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Human Immunodeficiency Virus Antiretroviral Resistance and Transmission in Mother-Infant Pairs Enrolled in a Large Perinatal St

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Human Immunodeficiency Virus Antiretroviral Resistance and Transmission in Mother-Infant Pairs Enrolled in a Large Perinatal St Clinical Infectious Diseases MAJOR ARTICLE Human Immunodeficiency Virus Antiretroviral Resistance and Transmission in Mother-Infant Pairs Enrolled in a XX Large Perinatal Study Nava Yeganeh,1 Tara Kerin,1 Bonnie Ank,1 D. Heather Watts,2 Margaret Camarca,3 Esau C. Joao,4 Jose Henrique Pilotto,5,6 Valdilea G. Veloso,7 XXXX Yvonne Bryson,1 Glenda Gray,8 Gerhard Theron,9 Ruth Dickover,1 Mariza G. Morgado,10 Breno Santos,11 Regis Kreitchmann,12 Lynne Mofenson,13 and Karin Nielsen-Saines1 1Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles; 2Office of the Global AIDS Coordinator and Health Diplomacy, US Department of State, Washington D.C.; 3Westat, Rockville, Maryland; 4Hospital Federal dos Servidores do Estado, 5Hospital Geral de Nova Iguaçu, 6Laboratório de AIDS e Imunologia Molecular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (Fiocruz), and 7Laboratório de Pesquisa Clínica em Doenças Sexualmente Transmissíveis e AIDS, Instituto de Pesquisa Clínica Evandro Chagas, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, Brazil; 8Chris Hani Baragwanath Hospital, University of the Witwatersrand, Johannesburg, and 9Department of Obstetrics and Gynecology, Stellenbosch University, Cape Town, South Africa; 10Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, and 11Hospital Conceicao, and 12Hospital Femina, Porto Alegre, Brazil; and 13Elizabeth Glaser Pediatric AIDS Foundation, Washington D.C. Background. The presence of antiretroviral drug-associated resistance mutations (DRMs) may be particularly problematic in human immunodeficiency virus (HIV)–infected pregnant women as it can lead to mother-to-child transmission (MTCT) of resistant HIV strains. This study evaluated the prevalence and the effect of antiretroviral DRMs in previously untreated mother-infant pairs. Methods. A case-control design of 1:4 (1 transmitter to 4 nontransmitters) was utilized to evaluate DRMs as a predictor of HIV MTCT in specimens obtained from mother-infant pairs. ViroSeq HIV-1 genotyping was performed on mother-infant specimens to assess for clinically relevant DRMs. Results. One hundred forty infants acquired HIV infection; of these, 123 mother-infant pairs (88%) had specimens successfully amplified using ViroSeq and assessed for drug resistance genotyping. Additionally, 483 of 560 (86%) women who did not transmit HIV to infants also had samples evaluated for DRMs. Sixty-three of 606 (10%) women had clinically relevant DRMs; 12 (2%) had DRMs against >1 drug class. Among 123 HIV-infected infants, 13 (11%) had clinically relevant DRMs, with 3 (2%) harboring DRMs against >1 drug class. In univariate and multivariate analyses, DRMs in mothers were not associated with increased HIV MTCT (adjusted odds ratio, 0.8 [95% confidence interval, .4–1.5]). Presence of DRMs in transmitting mothers was strongly associated with DRM presence in their infants (P < .001). Conclusions. Preexisting DRMs were common in untreated HIV-infected pregnant women, but did not increase the risk of HIV MTCT. However, if women with DRMs are not virologically suppressed, they may transmit resistant mutations, thus complicating infant management. Keywords. drug resistance mutations; mother-to-child transmission; HIV. STANDARD Eliminating new human immunodeficiency virus (HIV) infec- decrease the efficacy of ARV treatment (ART). DRMs can be tions in infants born to HIV-infected mothers while improv- acquired following receipt of ARV drugs but can also be trans- ing maternal health remains a high priority on the Joint United mitted during primary infection in individuals without prior Nations Programme on HIV/AIDS (UNAIDS) list of achievable ARV exposure. In the case of pregnant women, ARV DRMs goals [1]. HIV elimination depends largely on using combina- can be transmitted to the infant if the woman is not on effect- tions of antiretroviral (ARV) drugs to block HIV replication ive ART that suppresses viral replication [4]. Antiretroviral in HIV-infected individuals, thus serving the dual purpose resistance can thus impair the efficacy of future ART in moth- of improving the infected individuals’ health while prevent- ers and in HIV-infected infants if the presence of DRMs is not ing transmission to others [2, 3]. However, HIV can develop promptly diagnosed and treatment is not appropriately adjusted ARV drug-associated resistance mutations (DRMs), which can [5, 6]. On the other hand, DRM are associated with fitness costs, possibly decreasing the likelihood of mother to child transmis- Received 28 August 2017; editorial decision 9 December 