The letter by Dr. Harrison raises the important issue of the relationship between insulin resistance (IR) and chronic HCV infection, which was not dealt with in our review due to space constraints. It provides original data suggesting a correlation between IR, measured by the QUICKI index, and viral load, in keeping with a direct pathogenic effect of the virus on insulin signaling, either directly or indirectly.
The Authors do not report data on HCV genotype in their series, and genotype-specific effects on IR have been extensively demonstrated, with the highest degree of IR in genotype non-3.1 In these patients, IR is probably not the cause, but more likely, it is the consequence of both steatosis and fibrosis, and increased circulating insulin becomes a risk factor for disease progression through IR-induced steatosis.2
As to the reason(s) for the association, the hypothesis that IR may increase viral replication is discussed in the letter. Many more data point to a direct effect of the virus— namely, of specific genotypes — on insulin sensitivity, mediating sustained virological response (SVR) to combined interferon/ribavirin therapy. Interestingly, IR is common among groups of poor-response patients, such as those with cirrhosis or high BMI,3 African Americans,4 where the impaired response to antiviral therapy was related to their high rate of central obesity and IR, and those with HIV/HCV coinfection.5 In general, high levels of TNF-α expression, usually observed in IR states, may be predictive of a failed response to interferon therapy.
IR influences SVR in genotype 1–infected patients: SVR is attained in 60% of patients with HOMA-R <2 and only in 33% of patients with HOMA-IR >2.6 It is still unclear whether IR is a marker of difficult-to-treat patients or directly plays a role in interferon+ribavirin resistance. In the same study, insulin sensitivity improved in patients who achieved HCV-RNA clearance, while it did not improve in non-responders, despite a decrease in BMI.
Successful antiviral treatment has also been associated with improved glucose tolerance,7 suggesting a complex interrelationship between altered IR, glucose regulation and viral activity. Chronic HCV hepatitis has an indolent course, favoring the virus–host interaction and generating permissive conditions for survival. IR is meant to facilitate the persistence of the virus favoring its replication and reducing the efficacy of the antiviral therapy, as suggested by the recent observation quoted in the letter, relative to an in vitro model of HCV. HCV itself alters the intrahepatic insulin signaling through several mechanisms, including a downregulation of peroxisome proliferator-activated receptor-alpha and -gamma,8 proteosomal degradation of the insulin receptor substrate-1 and -2,9 and their functional impairment through increased levels of pro-inflammatory cytokines.10
The role of IR as a disease-modifier in chronic HCV infection suggests that combining antiviral therapy and insulin-sensitizers, acting in the liver (metformin) or in the periphery (thiazolidinediones) may increase SVR. A study with metformin is presently under way in Italy. Antiviral treatment should be tailored according to the metabolic state, and insulin sensitizers, together with lifestyle modifications might become an additional line of treatment once evaluated in randomized controlled trials.