Optimizing the Treatment of Chronic Viral Hepatitis C
Optimizing the Treatment of Chronic Viral Hepatitis C
Chronic hepatitis C is a major health concern. The current standard therapy is based on a combination of pegylated (PEG)-IFN-α and ribavirin (RBV). This treatment produces a sustained virological response (SVR) in approximately 55% of chronically infected patients. A number of virological factors (e.g., the hepatitis C virus [HCV] genotype and baseline titer of HCV RNA) may influence the treatment response. Indeed, the SVR rate is approximately 80% for patients infected with HCV genotypes 2 or 3, and approximately 45% for genotype 1 or 4 patients. Furthermore, the treatment duration can be modified as a function of the genotype. New drugs are being developed for the treatment of chronic hepatitis C but will probably be used in combination with the current standard therapy. This means that improvements in therapy based on a PEG-IFN-RBV combination will remain a true challenge in the coming years. Recent clinical trial results have demonstrated that the current therapy can be optimized. Modulation of the treatment duration and/or the RBV dose may increase the SVR rate. The present article reviews the current approaches to optimizing the treatment of chronic hepatitis C.
The hepatitis C virus (HCV) is a widespread infectious agent that affects approximately 170 million people worldwide. In WHO community and blood donor surveys, the African and Eastern Mediterranean countries report the highest prevalence rates (>10%). The virus is transmitted most efficiently by percutaneous exposure to infected blood (e.g., during blood transfusion, transplantation of infected organs and drug injection). Other less commonly reported modes of HCV acquisition include occupational exposure to blood, high-risk sexual activity, tattooing, body piercing and other forms of skin penetration.
Hepatitis C virus infection is a major contributor to cirrhosis and hepatocellular carcinoma (HCC), and is one of the most common indications for liver transplantation. These data justify the enormous research efforts that have been undertaken since the HCV genome was discovered in 1989. Initially, interferon (IFN)-α was administered to HCV patients three times a week for 24-48 weeks but outcomes were generally poor, with only 10-20% of patients achieving a sustained virological response (SVR; defined as undetectable HCV RNA 24 weeks post-treatment). Treatment of chronic HCV infection has since been improved by the combination of ribavirin (RBV; a broad-spectrum antiviral nucleoside analogue of guanosine) with IFN-α, yielding SVR rates of 30-40%. Several strategies for boosting IFN's therapeutic efficacy have emerged. In 2000, further progress was made with the advent of pegylated IFNs (PEG-IFNs). Two PEG-IFNs are currently available; PEG-IFN-α2a with a large, branched PEG moiety, administered at a fixed dose of 180 µg/week, and PEG-IFN-α2b, with a small, linear PEG structure, administered at a dose of 1.5 µg/kg/week.
Today's standard therapy is based on a weekly injection of PEG-IFN-α2a or -α2b and daily administration of RBV (800-1200 mg/day, adjusted for bodyweight) for 24 weeks (HCV genotypes 2 or 3) or 48 weeks (HCV genotypes 1 or 4) (Figure 1). The combination of PEG-IFN and RBV yielded SVR rates of over 50% for the first time.
(Enlarge Image)
Figure 1.
Standard treatment of chronic hepatitis C.
PEG-IFN: Pegylated interferon; RBV: Ribavirin.
Data from [70].
Several studies have highlighted the fact that the successful management of HCV-infected patients is related to the initial starting dose, the duration of therapy and the need to maintain adequate RBV exposure by minimizing RBV dose reductions whenever possible.
