Chronic Hepatitis C Patients Nonresponsive to Antiviral Therapy
Chronic Hepatitis C Patients Nonresponsive to Antiviral Therapy
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.
Despite improvement in the efficacy of treatment with the recently introduced pegylated interferon-alpha (PEG-IFNa)-based regimens, >40% of chronic hepatitis C patients still fail to achieve a sustained virologic response (SVR). The probability of SVR after treatment with PEG-IFNa-based regimens is lower in patients with HCV genotype 1 than 2 or 3, high (>800 000 IU/mL) than low baseline serum HCV RNA levels, heavy (>75 kg) than light baseline body weight, older (>40 years) than younger age, and/or with than without bridging fibrosis or cirrhosis. Additional factors, such as poor adherence to therapy, steatosis and perhaps ongoing alcohol use (at least consumption of >80 g/day), also reduce the likelihood of SVR. Compared to treatment-naïve chronic hepatitis C cases, patients who had previously failed to respond to standard interferon-alpha (IFNa) and ribavirin are expected to achieve lower SVR rates with PEG-IFNa and ribavirin combination, because they usually have several factors associated with a low probability of SVR. As approximately 55% of patients do not respond to the combination of standard IFNa and ribavirin, great numbers of such difficult-to-treat patients have been created during the last 4-5 years when this combination was the treatment of choice for chronic hepatitis C. The above rates of response were from clinical trials in which only chronic hepatitis C patients fulfilling certain inclusion and exclusion criteria were included. Thus, the proportion of nonresponders may be greater if (a) special groups of patients with relative low probability of response, such as patients with co-infection with human immunodeficiency virus (HIV) and thalassaemia, haemophilia, or transplant patients, and (b) patients with decompensated hepatitis C virus (HCV) cirrhosis or those with several contraindications to IFN-a and/or ribavirin are included in the overall chronic hepatitis C patient population. This review focuses on the efficacy of various regimens of antiviral therapy in nonresponding chronic hepatitis C patients as well as on the outcome and potential therapeutic options for those patients who may not respond to re-treatment.
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.
Despite improvement in the efficacy of treatment with the recently introduced pegylated interferon-alpha (PEG-IFNa)-based regimens, >40% of chronic hepatitis C patients still fail to achieve a sustained virologic response (SVR). The probability of SVR after treatment with PEG-IFNa-based regimens is lower in patients with HCV genotype 1 than 2 or 3, high (>800 000 IU/mL) than low baseline serum HCV RNA levels, heavy (>75 kg) than light baseline body weight, older (>40 years) than younger age, and/or with than without bridging fibrosis or cirrhosis. Additional factors, such as poor adherence to therapy, steatosis and perhaps ongoing alcohol use (at least consumption of >80 g/day), also reduce the likelihood of SVR. Compared to treatment-naïve chronic hepatitis C cases, patients who had previously failed to respond to standard interferon-alpha (IFNa) and ribavirin are expected to achieve lower SVR rates with PEG-IFNa and ribavirin combination, because they usually have several factors associated with a low probability of SVR. As approximately 55% of patients do not respond to the combination of standard IFNa and ribavirin, great numbers of such difficult-to-treat patients have been created during the last 4-5 years when this combination was the treatment of choice for chronic hepatitis C. The above rates of response were from clinical trials in which only chronic hepatitis C patients fulfilling certain inclusion and exclusion criteria were included. Thus, the proportion of nonresponders may be greater if (a) special groups of patients with relative low probability of response, such as patients with co-infection with human immunodeficiency virus (HIV) and thalassaemia, haemophilia, or transplant patients, and (b) patients with decompensated hepatitis C virus (HCV) cirrhosis or those with several contraindications to IFN-a and/or ribavirin are included in the overall chronic hepatitis C patient population. This review focuses on the efficacy of various regimens of antiviral therapy in nonresponding chronic hepatitis C patients as well as on the outcome and potential therapeutic options for those patients who may not respond to re-treatment.
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