title: Cryptococcal Antigenemia in Immunocompromised Human Immunodeficiency Virus Patients in Rural Tanzania: A Preventable Cause of Early Mortality.
abstract: Background.  Cryptococcal meningitis is a leading cause of death in people living with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome. The World Health Organizations recommends pre-antiretroviral treatment (ART) cryptococcal antigen (CRAG) screening in persons with CD4 below 100 cells/µL. We assessed the prevalence and outcome of cryptococcal antigenemia in rural southern Tanzania. Methods.  We conducted a retrospective study including all ART-naive adults with CD4 <150 cells/µL prospectively enrolled in the Kilombero and Ulanga Antiretroviral Cohort between 2008 and 2012. Cryptococcal antigen was assessed in cryopreserved pre-ART plasma. Cox regression estimated the composite outcome of death or loss to follow-up (LFU) by CRAG status and fluconazole use. Results.  Of 750 ART-naive adults, 28 (3.7%) were CRAG-positive, corresponding to a prevalence of 4.4% (23 of 520) in CD4 <100 and 2.2% (5 of 230) in CD4 100-150 cells/µL. Within 1 year, 75% (21 of 28) of CRAG-positive and 42% (302 of 722) of CRAG-negative patients were dead or LFU (P<.001), with no differences across CD4 strata. Cryptococcal antigen positivity was an independent predictor of death or LFU after adjusting for relevant confounders (hazard ratio [HR], 2.50; 95% confidence interval [CI], 1.29-4.83; P = .006). Cryptococcal meningitis occurred in 39% (11 of 28) of CRAG-positive patients, with similar retention-in-care regardless of meningitis diagnosis (P = .8). Cryptococcal antigen titer >1:160 was associated with meningitis development (odds ratio, 4.83; 95% CI, 1.24-8.41; P = .008). Fluconazole receipt decreased death or LFU in CRAG-positive patients (HR, 0.18; 95% CI, .04-.78; P = .022). Conclusions.  Cryptococcal antigenemia predicted mortality or LFU among ART-naive HIV-infected persons with CD4 <150 cells/µL, and fluconazole increased survival or retention-in-care, suggesting that targeted pre-ART CRAG screening may decrease early mortality or LFU. A CRAG screening threshold of CD4 <100 cells/µL missed 18% of CRAG-positive patients, suggesting guidelines should consider a higher threshold.
authors.affiliation: Swiss Tropical and Public Health Institute , Basel , Switzerland ; ISGLOBAL, Barcelona Centre for International Health Research (CRESIB) , Hospital Clínic-Universitat de Barcelona , Spain ; Ifakara Health Institute , Ifakara, Morogoro , United Republic of Tanzania.
authors.forename: Emilio
authors.initials: E
authors.lastname: Letang
authors.affiliation: Swiss Tropical and Public Health Institute , Basel , Switzerland ; Center for Infectious Diseases and Travel Medicine, Department of Medicine , Medical Center-University of Freiburg , Germany.
authors.forename: Matthias C
authors.initials: MC
authors.lastname: Müller
authors.affiliation: Ifakara Health Institute , Ifakara, Morogoro , United Republic of Tanzania.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Ntamatungiro
authors.affiliation: Ifakara Health Institute , Ifakara, Morogoro , United Republic of Tanzania.
authors.forename: Namvua
authors.initials: N
authors.lastname: Kimera
authors.affiliation: Ifakara Health Institute , Ifakara, Morogoro , United Republic of Tanzania.
authors.forename: Diana
authors.initials: D
authors.lastname: Faini
authors.affiliation: Department of Infectious Diseases , Bern University Hospital and University of Bern.
authors.forename: Hansjakob
authors.initials: H
authors.lastname: Furrer
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology , University Hospital Basel , Switzerland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Battegay
authors.affiliation: Swiss Tropical and Public Health Institute , Basel , Switzerland.
authors.forename: Marcel
authors.initials: M
authors.lastname: Tanner
authors.affiliation: Swiss Tropical and Public Health Institute , Basel , Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Hatz
authors.affiliation: University of Minnesota , Minneapolis.
authors.forename: David R
authors.initials: DR
authors.lastname: Boulware
authors.affiliation: Swiss Tropical and Public Health Institute , Basel , Switzerland.
authors.forename: Tracy R
authors.initials: TR
authors.lastname: Glass
keywords: cryptococcal antigen; cryptococcal meningitis; diagnosis; mortality; prevention; retention in care; screening; sub-Saharan Africa