title: Concurrent Anemia and Elevated C-Reactive Protein Predicts HIV Clinical Treatment Failure, Including Tuberculosis, After Antiretroviral Therapy Initiation.
abstract: BACKGROUND
  Anemia is a known risk factor for clinical failure following antiretroviral therapy (ART). Notably, anemia and inflammation are interrelated, and recent studies have associated elevated C-reactive protein (CRP), an inflammation marker, with adverse human immunodeficiency virus (HIV) treatment outcomes, yet their joint effect is not known. The objective of this study was to assess prevalence and risk factors of anemia in HIV infection and to determine whether anemia and elevated CRP jointly predict clinical failure post-ART.
  
  
  METHODS
  A case-cohort study (N = 470 [236 cases, 234 controls]) was nested within a multinational randomized trial of ART efficacy (Prospective Evaluation of Antiretrovirals in Resource Limited Settings [PEARLS]). Cases were incident World Health Organization stage 3, 4, or death by 96 weeks of ART treatment (clinical failure). Multivariable logistic regression was used to determine risk factors for pre-ART (baseline) anemia (females: hemoglobin <12.0 g/dL; males: hemoglobin <13.0 g/dL). Association of anemia as well as concurrent baseline anemia and inflammation (CRP ≥ 10 mg/L) with clinical failure were assessed using multivariable Cox models.
  
  
  RESULTS
  Baseline anemia prevalence was 51% with 15% prevalence of concurrent anemia and inflammation. In analysis of clinical failure, multivariate-adjusted hazard ratios were 6.41 (95% confidence interval [CI], 2.82-14.57) for concurrent anemia and inflammation, 0.77 (95% CI, .37-1.58) for anemia without inflammation, and 0.45 (95% CI, .11-1.80) for inflammation without anemia compared to those without anemia and inflammation.
  
