ORIGINAL STUDIES Drug Resistance in Human Immunodeficiency Virus Type-1 Infected Zambian Children Using Adult Fixed Dose Combination Stavudine, Lamivudine, and Nevirapine Ravindra K. Gupta, MA, MPH, MRCP,* Deborah Ford, PhD,† Veronica Mulenga, MSc, MB BS,‡ A. Sarah Walker, PhD,† Desire Kabamba, PhD,‡ Moxmalama Kalumbi, MSc,‡ Paul R. Grant, PhD,§ Alexander Ferrier, MSc,† Deenan Pillay, MB BS, MRCPath, PhD,*¶ Diana M. Gibb, MRCP, MD, MSc, Dip Obs, FRCPCH,† and Chifumbe Chintu, MD, FRCPC, FRCP‡ Background: There are few medium-term virologic data in children from resource-limited settings taking adult fixed-dose-combination antiretroviral therapy (cART) without viral load monitoring. Methods: CHAP2 (Children with HIV Antibiotic Prophylaxis 2) is a prospective cohort of Zambian children using d4T/3TC/NVP adult Trio- mune30 dosed according to WHO guidelines. Results: A total of 103 children (19 with previous antiretroviral therapy) had follow-up 6 months. Median age at cART initiation was 8 years (IQR, 6 –12) and CD4 8% (4 –12). At 24 months, CD4% had increased by a median of 15% (7–25). For 74 children viral load was known/inferred: 51 of 74 (69%) had viral load 50 copies/mL (45 of 63 71% with no previous cART, 6 of 11 55% with previous cART; difference P = 0.30); 22 of 74 (30%) had viral load 1000 copies/mL. Of 26 children with resistance data, 25 (96%) had NNRTI resistance; 22 (84%) had M184V; 2 (8%) had Q151M; and 1 (4%) each had K65R, L74V, or K70E. Eight (31%) had 1 TAM. Those failing virologically with a genotypic sensi- tivity score of 0 for first-line therapy had a somewhat smaller increase in CD4% from baseline compared with those failing therapy with a genotypic sensitivity score 0(+3 vs. +8, P = 0.13), and had somewhat lower CD4% at initiation of cART (2 vs. 11, P = 0.09). In 6 children with 1 resistance test, the estimated rate of accumulation of TAMs was 0.59/yr (95% confidence interval: 0.22–1.29). Conclusions: Twenty-four month virologic responses to cART were good. However, the rate of TAM accumulation in those with rebound was higher than reported in Western adult cohorts, and there was some indication of a detrimental effect of high level resistance on CD4% change from baseline. Key Words: HIV, resistance, children, pediatrics, HAART, antiretroviral (Pediatr Infect Dis J 2010;29: e57– e62) C ombination antiretroviral therapy (cART) deployment is pro- gressing worldwide, with most settings using WHO clinical and/or CD4 criteria to determine first-line treatment failure in the absence of viral load monitoring. 1 Concerns have been raised regarding development of resistance in such settings, with 88% and 81% of virologically failing adults reported to have major non-nucleoside reverse transcription (NNRTI) mutations and lami- vudine resistance, respectively, after 1 year of therapy. 2 Further- more, extensive NRTI resistance has been documented in substan- tial proportions of adults receiving NNRTI-based regimens up to 3 years after initiation of HAART (highly active antiretroviral ther- apy). 3 However, longer term resistance data from resource-limited settings, in particular for children remains scarce. Triomune (stavudine, lamivudine, and nevirapine) is the most widely used Fixed Dose Combination (FDC) first line cART in sub-Saharan Africa. Until recently, this was only available in adult formulation, with children dosed with quartered multiples of whole tablets. Use of adult Triomune has been associated with sub therapeutic nevirapine and lamivudine concentrations in younger children 4,5 and it is recognized that this group requires higher doses of nevirapine than adults as a consequence of more rapid metabolism. However, adult tablets are still being used in the majority of high prevalence countries (particularly for older children) where this is included as part of WHO guidelines. There is concern that sub therapeutic concentrations of nevirapine in younger children 15 kg may predispose to greater risk of viral rebound and drug resistance, especially given that younger children have higher viral loads com- pared with older children and adults. 6,7 We therefore sought to evaluate resistance in the Children with HIV Antibiotic Prophylaxis (CHAP2) cohort in Africa where adult nevirapine-containing FDCs are being used. The children and adolescents in this cohort were part of a previous study on nevirapine pharmacokinetics in children using adult Triomune, showing that nevirapine levels were adequate in the majority. 4 MATERIALS AND METHODS Study Population CHAP2 is a prospective cohort of HIV-infected Zambian children, who consented to be enrolled in a follow-up study following participation in a randomized controlled trial of cotri- moxazole prophylaxis before the introduction of cART. 8 Children eligible for cART according to WHO criteria were initiated on stavudine, lamivudine, and nevirapine FDC cART (adult Trio- mune30 whole or half tablets); all also received cotrimoxazole prophylaxis. Children were seen by a nurse and a doctor every 12 weeks, when they had a clinical examination including height and weight measurements. Routine biochemistry, full blood counts, and CD4 count were performed 6 monthly, and plasma was also stored for the purpose of retrospective testing. HIV-1 viral load Accepted for publication April 19, 2010. From the *Division of Infection and Immunity, University College London Medical School, London, United Kingdom; †Medical Research Council Clin- ical Trials Unit, London, United Kingdom; ‡Department of Paediatrics and Child Health, University Teaching Hospital, Lusaka, Zambia; §HIV Group, University College Hospital, London, United Kingdom; and ¶Department of Virology, Health Protection Agency, London, United Kingdom. Supported by the Wellcome Trust, fellowship number WT081772MA (to R.K.G.) and partly supported by the Cipla Foundation. Presented at (in part) the International AIDS Society (IAS) Conference; Cape Town, South Africa; July 19 –22, 2009. Address for correspondence: Ravindra K. Gupta, MA, MPH, MRCP, University College London Medical School, Windeyer Institute, London, United King- dom. E-mail: rebmrag@ucl.ac.uk. Copyright © 2010 by Lippincott Williams & Wilkins ISSN: 0891-3668/10/2908-0057 DOI: 10.1097/INF.0b013e3181e47609 The Pediatric Infectious Disease Journal • Volume 29, Number 8, August 2010 www.pidj.com | e57