Hepatitis C virus kinetics during antiviral treatment

Abstract

It is estimated that 170 million individuals have chronic hepatitis C virus (HCV) infection, whereof 20-30% will develop end stage liver disease within 20-30 years. Antiviral therapy can stop this deterioration and clear the infection in 40-80% of the patients depending on treatment and HCV genotype. Suboptimal therapy, however, is likely to promote selection of resistance and emergence of escape mutants and an unfavourable treatment outcome. We studied the early HCV RNA kinetics during different antiviral treatment schemes and correlated the early viral decay to the eventual virological outcome with regard to the different genotypes.

In paper I the addition of amantadine to IFN and ribavirin during 24 weeks treatment of 10 former responder/relapsers and 13 non-responders to standard IFN and ribavirin combination therapy was found to have only limited beneficial effect. At end of treatment, only one previous non-responder and 5 previous response/relapsers were HCV RNA negative but only one former response/relapser had sustained response.

In paper II a more pronounced viral decline was seen with induction therapy, when standard IFN was given as mono-therapy daily initially during treatment, as compared to when it was given as standard dosing three times a week (t.i.w.). This difference persisted during the initial 12 weeks for patients infected with genotype 1, but was not maintained from day 14 and onwards for patients infected with genotype non-1. Eighty percent of patients in the induction group versus 16% in the standard t.i.w. group achieved undetectable HCV RNA levels (<600 IU/mL) at week 12 (p<0.05).

In paper IV IFN induction mono-therapy resulted in a more pronounced HCV RNA decline at weeks 4, 8, and 12 compared to standard treatment. Most sustained responders were found to have a >3 log10 drop in serum HCV RNA levels week 4. Addition of ribavirin after 12 weeks IFN mono-therapy in two non-responders reverted them to sustained responders.

In paper III IFN induction therapy, in combination with ribavirin during treatment of naive patients, also resulted in a small but significantly more pronounced HCV RNA decline compared to standard dosing, in genotype non-1 infected patients but only day 2 and 7 during treatment, in contrast to what was found when IFN mono-therapy was given when this difference was more pronounced. The mean HCV RNA decline from baseline already day 1 was significantly greater in patients who became sustained virological responders as compared to non-responders. Hence, all sustained responders had a viral load decline of minimum 0.7 log (79%) after the first dose of standard IFN, whereas a lack of such response predicted a non-response.

In paper V pegylated-IFN alpha-2a (peg-IFN) was used in combination with ribavirin in naive patients. No difference in the decline of HCV RNA levels was noted between responders and non-responders after the first treatment day. At week 1 and week 4, however, sustained responders had a significantly more pronounced drop in HCV RNA levels as compared to response/relapsers and non-responders. Hence, the HCV RNA decline day 1 could not be used for prediction of response to peg-IFN treatment. At week 1, however, a positive predictive value of 92% was noted for a final virological sustained response in the subgroup of patients who had achieved a 2 log10 drop in HCV RNA levels. The best time point for prediction of a non-response was week 12 when a negative predictive value of 92% was noted in patients who did not meet this criterion.