  
  CONCLUSIONS
  ART-naive, HIV-infected individuals with concurrent anemia and inflammation are at particularly high risk of failing treatment, and understanding the pathogenesis could lead to new interventions. Reducing inflammation and anemia will likely improve HIV disease outcomes. Alternatively, concurrent anemia and inflammation could represent individuals with occult opportunistic infections in need of additional screening.
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Rupak
authors.initials: R
authors.lastname: Shivakoti
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Wei-Teng
authors.initials: WT
authors.lastname: Yang
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Gupte
authors.affiliation: Malawi College of Medicine-Johns Hopkins University Research Project, Blantyre.
authors.forename: Sima
authors.initials: S
authors.lastname: Berendes
authors.affiliation: Asociacion Civil Impacta Salud y Educacion, Lima, Peru.
authors.forename: Alberto La
authors.initials: AL
authors.lastname: Rosa
authors.affiliation: STD/AIDS Clinical Research Laboratory, Instituto de Pesquisa Clinica Evandro Chagas, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil.
authors.forename: Sandra W
authors.initials: SW
authors.lastname: Cardoso
authors.affiliation: Department of Medicine, University of Witwatersrand, Johannesburg, South Africa.
authors.forename: Noluthando
authors.initials: N
authors.lastname: Mwelase
authors.affiliation: University of North Carolina Lilongwe, Malawi.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Kanyama
authors.affiliation: Durban International Clinical Research Site, Durban University of Technology, South Africa.
authors.forename: Sandy
authors.initials: S
authors.lastname: Pillay
authors.affiliation: University of Zimbabwe Clinical Research Centre, Harare.
authors.forename: Wadzanai
authors.initials: W
authors.lastname: Samaneka
authors.affiliation: Les Centres GHESKIO, Port-Au-Prince, Haiti.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Riviere
authors.affiliation: Research Institute for Health Sciences, Chiang Mai, Thailand.
authors.forename: Patcharaphan
authors.initials: P
authors.lastname: Sugandhavesa
authors.affiliation: Hospital Nossa Senhora de Conceição, Porto Alegre, Brazil.
authors.forename: Brento
authors.initials: B
authors.lastname: Santos
authors.affiliation: Y. R. Gaitonde Center for AIDS Research and Education, Chennai.
authors.forename: Selvamuthu
authors.initials: S
authors.lastname: Poongulali
authors.affiliation: National AIDS Research Institute, Pune, India.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Tripathy
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Bollinger
authors.affiliation: Department of Medicine, University of California, Los Angeles.
authors.forename: Judith S
authors.initials: JS
authors.lastname: Currier
authors.affiliation: Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, Massachusetts.
authors.forename: Alice M
authors.initials: AM
authors.lastname: Tang
authors.affiliation: Department of Ophthalmology, Johns Hopkins University School of Medicine.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Semba
authors.affiliation: Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Parul
authors.initials: P
authors.lastname: Christian
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of Colorado School of Medicine, Aurora.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Campbell
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Amita
authors.initials: A
authors.lastname: Gupta
mesh_terms: D000328:Adult; D000368:Aged; D000740:Anemia / Q000175:diagnosis*; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D002097:C-Reactive Protein / Q000032:analysis*; D016022:Case-Control Studies; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy*; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012307:Risk Factors; D017211:Treatment Failure; D055815:Young Adult
chemical_list: D044966:Anti-Retroviral Agents; D002097:C-Reactive Protein
keywords: CRP; HIV; anemia; antiretroviral therapy; inflammation
references.citation: J Acquir Immune Defic Syndr. 2012 May 1;60(1):91-8
references.pmid: 22293548
references.citation: J Clin Epidemiol. 1999 Dec;52(12):1165-72
references.pmid: 10580779
references.citation: J Acquir Immune Defic Syndr. 2001 Jan 1;26(1):28-35
references.pmid: 11176266
references.citation: Clin Infect Dis. 2002 Jan 15;34(2):260-6
references.pmid: 11740716
references.citation: Eur J Clin Nutr. 2003 Sep;57(9):1157-63
references.pmid: 12947436
references.citation: Am J Med. 2004 Apr 5;116 Suppl 7A:27S-43S
references.pmid: 15050884
references.citation: Clin Infect Dis. 2004 May 15;38(10):1454-63
references.pmid: 15156485
references.citation: J Acquir Immune Defic Syndr. 2004 Oct 1;37(2):1245-52
references.pmid: 15385731
references.citation: Arch Intern Med. 1993 Sep 27;153(18):2149-54
references.pmid: 8379807
references.citation: AIDS. 1996 Oct;10(12):1349-56
references.pmid: 8902063
references.citation: Blood. 1997 Feb 1;89(3):1052-7
references.pmid: 9028338
references.citation: Blood. 1998 Jan 1;91(1):301-8
references.pmid: 9414298
references.citation: Biometrics. 2004 Dec;60(4):1015-24
references.pmid: 15606422
references.citation: N Engl J Med. 2005 Mar 10;352(10):1011-23
references.pmid: 15758012
references.citation: J Nutr. 2005 May;135(5):1106-12
references.pmid: 15867289
references.citation: J Infect Dis. 2011 Mar 15;203(6):780-90
references.pmid: 21252259
references.citation: Am J Trop Med Hyg. 2011 Mar;84(3):456-60
references.pmid: 21363986
references.citation: Lancet. 2011 Dec 17;378(9809):2123-35
references.pmid: 21813172
references.citation: PLoS One. 2011;6(12):e28691
references.pmid: 22220193
references.citation: HIV Med. 2006 Jul;7(5):323-30
references.pmid: 16945078
references.citation: J Korean Med Sci. 2006 Dec;21(6):1028-32
references.pmid: 17179681
references.citation: HIV Med. 2007 Jan;8(1):38-45
references.pmid: 17305931
references.citation: J Clin Epidemiol. 2007 Apr;60(4):350-5
references.pmid: 17346608
references.citation: AIDS. 2007 Mar 30;21(6):713-9
references.pmid: 17413692
references.citation: AIDS. 2007 Oct 1;21(15):2067-75
references.pmid: 17885297
references.citation: J Nutr. 2007 Oct;137(10):2317-23
references.pmid: 17885017
references.citation: AIDS. 2007 Nov 30;21(18):2483-91
references.pmid: 18025885
references.citation: Chronic Illn. 2008 Mar;4(1):65-79
references.pmid: 18322031
references.citation: PLoS Med. 2008 Oct 21;5(10):e203
references.pmid: 18942885
references.citation: Antivir Ther. 2008;13(8):959-67
references.pmid: 19195321
references.citation: Public Health Nutr. 2009 Apr;12(4):444-54
references.pmid: 18498676
references.citation: Int J STD AIDS. 2009 Jul;20(7):489-92
references.pmid: 19541892
references.citation: BMC Public Health. 2010;10:433
references.pmid: 20653940
references.citation: Int J Infect Dis. 2010 Dec;14(12):e1088-92
references.pmid: 20961784
references.citation: Am J Clin Nutr. 2012 May;95(5):1231-7
references.pmid: 22456661
references.citation: PLoS One. 2012;7(8):e43375
references.pmid: 22905264
references.citation: PLoS Med. 2012;9(8):e1001290
references.pmid: 22936892
references.citation: J Infect Dis. 2013 May 1;207(9):1370-8
references.pmid: 23319741
references.citation: J Acquir Immune Defic Syndr. 2014 Apr 15;65(5):551-6
references.pmid: 24346636
references.citation: J Infect Dis. 2014 Jul 15;210(2):244-53
references.pmid: 24799602
references.citation: BMC Res Notes. 2014;7:439
references.pmid: 25005803
references.citation: PLoS One. 2014;9(8):e104178
references.pmid: 25153084
references.citation: Lancet. 2014 Sep 13;384(9947):1005-70
references.pmid: 25059949
references.citation: J Cardiovasc Med (Hagerstown). 2015 Feb;16(2):106-11
references.pmid: 23846678