Chronic hepatitis C and no response to antiviral therapy: potential current and future therapeutic options

Abstract

A significant proportion of chronic hepatitis C patients fails to achieve sustained virologic response even after treatment with the current, more potent, combination of pegylated interferon-alpha (IFNa) plus ribavirin. Such patients represent a rather heterogeneous group and may be divided initially into relapsers and nonresponders. Both the type of previous therapy and of previous response are very important factors for the indication and the type of re-treatment. The combination of pegylated IFNa and ribavirin seems to be a rational approach for patients who failed to respond to IFNa monotherapy. Pegylated IFNa-based regimens appear to induce sustained responses in 40-68% of relapsers but in only 11% of nonresponders to previous therapy with standard IFNa plus ribavirin. Thus, new therapeutic approaches are needed for the latter subgroup of patients as well as those who fail to respond to pegylated IFNa-based regimens. Such new approaches currently under evaluation include the triple combination of pegylated IFNa, ribavirin, and amantadine, alternative types of IFN, use of agents with ribavirin like activity but lesser degrees of side-effects, inhibitors of hepatitis C virus (HCV) replication, mainly inhibitors of NS3 protease or helicase, antisense oligonucleotides, and ribozymes, and several immunomodulators. Moreover, maintenance antifibrotic therapy, mostly with low doses of pegylated IFNa, are under evaluation in patients with advanced fibrosis. Thus, even in the current era of the potent pegylated IFNa-based regimens, the management of these difficult-to-treat patients represents an increasingly frequent problem and perhaps the most challenging therapeutic task in chronic hepatitis C.

Recent peginterferon and ribavirin combination trials

“…Another important issue is that the efficacy of therapy, although improved, is still suboptimal in patients with HCV genotype 1 or with several unfavorable factors of response, because SVR can be achieved in only a minority of such cases [16••,17••]. In addition, in patients who had previously failed to respond to the combination of standard IFN alpha and ribavirin, the probability of SVR after treatment with pegylated IFN alpha-based regimens has been found to be rather low [25]. Finally, it must be remembered that the strict criteria, used in the selection of patients included in the discussed pegylated IFN alpha and ribavirin combination pivotal trials [16••,17••], do not appear to apply to a significant proportion of patients with chronic hepatitis C seen in clinical practice.…”

New Drug Targets for HIV and Hepatitis C Virus Coinfection

“…The compound administered intravenously 3 times weekly did demonstrate a 11 log 10 decrease in HCV RNA levels for approximately one-third of participants, but this was offset by frequent elevations in hepatic transaminase levels. The parenteral route will also limit the usefulness of this compound [20].…”

“…Theoretically, more than one binding site could be targeted or other genetic material introduced. Toxicity concerns have limited further development of these concepts [20].…”

A Novel Ex Vivo Assay of Interferon‐Based Suppression, to Predict the Outcome of Antiviral Therapy for Hepatitis C

“…Currently, interferonbased therapy can achieve a sustained virological response (SVR) in ∼50% of patients [6]. However, in some special groups of patients, the efficacy is far from satisfactory [7]. Furthermore, the strategy of interferon-based therapy is hindered by appreciable side effects and high costs.…”