Downloaded from http://journals.lww.com/pidj by BhDMf5ePHKbH4TTImqenVGLGjjqParD6lgaO40YDhMlmZmz/zFIYswf20GATnb2JvuFPr2JfyEk= on 02/24/2019 Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. The Pediatric Infectious Disease Journal • Volume 38, Number 1, January 2019 www.pidj.com | 65 Background: Recent studies report delayed anti-HIV antibody clearance (seroreversion) among HIV-exposed uninfected infants that may affect diagnostic practices. We evaluated the age-specific seroreversion rates in Thailand. Methods: The medical records of HIV-exposed uninfected infants born in January 2000–December 2014 were reviewed. Anti-HIV seroreversion rates at 12, 18 and 24 months were analyzed in 3 periods according to the Thai National Guidelines of prevention of mother-to-child transmission of HIV: zidovudine with or without single dose nevirapine to all women (2000–2006), adding lamivudine plus nevirapine to zidovudine in women with CD4 count <200 cells/mm 3 (2007–2009) and zidovudine plus lamivu- dine plus boosted lopinavir to all women (2010–2014). In 2013, the sero- logic test kit was changed from third- to fourth-generation (4G) assay. All the infants were formula fed. Results: Among 736 infants, the overall seroreversion rates at 12, 18 and 24 months of age were 59.38%, 94.57% and 100%, respectively. The seror- eversion rates at 12 months of age declined from 68% in 2000–2006 and 65.9% in 2007–2009, to 42.9% in 2010–2014 (P = 0.001). Seroreversion rates at 18 months of age were more than 96.5% before 2013 and decreased to 79.1% in 2013–2014 (P = 0.001) with use of 4G. Multivariate analysis identified antepartum protease inhibitors treatment and the use of 4G testing as independent factors associated with delayed seroreversion. Conclusions: Anti-HIV seroreversion delay in HIV-exposed uninfected infants was associated with use of protease inhibitors and 4G HIV testing, complicating the interpretation to exclude perinatal HIV infection. Key Words: seroreversion, HIV antibody, HIV-exposed uninfected infant, diagnosis, prevention of mother-to-child transmission, Thailand (Pediatr Infect Dis J 2019;38:65–69) T he diagnosis of HIV infection using anti-HIV serology in infants less than 18 months of age is complicated by trans- placental transfer of maternal antibodies. Virologic assays using nucleic acid testing (NAT) have been recommended for early diag- nosis and treatment, as well as for monitoring the prevention of mother-to-child transmission program. However, NAT is less com- monly available than HIV serology especially in resource limited setting. 1,2 Anti-HIV serology in infants has been used limited to confirmation of HIV exposure and to exclude HIV infection in older infants with perinatal exposure. The World Health Organiza- tion recommends HIV serologic testing, using rapid diagnostic test (RDT), at around 9 months of age (or during the last immuniza- tion visit) for HIV-exposed infants who are otherwise healthy. 3 If the test is negative, and the infant had not been breast-fed for at least 3 months, they are considered uninfected. A positive serology requires NAT to inform decisions regarding antiretroviral therapy. Using HIV serology in older infants to screen for HIV infection can reduce the need for NAT. Maternal passive immunoglobulin G (IgG) levels gradu- ally decline with increasing age of the infant, eventually resulting in seroreversion of anti-HIV antibody in exposed but uninfected infants. Before the year 2000, studies in the United States and Europe revealed the median age at clearance of maternal anti-HIV antibody as measured by enzyme-linked immunosorbent assay (ELISA) serologic assay of 9.4–10.9 months. 4–6 Less than 2% of uninfected children were found to have a positive anti-HIV serol- ogy at 18 months. 4 A study in 1995 in HIV-exposed uninfected South African infants reported a seroreversion rate of 95% by 12 months of age. 7 More recent studies have reported an increased age at seroreversion. A study in Vietnam in 2009 reported the median age at seroreversion of 18.8 months and a seroreversion rate of only 22% at 12 months. 8 Likewise, a US study during 2000–2007 reported a seroreversion rate of only 25% at 12 months. 9 A study in Malawi found delayed seroreversion in infants born after the year 1999 compared with those born before 1997. 10 The reasons for these findings are unclear. Prior studies found various cofactors related to seroreversion such as type of antibody test kit, maternal HIV IgG concentrations, severity of maternal HIV status, protease inhibitors (PIs)–based antiretroviral drug regimen during preg- nancy, nutritional status of infants and clearance rate of HIV IgG of infants. 8,9,11–14 It is not known whether this trend of increasing age at seroreversion occurs in different settings, populations and type of test. Delayed seroreversion can influence the diagnostic approach. The utility of earlier HIV serology is reduced if the likelihood of seroreversion is low, and positive tests may increase parental anxi- ety. In our setting with exclusive infant formula feeding, serology has been recommended in all HIV-exposed infants at 12–18 months of age to exclude infection before discharge from the HIV clinic. Any trend towards delayed seroreversion could impact the timing of diagnostic testing. Therefore, we aimed to evaluate the proportion of seroreversion of anti-HIV antibody in HIV-exposed but unin- fected infants at 12, 18 and 24 months and to determine factors associated with seroreversion at 12 months of age. MATERIALS AND METHODS This retrospective study was conducted at the pediatric HIV clinic of Siriraj hospital, a large tertiary public hospital in Bang- kok. HIV-exposed uninfected infants who were born during Janu- ary 2000 to December 2014 were included. The HIV status was based on US-Centers for Disease Control and Prevention recom- mendations for nonbreastfed infants who required 2 or more nega- tive virologic tests; at age ≥1 month and at age ≥4 months. 1 The child must not have other laboratory or clinical evidence of HIV infection. Breastfeeding is contraindicated for HIV-exposed infants Accepted for publication August 23, 2018. From the Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahi- dol University, Bangkok, Thailand. The authors have no funding or conflicts of interest to disclose. Address for correspondence: Kulkanya Chokephaibulkit, MD, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok 10700, Thailand. E-mail: kulkanya. cho@mahidol.ac.th. 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 (www.pidj.com). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. HIV REPORTS ISSN: 0891-3668/19/3801-0065 DOI: 10.1097/INF.0000000000002196 Delayed Seroreversion in HIV-exposed Uninfected Infants Sunsanee Chatpornvorarux, MD, Alan Maleesatharn, MBA, Supattra Rungmaitree, MD, Orasri Wittawatmongkol, MD, Wanatpreeya Phongsamart, MD, Keswadee Lapphra, MD, Nantaka Kongstan, BN.Msc, Benjawan Khumcha, BA, and Kulkanya Chokephaibulkit, MD