sustainable Developmental Goals; SMARTT, Surveillance Monitoring of ART Toxicities; UBC, University of British Columbia; WLHIV, Women Living with HIV.

References

1. Joint United Nations HIV/AIDS Programme. Ending AIDS Progress Towards the 90-90-90 Targets - Global AIDS Update 2017. Geneva: UNAIDS (2017) Available online at: http://www.unaids.org/sites/default/files/media_asset/Global_AIDS_update_2017_en.pdf

2. le Roux SM, Abrams EJ, Nguyen K, Myer L. Clinical outcomes of HIV-exposed, HIV-uninfected children in sub-Saharan Africa. Trop Med Int Health (2016) 21:829–45. doi: 10.1111/tmi.12716

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Evans C, Humphrey JH, Ntozini R, Prendergast AJ. HIV-Exposed uninfected infants in zimbabwe: insights into health outcomes in the pre-antiretroviral therapy era. Front Immunol. (2016) 7:190. doi: 10.3389/fimmu.2016.00190

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Brennan AT, Bonawitz R, Gill CJ, Thea DM, Kleinman M, Useem J, et al. A meta-analysis assessing all-cause mortality in HIV-exposed uninfected compared with HIV-unexposed uninfected infants and children. AIDS (2016) 30:2351–60. doi: 10.1097/QAD.0000000000001211

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Powis KM, Smeaton L, Ogwu A, Lockman S, Dryden-Peterson S, van Widenfelt E, et al. Effects of in utero antiretroviral exposure on longitudinal growth of HIV-exposed uninfected infants in Botswana. J Acquir Immune Defic Syndr. (2011)56:131–8. doi: 10.1097/QAI.0b013e3181ffa4f5

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Hofer CB, Keiser O, Zwahlen M, Lustosa CS, Frota AC, de Oliveira RH, et al. In utero exposure to antiretroviral drugs: effect on birth weight and growth among HIV-exposed uninfected children in Brazil. Pediatr Infect Dis J. (2016)35:71–7. doi: 10.1097/INF.0000000000000926

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Slogrove AL, Goetghebuer T, Cotton MF, Singer J, Bettinger JA. Pattern of infectious morbidity in HIV-exposed uninfected infants and children. Front Immunol. (2016) 7:164. doi: 10.3389/fimmu.2016.00164

PubMed Abstract | CrossRef Full Text | Google Scholar

8. 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. doi: 10.1111/cei.12251

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Ezeamama AE, Kizza FN, Zalwango SK, Nkwata AK, Zhang M, Rivera ML, et al. Perinatal HIV status and executive function during school-age and adolescence: a comparative study of long-term cognitive capacity among children from a high HIV prevalence setting. Medicine (2016) 95:e3438. doi: 10.1097/MD.0000000000003438

PubMed Abstract | CrossRef Full Text | Google Scholar

10. United Nations Development Programme. From the MDGs to Sustainable Development for All - Lessons from 15 Years of Practice. (2016). Available online at http://www.undp.org/content/undp/en/home/librarypage/sustainable-development-goals/from-mdgs-to-sustainable-development-for-all.html

11. Slogrove AL, Archary M, Cotton MF. Optimizing research methods to understand HIV-exposed uninfected infant and child morbidity: report of the second HEU infant and child workshop. Front Immunol. (2016) 7:576. doi: 10.3389/fimmu.2016.00576

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Arikawa S, Rollins N, Jourdain G, Humphrey J, Kourtis AP, Hoffman I, et al. Contribution of maternal ART and breastfeeding to 24-month survival in HIV-exposed uninfected children: an individual pooled analysis of African and Asian studies. Clin Infect Dis. (2017). 66:1668–77. doi: 10.1093/cid/cix1102

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Papp E, Mohammadi H, Loutfy MR, Yudin MH, Murphy KE, Walmsley SL, et al. HIV protease inhibitor use during pregnancy is associated with decreased progesterone levels, suggesting a potential mechanism contributing to fetal growth restriction. J Infect Dis. (2015) 211:10–8. doi: 10.1093/infdis/jiu393

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Balogun KA, Guzman Lenis MS, Papp E, Loutfy M, Yudin MH, MacGillivray J, et al. Elevated levels of estradiol in human immunodeficiency virus-infected pregnant women on protease inhibitor-based regimens. Clin Infect Dis. (2018) 66:420–7. doi: 10.1093/cid/cix761

PubMed Abstract | CrossRef Full Text | Google Scholar

15. McDonald CR, Conroy AL, Gamble JL, Papp E, Hawkes M, Olwoch P, et al. Estradiol Levels are altered in human immunodeficiency virus-infected pregnant women randomized to efavirenz-versus lopinavir/ritonavir-based antiretroviral therapy. Clin Infect Dis. (2018) 66:428–36. doi: 10.1093/cid/cix772

