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To identify immunologic and virologic predictors of AIDS-associated Kaposi's sarcoma (KS).Nested case–control analysis of KS risk in a cohort of 132 HIV-infected homosexual men in New York and Washington, DC, USA.For each KS case, we selected two HIV-infected controls, matched for CD4 cell count and Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8; KSHV) serostatus (enzyme immunoassay for antibody to KSHV protein K8.1). Cell-associated KSHV and Epstein–Barr virus (EBV) viral loads were measured with quantitative real-time PCR assays on samples collected 1 year (median) before KS diagnosis.Thirty-one men developed AIDS-associated KS (incidence 3.1 per 100 person years). Among HIV-infected men, KS incidence was higher among those with K8.1 seropositivity (5.0 versus 1.4 per 100 person years; P = 0.004), low CD4 cell count [hazard ratio (HR), 1.49; 95% confidence interval (CI), 1.24–1.79 per 100 × 106 cells/l decline), or high HIV RNA level (HR, 3.96; 95% CI, 2.19–7.16 per log10). In the case–control analysis, nine of 70 evaluated subjects had KSHV viremia, generally low level (median viral load 180 copies per 1 × 106 cells). KSHV viremia was associated with increased KS risk (unadjusted odds ratio, 9.1; 95% CI, 1.7–48; odds ratio, 11.7; 95% CI, 1.8–76 after adjustment for K8.1 serostatus, CD4 cell count, and HIV RNA). Among K8.1-seropositive subjects, KS incidence was tenfold higher in those with KSHV viremia (30.3 per 100 person years versus 3.4 per 100 person years in those without viremia). Also, EBV viral loads were higher in cases than in controls (P = 0.07).Among individuals with HIV–KSHV coinfection, KSHV viremia identifies a subgroup with extremely high risk for developing KS.