Rami Kantor1, Laura Smeaton2, Saran Vardhanabhuti2, Sarah E Hudelson3, Carol L Wallis4, Srikanth Tripathy5, Mariza G Morgado6, Shanmugham Saravanan7, Pachamuthu Balakrishnan7, Marissa Reitsma1, Stephen Hart8, John W Mellors9, Elias Halvas9, Beatriz Grinsztejn10, Mina C Hosseinipour11, Johnstone Kumwenda12, Alberto La Rosa13, Umesh G Lalloo14, Javier R Lama13, Mohammed Rassool15, Breno R Santos16, Khuanchai Supparatpinyo17, James Hakim18, Timothy Flanigan1, Nagalingeswaran Kumarasamy6, Thomas B Campbell19, Susan H Eshleman3. 1. Division of Infectious Diseases, Department of Medicine, Brown University, Providence, Rhode Island. 2. Center for Biostatistics in AIDS Research, Harvard School of Public Health, Harvard University, Boston, Massachusetts. 3. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. 4. Lancet Laboratories, Johannesburg, South Africa. 5. National AIDS Research Institute, Pune, India. 6. Laboratory of AIDS and Molecular Immunology, Oswaldo Cruz Institute, Rio de Janeiro, Brazil. 7. YRG-CARE, Chennai, India. 8. Frontier Science and Technology Research Foundation, Amherst, New York. 9. Division of Infectious Diseases, Department of Medicine, University of Pittsburgh, Pennsylvania. 10. Instituto de Pesquisa Clinica Evandro Chagas-Fiocruz, Rio de Janeiro, Brazil. 11. University of North Carolina Project-Malawi, Lilongwe. 12. Department of Internal Medicine, University of Malawi, College of Medicine, Blantyre. 13. Asociacion Civil Impacta Salud y Educacion, Barranco, Lima, Peru. 14. Enhancing Care Foundation, Durban, South Africa. 15. Department of Medicine, University of Witwatersrand; Helen Joseph Hospital, Themba Lethu Clinic, Johannesburg, South Africa. 16. Serviço de Infectologia, Hospital Nossa Senhora da Conceição, Porto Alegre, Brazil. 17. Research Institute for Health Sciences and Faculty of Medicine, Chiang Mai University, Thailand. 18. Department of Medicine, University of Zimbabwe, Harare. 19. Division of Infectious Diseases, Department of Medicine, University of Colorado Denver, Aurora.
Abstract
BACKGROUND: Evaluation of pretreatment HIV genotyping is needed globally to guide treatment programs. We examined the association of pretreatment (baseline) drug resistance and subtype with virologic failure in a multinational, randomized clinical trial that evaluated 3 antiretroviral treatment (ART) regimens and included resource-limited setting sites. METHODS: Pol genotyping was performed in a nested case-cohort study including 270 randomly sampled participants (subcohort), and 218 additional participants failing ART (case group). Failure was defined as confirmed viral load (VL) >1000 copies/mL. Cox proportional hazards models estimated resistance-failure association. RESULTS: In the representative subcohort (261/270 participants with genotypes; 44% women; median age, 35 years; median CD4 cell count, 151 cells/µL; median VL, 5.0 log10 copies/mL; 58% non-B subtypes), baseline resistance occurred in 4.2%, evenly distributed among treatment arms and subtypes. In the subcohort and case groups combined (466/488 participants with genotypes), used to examine the association between resistance and treatment failure, baseline resistance occurred in 7.1% (9.4% with failure, 4.3% without). Baseline resistance was significantly associated with shorter time to virologic failure (hazard ratio [HR], 2.03; P = .035), and after adjusting for sex, treatment arm, sex-treatment arm interaction, pretreatment CD4 cell count, baseline VL, and subtype, was still independently associated (HR, 2.1; P = .05). Compared with subtype B, subtype C infection was associated with higher failure risk (HR, 1.57; 95% confidence interval [CI], 1.04-2.35), whereas non-B/C subtype infection was associated with longer time to failure (HR, 0.47; 95% CI, .22-.98). CONCLUSIONS: In this global clinical trial, pretreatment resistance and HIV-1 subtype were independently associated with virologic failure. Pretreatment genotyping should be considered whenever feasible. CLINICAL TRIALS REGISTRATION: NCT00084136.
BACKGROUND: Evaluation of pretreatment HIV genotyping is needed globally to guide treatment programs. We examined the association of pretreatment (baseline) drug resistance and subtype with virologic failure in a multinational, randomized clinical trial that evaluated 3 antiretroviral treatment (ART) regimens and included resource-limited setting sites. METHODS: Pol genotyping was performed in a nested case-cohort study including 270 randomly sampled participants (subcohort), and 218 additional participants failing ART (case group). Failure was defined as confirmed viral load (VL) >1000 copies/mL. Cox proportional hazards models estimated resistance-failure association. RESULTS: In the representative subcohort (261/270 participants with genotypes; 44% women; median age, 35 years; median CD4 cell count, 151 cells/µL; median VL, 5.0 log10 copies/mL; 58% non-B subtypes), baseline resistance occurred in 4.2%, evenly distributed among treatment arms and subtypes. In the subcohort and case groups combined (466/488 participants with genotypes), used to examine the association between resistance and treatment failure, baseline resistance occurred in 7.1% (9.4% with failure, 4.3% without). Baseline resistance was significantly associated with shorter time to virologic failure (hazard ratio [HR], 2.03; P = .035), and after adjusting for sex, treatment arm, sex-treatment arm interaction, pretreatment CD4 cell count, baseline VL, and subtype, was still independently associated (HR, 2.1; P = .05). Compared with subtype B, subtype C infection was associated with higher failure risk (HR, 1.57; 95% confidence interval [CI], 1.04-2.35), whereas non-B/C subtype infection was associated with longer time to failure (HR, 0.47; 95% CI, .22-.98). CONCLUSIONS: In this global clinical trial, pretreatment resistance and HIV-1 subtype were independently associated with virologic failure. Pretreatment genotyping should be considered whenever feasible. CLINICAL TRIALS REGISTRATION: NCT00084136.
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