Ashwin Balagopal1, David M Asmuth, Wei-Teng Yang, Thomas B Campbell, Nikhil Gupte, Laura Smeaton, Cecilia Kanyama, Beatriz Grinsztejn, Breno Santos, Khuanchai Supparatpinyo, Sharlaa Badal-Faesen, Javier R Lama, Umesh G Lalloo, Fatima Zulu, Jyoti S Pawar, Cynthia Riviere, Nagalingeswaran Kumarasamy, James Hakim, Xiao-Dong Li, Richard B Pollard, Richard D Semba, David L Thomas, Robert C Bollinger, Amita Gupta. 1. *Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; †Department of Medicine, University of California Davis, Sacramento, CA; ‡Department of Medicine, University of Colorado Denver, Aurora, CO; §Harvard University Center for AIDS Research, Harvard School of Public Health, Boston, MA; ‖University of North Carolina Project, Lilongwe, Malawi; ¶Instituto de Pesquisa Clinica Evandro Chagas, Manguinhos, Brazil; #Hospital Nossa Senhora da Conceição, Porto Alegre, Brazil; **Department of Medicine, Chiang Mai University, Chiang Mai, Thailand; ††Department of Medicine, University of Witwatersrand, Johannesburg, South Africa; ‡‡IMPACTA PERU Clinical Trials Unit, Asociacion Civil Impacta Salud y Educacion, Lima, Peru; §§Department of Pulmonology, Nelson R Mandela School of Medicine, University of KwaZulu Natal, Durban, South Africa; ‖‖Malawi College of Medicine-Johns Hopkins Research Project, Kachere Rehabilitation Centre, Blantyre, Malawi; ¶¶National AIDS Research Institute, Pune, India; ##Les Centres GHESKIO, Port-au-Prince, Haïti; ***YR Gaitonde Center for AIDS Research and Education, Chennai, India; †††Department of Medicine, University of Zimbabwe, Harare, Zimbabwe; ‡‡‡Department of Medicine, University of California Davis, Sacramento, CA; and §§§Department of Ophthalmology, Johns Hopkins University, Baltimore, MD.
Abstract
BACKGROUND: Despite the success of combination antiretroviral therapy (cART), a subset of HIV-infected patients who initiate cART develop early clinical progression to AIDS; therefore, some cART initiators are not fully benefitted by cART. Immune activation pre-cART may predict clinical progression in cART initiators. METHODS: A case-cohort study (n = 470) within the multinational Prospective Evaluation of Antiretrovirals in Resource-Limited Settings clinical trial (1571 HIV treatment-naive adults who initiated cART; CD4 T-cell count <300 cells/mm; 9 countries) was conducted. A subcohort of 30 participants per country was randomly selected; additional cases were added from the main cohort. Cases [n = 236 (random subcohort 36; main cohort 200)] had clinical progression (incident WHO stage 3/4 event or death) within 96 weeks after cART initiation. Immune activation biomarkers were quantified pre-cART. Associations between biomarkers and clinical progression were examined using weighted multivariable Cox-proportional hazards models. RESULTS: Median age was 35 years, 45% were women, 49% black, 31% Asian, and 9% white. Median CD4 T-cell count was 167 cells per cubic millimeter. In multivariate analysis, highest quartile C-reactive protein concentration [adjusted hazard ratio (aHR), 2.53; 95% confidence interval (CI): 1.02 to 6.28] and CD4 T-cell activation (aHR, 5.18; 95% CI: 1.09 to 24.47) were associated with primary outcomes, compared with lowest quartiles. sCD14 had a trend toward association with clinical failure (aHR, 2.24; 95% CI: 0.96 to 5.21). CONCLUSIONS: Measuring C-reactive protein and CD4 T-cell activation may identify patients with CD4 T-cell counts <300 cells per cubic millimeter at risk for early clinical progression when initiating cART. Additional vigilance and symptom-based screening may be required in this subset of patients even after beginning cART.
BACKGROUND: Despite the success of combination antiretroviral therapy (cART), a subset of HIV-infectedpatients who initiate cART develop early clinical progression to AIDS; therefore, some cART initiators are not fully benefitted by cART. Immune activation pre-cART may predict clinical progression in cART initiators. METHODS: A case-cohort study (n = 470) within the multinational Prospective Evaluation of Antiretrovirals in Resource-Limited Settings clinical trial (1571 HIV treatment-naive adults who initiated cART; CD4 T-cell count <300 cells/mm; 9 countries) was conducted. A subcohort of 30 participants per country was randomly selected; additional cases were added from the main cohort. Cases [n = 236 (random subcohort 36; main cohort 200)] had clinical progression (incident WHO stage 3/4 event or death) within 96 weeks after cART initiation. Immune activation biomarkers were quantified pre-cART. Associations between biomarkers and clinical progression were examined using weighted multivariable Cox-proportional hazards models. RESULTS: Median age was 35 years, 45% were women, 49% black, 31% Asian, and 9% white. Median CD4 T-cell count was 167 cells per cubic millimeter. In multivariate analysis, highest quartile C-reactive protein concentration [adjusted hazard ratio (aHR), 2.53; 95% confidence interval (CI): 1.02 to 6.28] and CD4 T-cell activation (aHR, 5.18; 95% CI: 1.09 to 24.47) were associated with primary outcomes, compared with lowest quartiles. sCD14 had a trend toward association with clinical failure (aHR, 2.24; 95% CI: 0.96 to 5.21). CONCLUSIONS: Measuring C-reactive protein and CD4 T-cell activation may identify patients with CD4 T-cell counts <300 cells per cubic millimeter at risk for early clinical progression when initiating cART. Additional vigilance and symptom-based screening may be required in this subset of patients even after beginning cART.
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