Antiviral treatment for chronic hepatitis C infection. Prediction of treatment response and side effects

Chronic hepatitis C (CHC) can lead to cirrhosis, end-stage liver disease and hepatocellular carcinoma. The last few years antiviral treatment for CHC consisted of PEG-interferon injections and oral ribavirin. With this combination treatment, sustained virological response (SVR) rates of 50-80% are achieved. Antiviral treatment has also considerable side-effects, including anemia, neutropenia, flu-like symptoms and depression. Known predictors of treatment response, for example HCV genotype, baseline viral load and presence of cirrhosis, cannot be modified. Therefore, it is important to identify modifiable factors that affect response rates in order to develop effective strategies to improve outcome of antiviral treatment in the future. In this thesis we focused on ribavirin concentrations and adherence to antiviral therapy, both potentially modifiable factors. Despite weight-based ribavirin dosing, a large variation in ribavirin bioavailability is found between individuals. We showed that SVR rates increased with increasing steady-state ribavirin concentrations: 47%, 69%, 76% and 95% in case of ribavirin concentrations ≤2, 2–3, 3–4, and ≥4 mg/L respectively (p=0.001). Higher ribavirin concentration was an independent predictor of SVR (OR 1.72, 95%CI 1.13-2.63, p=0.01). We also measured ribavirin concentrations during the first weeks of treatment, since measurement of steady-state concentration does not provide an opportunity for intervention. We found that week 8 ribavirin concentration was an independent predictor of SVR (OR 2.3, 95% CI 1.1-4.9, p=0.03). Also, ribavirin concentrations after 1, 2 and 4 weeks of treatment can be used to predict a therapeutic week 8 ribavirin concentration (2.2 mg/L). These findings clearly demonstrate that higher ribavirin exposure is associated with an increase in SVR rates. One might speculate that interventions early in the treatment course, for example discussing adherence and increasing ribavirin dose, might lead to higher ribavirin concentrations and subsequently to higher SVR rates. Non-adherence to treatment is a frequent phenomenon for various chronic diseases. In our systematic review we conclude that mean adherence to antiviral treatment for chronic hepatitis C varied from 27% to 97%, with poor adherence being associated with an increased risk of virological failure in most studies. Subsequently, in a randomized trial we investigated the effect of real-time medication monitoring (RTMM) with text message reminders on ribavirin adherence and virological response in CHC patients on antiviral treatment. Adherence, ribavirin concentrations and virological response were not different between the intervention and control group. These findings suggest that non-adherence could be a less frequent phenomenon in chronic hepatitis C patients compared to other chronic diseases. Given the possible increased risk of virological failure in poorly adherent patients, clinicians should routinely address adherence issues in all patients treated for chronic viral hepatitis. The findings in this thesis can be used to improve response to antiviral treatment for CHC in the future. In the next years, various direct-acting antiviral agents will be approved for CHC treatment, with or without PEG-interferon. Since ribavirin will remain a cornerstone of CHC treatment, optimizing exposure to ribavirin remains an important goal. Furthermore, adherence to treatment for CHC will become an even more important issue in case of triple therapy