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Papp E, Balogun K, Banko N, Mohammadi H, Loutfy M, Yudin MH, et al. Low prolactin and high 20-alpha-hydroxysteroid dehydrogenase levels contribute to lower progesterone levels in HIV-infected pregnant women exposed to protease inhibitor-based combination antiretroviral therapy. J Infect Dis. (2016) 213:1532–40. doi: 10.1093/infdis/jiw004

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Budd M, Sampson L, Bowes J, Calli K, Lewis M, Cote H, et al. Elevated mitochondria DNA content in HIV-exposed uninfected children with autism. In Conference on Opportunistic Infections and Retroviruses. Boston, MA (2016).

Google Scholar

18. Piske M, Budd MA, Qiu AQ, Maan EJ, Sauve LJ, Alimenti A, et al. Long-term developmental outcomes and in utero antiretroviral exposure to HIV-exposed uninfected (HEU) children born to mothers living with HIV in British Columbia (BC), Canada. In International AIDS Society Conference on HIV Science (Paris) (2017).

19. Luu TM, Rehman Mian MO, Nuyt AM. Long-term impact of preterm birth: neurodevelopmental and physical health outcomes. Clin Perinatol. (2017)44:305–14. doi: 10.1016/j.clp.2017.01.003

PubMed Abstract | CrossRef Full Text | Google Scholar

20. Sucksdorff M, Lehtonen L, Chudal R, Suominen A, Joelsson P, Gissler M, et al. Preterm birth and poor fetal growth as risk factors of attention-deficit/ hyperactivity disorder. Pediatrics (2015)136:e599–608. doi: 10.1542/peds.2015-1043

PubMed Abstract | CrossRef Full Text | Google Scholar

21. Arpino C, Compagnone E, Montanaro ML, Cacciatore D, De Luca A, Cerulli A, et al. Preterm birth and neurodevelopmental outcome: a review. Childs Nerv Syst. (2010) 26:1139–49. doi: 10.1007/s00381-010-1125-y

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Dong Y, Yu JL. An overview of morbidity, mortality and long-term outcome of late preterm birth. World J Pediatr. (2011) 7:199–204. doi: 10.1007/s12519-011-0290-8

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Williams PL, Seage GRIII, Van Dyke RB, Siberry GK, Griner R, Tassiopoulos K, et al. A trigger-based design for evaluating the safety of in utero antiretroviral exposure in uninfected children of human immunodeficiency virus-infected mothers. Am J Epidemiol. (2012) 175:950–61. doi: 10.1093/aje/kwr401

PubMed Abstract | CrossRef Full Text | Google Scholar

24. Joint United Nations HIV/AIDS Programme Global Plan Towards the Elimination of New HIV Infections among Children by 2015 Keeping Their Mothers Alive. Geneva: UNAIDS, (2011). Available online at: http://www.unaids.org/sites/default/files/media_asset/20110609_JC2137_Global-Plan-Elimination-HIV-Children_en_1.pdf

25. Joint United Nations HIV/AIDS Programme. Start Free, Stay Free, AIDS Free. Geneva: UNAIDS (2015) Available online at: http://www.unaids.org/sites/default/files/media_asset/Stay_free_vision_mission_En.pdf

Keywords: HIV-exposed uninfected, HEALTH OUTCOMES RESEARCH, developmental outcomes, survival, health monitoring

Citation: Slogrove AL, Becquet R, Chadwick EG, Côté HCF, Essajee S, Hazra R, Leroy V, Mahy M, Murenga M, Wambui Mwangi J, Oyiengo L, Rollins N, Penazzato M, Seage GR III, Serghides L, Vicari M and Powis KM (2018) Surviving and Thriving—Shifting the Public Health Response to HIV-Exposed Uninfected Children: Report of the 3rd HIV-Exposed Uninfected Child Workshop. Front. Pediatr. 6:157. doi: 10.3389/fped.2018.00157

Received: 04 April 2018; Accepted: 10 May 2018;
Published: 30 May 2018.

Edited by:

Frederick Robert Carrick, Bedfordshire Centre for Mental Health Research in Association with the University of Cambridge (BCMHR-CU), United Kingdom

Reviewed by:

Lucy Thairu, Stanford University, United States
Chris Fradkin, Pontifical Catholic University of Rio de Janeiro, Brazil

Copyright © 2018 Slogrove, Becquet, Chadwick, Côté, Essajee, Hazra, Leroy, Mahy, Murenga, Wambui Mwangi, Oyiengo, Rollins, Penazzato, Seage, Serghides, Vicari and Powis. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Kathleen M. Powis, kpowis@mgh.harvard.edu