2017; accepted 18 December 2017; sion (MTCT) [7]. The experience with single-dose nevirapine published online December 19, 2017. (NVP) administered to mothers before birth and to infants at Correspondence: N. Yeganeh, David Geffen School of Medicine at UCLA, Department of Pediatrics, Division of Infectious Disease, MDCC 22-442, 10833 Le Conte Ave, Los Angeles, CA birth demonstrated the rapid development of DRMs in both 90095 ([email protected]). mothers and infants because of the long half-life of NVP and Clinical Infectious Diseases® 2018;66(11):1770–7 because a single mutation can result in high-level NVP drug © The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [email protected]. resistance [8]. It has been demonstrated that resistant virus DOI: 10.1093/cid/cix1104 can be transmitted from mother to infant during pregnancy/ 1770 • CID 2018:66 (1 June) • Yeganeh et al Downloaded from https://academic.oup.com/cid/article-abstract/66/11/1770/4762480 by IDSA Member Access user on 21 May 2018 labor or through breast milk [9]. DRMs can remain detectable The time point for infant ART resistance testing varied from for extended periods in an individual’s viral population and birth to 6 months; however, most specimens were obtained from indefinitely in viral reservoirs, rapidly reemerging in the set- study visits after infants had completed receiving study-related ting of reexposure to the specific drug(s) [10]. Viral evolution ARVs (eg, after the 6-week ARV prophylaxis regimen was com- in the setting of DRMs can compromise the treatment of HIV- pleted). The majority of infants were tested for the presence of infected infants and postpartum women [11, 12]. DRMs at the 3-month visit (81%). The study was approved by To evaluate the effect of maternal DRMs on HIV MTCT, we local and collaborating institutional review boards. reviewed the prevalence of DRMs in a subset of treatment-na- ive mother-infant pairs enrolled in the Eunice Kennedy Shriver Genotypic Drug Resistance National Institute of Child Health and Human Development ViroSeq testing (ViroSeq HIV-1 Genotyping System, Celera (NICHD)/HIV Prevention Trials Network (HPTN) 040 (P1043) Diagnostics, Alameda, California) [14] was performed on all perinatal clinical trial [13] (see Appendix). We also evaluated available mother-infant specimens to assess the presence of risk factors potentially associated with DRMs in both mothers clinically relevant DRMs. Plasma was isolated from ethylene- and HIV-infected infants. diaminetetraacetic acid–anticoagulated whole blood within 6 hours of sample collection. Specimens with HIV-1 RNA levels METHODS (viral load) >750 000 copies/mL were analyzed following 1:100 Study Population dilution. Plasma samples were stored frozen at –70°C prior to This was a secondary analysis evaluating the presence of DRMs genotypic analysis. Specimens were analyzed at 3 laboratories in plasma specimens collected from participants who were including the Fiocruz reference laboratory for the 040 study in enrolled and followed between April 2004 through January Brazil, the University of California, Los Angeles, and Clinical 2011 in the NICHD/HPTN 040 (P1043) study at sites in South Laboratory Services in Johannesburg, South Africa. All labo- Africa, Brazil, and Argentina. Subjects in this study had not ratories were Clinical Laboratory Improvement Amendments received ART during current pregnancy prior to labor because certified and certified by the National Institute of Allergy and of late presentation to medical care and/or lack of prenatal Infectious Diseases (NIAID) for the performance of ViroSeq care. Women were enrolled during labor or immediately after assay testing. HIV-1 genotyping was performed using the delivery. The aim of the parent study was to evaluate optimal ViroSeq HIV-1 Genotyping System according to the manu- infant ARV prophylaxis to prevent intrapartum HIV transmis- facturer’s instructions, with the following exception: Where sion. Infants in group A received 6 weeks of zidovudine (ZDV) limited volume was available, <0.5 mL of plasma was used for alone, infants randomized to group B received 6 weeks of ZDV analysis. In this system, HIV-1 RNA is extracted from plasma plus 3 doses of NVP during the first week of life, and infants samples, and one-fifth of the extracted RNA is reverse tran- in group C received 6 weeks of ZDV plus nelfinavir and lami- scribed with murine Moloney virus reverse transcriptase. vudine for the first 2 weeks of life. Infants enrolled in 040 were A 1.8-kb DNA fragment is then amplified in the same tube in a formula fed as breastfeeding was an exclusion criterion [13]. single 40-cycle PCR with AmpliTaq gold polymerase and uracil For this analysis, our primary endpoint was whether DRMs N-deglycosylase decontamination control. PCR products are resulted in an increase in HIV mother-to-child transmission
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