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The link between human herpesvirus 8 (KSHV) and Kaposi's Sarcoma (KS) has been proven, but many important aspects including risk factors, genetic predisposition to tumor development, transmission of KHSV, and the pathogenic potential of different genotypes remain to be elucidated.Possible associations between clinical parameters and antibody levels, viral load fluctuations, and viral genotype were analyzed by quantitative real-time PCR, an in-house developed IFA assay, and sequence analysis of ORF K1-VR1 in blood, serum and saliva of 38 subjects with classic KS (cKS). KHSV lytic antibodies were significantly increased in stage IV compared to stage I and II patients (p= 0.006 and p=0.041, respectively). KHSV blood, serum, and saliva viral load was comparable in all stages. The highest viral loads were detected in saliva, and they decreased in stage III-IV compared to stage I-II patients. Higher concentrations of lytic antibodies and higher viral loads were observed in fast progressing cKS patients, in whom KHSV detection from blood was also more frequent. Type A KSHV strain was almost exclusively present in fast progressors (12/17 cases), while C type was mainly present in slow progressing patients (6/7 cases). Finally, detection of type A KHSV strain associated with higher blood viral loads.KHSV lytic antibody levels and viral load can be used to monitor clinical evolution of cKS. Infection supported by KHSV A subtype is associated with faster progressing disease. Careful monitoring and aggressive therapeutic protocols should be considered in patients with KHSV A-supported infection.