In this large multicenter cohort of individuals with hemophilia, who had detectable HCV viremia at baseline and no history of interferon therapy, we evaluated whether high HCV-RNA load was associated with several demographic, clinical, and laboratory parameters. As noted in many studies (17
), we found that high HCV-RNA load was significantly more common with HIV co-infection. Among HIV-negative individuals, we found that high HCV-RNA load was associated with older age at infection, longer duration of infection, and being overweight or obese. With adjustment for these variables, high HCV-RNA load also was significantly associated with having a low AST/platelet ratio. This may seem paradoxical, because high AST/platelet ratio is a marker for significant liver fibrosis and cirrhosis (31
). An inverse association between HCV load and hepatic cirrhosis has been reported previously and suggests that a critical mass of healthy hepatic parenchyma may be necessary to generate a high HCV-RNA load (20
Longitudinal studies of both people with hemophilia (24
) and injection drug users (17
) have clearly shown that HCV-RNA level increases with duration of infection. An independent association between high HCV-RNA level and older age at primary infection has not been reported previously. Older age at primary HCV infection is strongly associated with lower likelihood of spontaneous clearance of HCV RNA (25
), and thus it is quite plausible that it also would be associated with high HCV-RNA level in those who fail to clear the virus spontaneously. Zhang and colleagues postulated that this may have been due to a smaller inoculum of HCV in clotting factor therapy administered to younger patients, thereby affording a better chance for an effective immune response against the virus (25
In HIV-positive individuals, none of the variables evaluated were associated with high HCV load except for current use of cART or other ART, both of which were associated with an 80% increase in the odds of having high viral load compared to no ART. The observed null association with duration of HCV infection or age at acquisition might be affected by survival bias, where individuals who were HCV/HIV co-infected for longer duration were more likely to die and therefore not be included in this study. This possibility does not seem to fully explain this null association, as HIV co-infected individuals in this study were more likely to have longer duration of HCV infection (>25 years) than HCV mono-infected individuals (70.2% vs. 50.6%, respectively). Our results on cART agree with the results from a longitudinal study of 21 patients with hemophilia, in which HCV load increased at 48 and 96 weeks after cART initiation and dropped after cART discontinuation (34
). Two other studies have pointed to a specific relationship of protease inhibitors (PI) on HCV load (35
), suggesting that differences in the use of PI-based and non-PI-based ART may yield inconsistent associations with HCV load.
High HCV-RNA level was significantly associated with being overweight or obese in the HIV-negative participants. A similar association was reported previously for non-hemophilic HIV-negative patients (37
). We also noted that high BMI was associated with high HCV-RNA in the subgroup of HIV-positive participants who were not on ART, which has not been previously reported and will require corroboration. An association between BMI and HCV-RNA level might be mediated through interferon-gamma inducible protein 10 (IP-10), a chemokine that is over-expressed in the liver of obese infected individuals (38
). IP-10 was directly correlated with HCV-RNA load in an earlier study (39
Our study is the largest to evaluate HCV-RNA levels in individuals with hemophilia. However, we could not assess temporal relationships, because our study was cross-sectional. In addition, our results may not easily generalize to non-hemophilic patients, as almost all of our participants were male, infected at a young age and repeatedly exposed to HCV. Further, we lacked liver biopsies to directly assess the degree of liver fibrosis. Instead, as a surrogate marker for advanced liver fibrosis and cirrhosis, we used AST/platelet ratio, which is reported to have sensitivity and specificity >80% in non-hemophilic patients (40
Despite some limitations, our study of chronic HCV infection suggests that the infection may be more poorly controlled, and thereby more pathogenic and resistant to treatment, in people who are overweight or obese. Corroboration and deeper understanding of this are needed, aiming to identify individuals for whom current HCV therapy is likely to be inadequate.