title: Drug resistance and coreceptor usage in HIV type 1 subtype C-infected children initiating or failing highly active antiretroviral therapy in South Africa.
abstract: HIV-1 drug resistance monitoring in resource-poor settings is crucial due to limited drug alternatives. Recent reports of the increased prevalence of CXCR4 usage in subtype C infections may have implications for CCR5 antagonists in therapy. We investigated the prevalence of drug resistance mutations and CXCR4 coreceptor utilization of viruses from HIV-1 subtype C-infected children. Fifty-one children with virological failure during highly active antiretroviral therapy (HAART) and 43 HAART-naive children were recruited. Drug resistance genotyping and coreceptor utilization assessment by phenotypic and genotypic methods were performed. At least one significant drug resistance mutation was present in 85.4% of HAART-failing children. Thymidine analogue mutations (TAMs) were detected in 58.5% of HAART-failing children and 39.0% had ≥3 TAMs. CXCR4 (X4) or dual (R5X4)/mixed (R5, X4) (D/M)-tropic viruses were found in 54.3% of HAART-failing and 9.4% of HAART-naive children (p<0.0001); however, the HAART-failing children were significantly older (p<0.0001). In multivariate logistic regression, significant predictors of CXCR4 usage included antiretroviral treatment, older age, and lower percent CD4(+) T cell counts. The majority of genotypic prediction tools had low sensitivity (≤65.0%) and high specificity (≥87.5%) for predicting CXCR4 usage. Extensive drug resistance, including the high percentage of TAMs found, may compromise future drug choices for children, highlighting the need for improved treatment monitoring and adherence counseling. Additionally, the increased prevalence of X4/D/M viruses in HAART-failing children suggests limited use of CCR5 antagonists in salvage therapy. Enhanced genotypic prediction tools are needed as current tools are not sensitive enough for predicting CXCR4 usage.
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Taryn N
authors.initials: TN
authors.lastname: Green
authors.forename: Mohendran
authors.initials: M
authors.lastname: Archary
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Gordon
authors.forename: Nagavelli
authors.initials: N
authors.lastname: Padayachi
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Lie
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Anton
authors.forename: Jacqueline D
authors.initials: JD
authors.lastname: Reeves
authors.forename: Anneke
authors.initials: A
authors.lastname: Grobler
authors.forename: Raziya
authors.initials: R
authors.lastname: Bobat
authors.forename: Hoosen
authors.initials: H
authors.lastname: Coovadia
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
mesh_terms: D019380:Anti-HIV Agents / Q000008:administration & dosage*; D023241:Antiretroviral Therapy, Highly Active; D065100:CCR5 Receptor Antagonists; D018791:CD4 Lymphocyte Count; D002648:Child; D002675:Child, Preschool; D003510:Cyclohexanes / Q000008:administration & dosage*; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D006679:HIV Seropositivity / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D016015:Logistic Models; D008297:Male; D000077592:Maraviroc; D015999:Multivariate Analysis; D010802:Phylogeny; D011237:Predictive Value of Tests; D019718:Receptors, CXCR4 / Q000302:isolation & purification; D015728:Receptors, HIV / Q000187:drug effects*; D012680:Sensitivity and Specificity; D013019:South Africa / Q000453:epidemiology; D017211:Treatment Failure; D014230:Triazoles / Q000008:administration & dosage*; D016903:Drug Monitoring
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D019718:Receptors, CXCR4; D015728:Receptors, HIV; D014230:Triazoles; D000077592:Maraviroc