Greater than half of immunocompetent, HCV-infected patients develop chronic hepatitis, and about 20% develop cirrhosis after 10-20 yr of infection. Approximately 15% ofpatients with HCV-related cirrhosis will develop hepatocellular carcinoma. Immunosuppression caused by HIV significantly alters the natural history of HCV infection. Hepatic damage resulting from HCV infection is believed to be predominantly caused by direct viral cytotoxicity, with contributions from the host immune response. Cell-mediated immunity, T-helper 1 (TH1) clones that recognize multiple core epitopes of HCV, are important in immune clearance of HCV, through elimination of virally infected hepatocytes (8-10). The decline in CD4 cells associated with progressive HIV infection appears to permit greater HCV replication, with more hepatic spread of HCV, and therefore vast hepatocyte injury. Co-infection with HIV also probably alters the response of immune cells to HCV; when CD3+/CD30+ cells are infected with both HIV and HCV, their cytokine production is skewed toward an anti-inflammatory TH2 response, rather than the protective TH1 response seen when cells are infected with HCV alone (11). HCV can also escape from immunologic control through mutation of its hypervariable region, which is a major target of cell-mediated and humoral immune mechanisms (12); thus, heterogeneity of this region, as seen to a greater degree in HIV-infected patients, may permit increased viral replication (13). Although there is not a direct correlation between the plasma titers of HCV RNA and disease course, co-infected patients harbor greater amounts of HCV than immunocompetent patients, both in their plasma (14,15) and in their liver (16).
A number of studies have suggested that the presence of HIV infection accelerates the course of HCV-related liver disease. When compared to HIV-negative patients, co-infected patients have a greater degree of piecemeal necrosis, portal inflammation, and fibrosis, which is the most important prognostic factor (17,18). These pathologic findings appear to be clinically significant. Studies comparing HCV singly infected patients with HCV-HIV co-infected patients have shown that progression to cirrhosis occurs more commonly and more rapidly in those patients with HIV (19,20). Studies comparing HCV and HCV-HIV co-infected hemophiliacs showed a significantly greater risk of hepatic decompensation and liver failure in the co-infected patients (21,22). Another explanation for worsened hepatic damage in these patients is the greater use of hepatotoxic medications by HIV-infected patients, which may exacerbate the HCV-related hepatic disease. Some studies have suggested that HIV infection does not effect progression of HCV infection (23), and all of these natural history studies are limited by the inability to precisely pinpoint the onset of HCV infection.
Less clear is what effect HCV infection has on the natural history of HIV infection. Most cross-sectional and longitudinal studies have not shown an effect of HCV infection on the course HIV disease, but controversy remains. For instance, one study showed that HIV-HCV co-infected patients, with CD4 cell counts greater than 500, experienced a greater progression to AIDS, wasting, and death (24), and others have shown faster progression to AIDS and death in subjects infected with HCV genotype 1 (25).
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