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The discovery that antiretroviral interventions can prevent mother-to-child human immunodeficiency virus (HIV) transmission during pregnancy, delivery, and more recently, during breastfeeding, and implementation of these interventions in low-resource as well as highresource countries, has been one of the great success stories of the HIV epidemic. Increased global availability of combination antiretroviral therapy (ART) for HIV-infected individuals in general, and for pregnant women specifically, has dramatically decreased the number of newly infected infants from an estimated 570 000 in 1999 to 240 000 in 2013; 40% of this decline occurred between 2009 and 2013, greater than observed in the entire prior decade [1]. Progress was spurred by the 2011 United Nations Joint Programme for HIV/AIDS Global Plan for the Elimination of New HIV Infection Among Children by 2015 and Keeping Their Mothers Alive and infusion of the US President’s Emergency Plan for AIDS Relief funding to increase treatment availability in low-resource settings, including lifelong therapy for pregnant women living with HIV [2, 3]. Although the goal of a 90% decrease in new pediatric infections may not be met by the end of 2015, it is clearly within reach, with nearly 70% of the estimated 1.5 million pregnant women living with HIV in 2013 receiving antiretroviral drugs [1, 4]. One consequence of this dramatic success is that millions of infants who are now uninfected will have in utero and in some cases up to 2 years of breastfeeding exposure to both HIV and multiple antiretroviral drugs for which there are limited data on long-term safety. Thus, any health problems that might be associated with HIV and/or antiretroviral exposure in this large number of uninfected children could have important public health significance. However, there have been limited studies to date to evaluate the long-term effects of such exposures on HIV-exposed but uninfected (HEU) children, particularly in low-resource settings, where nutritional deficiencies and endemic coinfections are common and could exacerbate any potential adverse effects of HIV/antiretroviral drug exposure [5, 6]. In this issue of Clinical Infectious Diseases, von Mollendorf and colleagues report a significantly increased risk of invasive pneumococcal disease (IPD) and mortality among HEU children compared with HIV-unexposed young infants in South Africa [7]. A number of studies have suggested that HEU infants have an increased risk of morbidity and mortality, primarily from infectious causes, compared with children born to HIV-uninfected mothers [8–14]. Whereas the majority of studies are from the pre-ART era and lowresource settings, similar reports have been published in the ART era from higher-resource settings in Latin America and Europe [15–17]. The reasons for this increased risk are likely multifactorial. In addition to adverse social and economic factors associated with being born into an HIV-affected household, increased exposure to infectious pathogens from their HIV-infected mother or other family members, and shortened duration of breastfeeding, some data suggest that in utero exposure to HIV itself can affect the immune response in the fetus, with lasting effects into childhood [18, 19]. Increased risk of morbidity and mortality in HEU children has been associated with advanced maternal HIV disease during pregnancy, including low maternal CD4 cell count and viremia [12, 17, 20, 21]. Received 14 January 2015; accepted 14 January 2015; electronically published 2 February 2015. Correspondence: Lynne M. Mofenson, MD, Elizabeth Glaser Pediatric AIDS Foundation, 1140 Connecticut Ave NW, Ste 200, Washington, DC 20036 (lmofenson@pedaids.org). Clinical Infectious Diseases 2015;60(9):1357–60 © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/cid/civ064

New Challenges in the Elimination of Pediatric HIV Infection: The Expanding Population of HIV-Affected but Uninfected Children