Clinical and therapeutic aspects of viral hepatitis: exploring the role of ribavirin

Since the broad spectrum antiviral activity of ribavirin was discovered in 1972, the use of this nucleoside analogue has played a major role in the changing landscape of treatment for viral hepatitis. In this thesis various aspects of ribavirin use for the treatment of hepatitis C and E are described.
Part one of this thesis focuses on hepatitis C. In chapter 2, the results of the multicenter randomized controlled VIRID trial are discussed. This study shows that patients with genotype 1 or 4 and a high baseline viral load treated with peginterferon and ribavirin achieve higher sustained virological response rates if they receive a double dose of ribavirin, given they complete at least 80% of the treatment. In chapter 3, we show that optimization of the ribavirin dose can be achieved by adjusting the ribavirin dose through calculating the area under the curve, after patients take a single dose of ribavirin. Chapter 4 shows that ribavirin does not cause DNA damage in sperm cells. Chapter 5 and 6 describe the first experiences with the first generation of 'direct acting antivirals' in liver transplant patients. We present a theoretical model that describes the cascade leading to anemia and nephrotoxicity during this triple therapy. In chapter 7 we show that liver transplant patients who develop cytopenias during therapy with (peg)interferon and/or ribavirin are at increased risk of bleeding and infection.
Part two of this thesis focuses on hepatitis E. In chapter 8, for the first time an American (liver) transplant cohort, infected with hepatitis C, is screened for the occurrence of hepatitis E. Although more than 1 in 3 patients were seropositive, none of them had an active or chronic hepatitis E infection. We describe how infected patients may have been mistakenly treated for re-infection with hepatitis C with (peg)interferon and/or ribavirin, agents that are also active against hepatitis E. Finally, in chapter 9, our experience with ribavirin therapy for the treatment of chronic hepatitis E in six heart transplant patients is discussed.