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Up to 10% of all patients with Hepatitis C virus (HCV) infection are co-infected with human immunodeficiency virus (HIV); 25–30% of HIV patients are co-infected with HCV. The aim of this study was to examine the association of HCV/HIV co-infection with outcomes of hospitalized patients compared to those with HCV or HIV monoinfection. Using the 2006 Nationwide Inpatient Sample, patients with HCV or HIV monoinfection or HCV/HIV co-infection were identified using ICD-9-CM codes. We compared liver-related and infection-related admission between the three groups of patients. Multivariate logistic regression was performed to identify independent predictors of in-hospital mortality. A total of 474 843 discharges with HCV monoinfection, 206 758 with HIV monoinfection and 56 304 with HCV/HIV co-infection were included. Liver-related admissions were more common in co-infected patients (15.4%) compared to those with HIV monoinfection (3.3%, P < 0.001). Primary infectious hospitalizations were more common in HIV monoinfection (33.9%) compared to co-infected patients (26%, P < 0.001). HCV/HIV co-infection was associated with higher mortality compared to HCV monoinfection (OR 1.41, 95% CI 1.20–1.65) but not when compared to monoinfected-HIV patients. HCV-associated cirrhosis or complications thereof conferred four times greater mortality risk in patients with HIV (OR 3.96, 95% CI 3.29–4.79). The rate of hospitalization for HCV/HIV co-infected patients (23.5%) was significantly higher than those with HCV (14.8%) or HIV (19.9%) (P < 0.001). HCV/HIV co-infection is associated with significantly higher rates of hospitalization and is a risk factor for in-hospital mortality compared to patients with isolated HCV.