title: Pre-cART Elevation of CRP and CD4+ T-Cell Immune Activation Associated With HIV Clinical Progression in a Multinational Case-Cohort Study.
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.
authors.affiliation: *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.
authors.forename: Ashwin
authors.initials: A
authors.lastname: Balagopal
authors.forename: David M
authors.initials: DM
authors.lastname: Asmuth
authors.forename: Wei-Teng
authors.initials: WT
authors.lastname: Yang
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Campbell
authors.forename: Nikhil
authors.initials: N
authors.lastname: Gupte
authors.forename: Laura
authors.initials: L
authors.lastname: Smeaton
authors.forename: Cecilia
authors.initials: C
authors.lastname: Kanyama
authors.forename: Beatriz
authors.initials: B
authors.lastname: Grinsztejn
authors.forename: Breno
authors.initials: B
authors.lastname: Santos
authors.forename: Khuanchai
authors.initials: K
authors.lastname: Supparatpinyo
authors.forename: Sharlaa
authors.initials: S
authors.lastname: Badal-Faesen
authors.forename: Javier R
authors.initials: JR
authors.lastname: Lama
authors.forename: Umesh G
authors.initials: UG
authors.lastname: Lalloo
authors.forename: Fatima
authors.initials: F
authors.lastname: Zulu
authors.forename: Jyoti S
authors.initials: JS
authors.lastname: Pawar
authors.forename: Cynthia
authors.initials: C
authors.lastname: Riviere
authors.forename: Nagalingeswaran
authors.initials: N
authors.lastname: Kumarasamy
authors.forename: James
authors.initials: J
authors.lastname: Hakim
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Li
authors.forename: Richard B
authors.initials: RB
authors.lastname: Pollard
authors.forename: Richard D
authors.initials: RD
authors.lastname: Semba
authors.forename: David L
authors.initials: DL
authors.lastname: Thomas
authors.forename: Robert C
authors.initials: RC
authors.lastname: Bollinger
authors.forename: Amita
authors.initials: A
authors.lastname: Gupta
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D015415:Biomarkers; D002097:C-Reactive Protein / Q000378:metabolism*; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D015331:Cohort Studies; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D038622:Internationality; D008297:Male
chemical_list: D019380:Anti-HIV Agents; D015415:Biomarkers; D002097:C-Reactive Protein