title: Persistently elevated serum interleukin-6 predicts mortality among adults receiving combination antiretroviral therapy in Botswana: results from a clinical trial.
abstract: Elevated serum levels of inflammatory biomarkers have been associated with increased mortality and morbidity among HIV-infected individuals receiving combination antiretroviral therapy (cART) in European and U.S. cohorts. Few similar data are available from sub-Saharan Africa, where most cART-treated adults reside and the prevalence of advanced immunosuppression and opportunistic infections (OIs) at cART initiation is higher. This was a retrospective nested case-control analysis of clinical trial data from the completed Adult Antiretroviral Treatment and Drug Resistance ("Tshepo") study, 2002-2007, Gaborone, Botswana. We measured pretreatment serum levels of interleukin-6 (IL-6), high sensitivity C-reactive protein, and D-dimer in stored plasma samples from 32 deceased participants (cases) and 64 survivors (controls), matched for age, sex, baseline CD4(+) cell count, and plasma HIV-1 RNA. Multivariate conditional logistic regression analyses were used to compare inflammatory biomarker levels, adjusting for pretreatment body mass index (BMI) and the presence of OIs. A total of 37 (5.7%) of 650 patients died on study, for a crude mortality rate of 20.6/1,000 person-years. Of 37 (86%) study participants who died on study 32 were included in this analysis. Causes of death (n=32) included non-AIDS-defining events (31.3%), HIV-related OIs (28.1%), cART/toxicity-related (21.9%), other infectious etiologies (15.6%), and unknown (3.1%). Median time to death was 31 weeks [interquartile range (IQR) 14-64]. Median baseline levels of all three biomarkers were higher in cases compared to matched controls. After adjusting for BMI and the presence of OIs, only baseline and most recent (near time of event) levels of IL-6 remained as significant predictors of all-cause mortality [adjusted OR (aOR)=1.25, 95% CI (1.05-1.48); p=0.012; and aOR=1.48 (1.05-2.09); p=0.027, respectively]. Serum IL-6 levels are important predictors of all-cause mortality in this adult urban sub-Saharan African cART-treated population. Future translational studies are warranted to better elucidate pathophysiology and inform the design of novel interventions to ameliorate the risk of death among these "at-risk" individuals.
authors.affiliation: Harvard School of Public Health AIDS Initiative, Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Bethan
authors.initials: B
authors.lastname: McDonald
authors.forename: Sikhulile
authors.initials: S
authors.lastname: Moyo
authors.forename: Lesego
authors.initials: L
authors.lastname: Gabaitiri
authors.forename: Simani
authors.initials: S
authors.lastname: Gaseitsiwe
authors.forename: Hermann
authors.initials: H
authors.lastname: Bussmann
authors.forename: John R
authors.initials: JR
authors.lastname: Koethe
authors.forename: Rosemary
authors.initials: R
authors.lastname: Musonda
authors.forename: Joseph
authors.initials: J
authors.lastname: Makhema
authors.forename: Vladimir
authors.initials: V
authors.lastname: Novitsky
authors.forename: Richard G
authors.initials: RG
authors.lastname: Marlink
authors.forename: C William
authors.initials: CW
authors.lastname: Wester
authors.forename: Max
authors.initials: M
authors.lastname: Essex
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D015415:Biomarkers / Q000097:blood; D001902:Botswana / Q000453:epidemiology; D016022:Case-Control Studies; D015331:Cohort Studies; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy* / Q000401:mortality; D015497:HIV-1; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D015850:Interleukin-6 / Q000097:blood*; D008297:Male; D012189:Retrospective Studies
chemical_list: D019380:Anti-HIV Agents; D015415:Biomarkers; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6