Many patients will either fail to respond to standard treatment or will have major side effects. Hence, the prediction of nonresponse (NR) before initiating a treatment is an attractive idea. Gene expression profiling studies are a promising approach to understanding altered molecular pathways in relation to disease outcome and response to treatment in chronic hepatitis C. Since genetic profiling is not widely available, attention has focused on the rapid virological response (RVR; defined as the achievement of an undetectable viral load after 4 weeks of treatment) and the early virological response (EVR; defined as a log 2 reduction in HCV RNA after 12 weeks of treatment) (Figure 2). Indeed, mathematical modeling and statistical analyses have revealed that the drop in HCV RNA levels in response to IFN-based therapy is bi- or possibly tri-phasic. An early study showed that the third phase of viral decay was significantly faster in patients treated with a combination of PEG-IFN-α2a plus RBV, compared with PEG-IFN-α2a alone. This third phase of viral decay may represent a delayed, treatment-induced inflation of infected cell loss. Virus-, host- or treatment-related factors (especially HCV genotype, patient ethnicity, steatosis, cirrhosis status and BMI) have been shown to influence these important kinetic parameters.
(Enlarge Image)
Figure 2.
Different types of responses to pegylated IFN-α and ribavirin. Sustained virological response: plasma hepatits C virus (HCV) RNA-negative 24 weeks after cessation of treatment. Relapse: the reappearance of HCV RNA in the plasma after therapy is discontinued. Rapid virological response: HCV RNA-negative after 1 month of treatment. Early virological response: greater than 2 log decrease in HCV RNA titer, compared with baseline. Nonresponse: failure to decrease the plasma HCV RNA titer after 24 weeks of treatment.
EVR: Early virological response; RVR: Rapid virological response; SVR: Sustained virological response.
Optimizing the standard of care may be an effective strategy for improving outcomes over the next few years.
Abstract and Chronic Hepatitis C Infection: From Interferon Alone to Response-guided Therapy
Abstract
Chronic hepatitis C is a major health concern. The current standard therapy is based on a combination of pegylated (PEG)-IFN-α and ribavirin (RBV). This treatment produces a sustained virological response (SVR) in approximately 55% of chronically infected patients. A number of virological factors (e.g., the hepatitis C virus [HCV] genotype and baseline titer of HCV RNA) may influence the treatment response. Indeed, the SVR rate is approximately 80% for patients infected with HCV genotypes 2 or 3, and approximately 45% for genotype 1 or 4 patients. Furthermore, the treatment duration can be modified as a function of the genotype. New drugs are being developed for the treatment of chronic hepatitis C but will probably be used in combination with the current standard therapy. This means that improvements in therapy based on a PEG-IFN-RBV combination will remain a true challenge in the coming years. Recent clinical trial results have demonstrated that the current therapy can be optimized. Modulation of the treatment duration and/or the RBV dose may increase the SVR rate. The present article reviews the current approaches to optimizing the treatment of chronic hepatitis C.
Chronic Hepatitis C Infection: From Interferon Alone to Response-guided Therapy
The hepatitis C virus (HCV) is a widespread infectious agent that affects approximately 170 million people worldwide. In WHO community and blood donor surveys, the African and Eastern Mediterranean countries report the highest prevalence rates (>10%). The virus is transmitted most efficiently by percutaneous exposure to infected blood (e.g., during blood transfusion, transplantation of infected organs and drug injection). Other less commonly reported modes of HCV acquisition include occupational exposure to blood, high-risk sexual activity, tattooing, body piercing and other forms of skin penetration.
Hepatitis C virus infection is a major contributor to cirrhosis and hepatocellular carcinoma (HCC), and is one of the most common indications for liver transplantation. These data justify the enormous research efforts that have been undertaken since the HCV genome was discovered in 1989. Initially, interferon (IFN)-α was administered to HCV patients three times a week for 24-48 weeks but outcomes were generally poor, with only 10-20% of patients achieving a sustained virological response (SVR; defined as undetectable HCV RNA 24 weeks post-treatment). Treatment of chronic HCV infection has since been improved by the combination of ribavirin (RBV; a broad-spectrum antiviral nucleoside analogue of guanosine) with IFN-α, yielding SVR rates of 30-40%. Several strategies for boosting IFN's therapeutic efficacy have emerged. In 2000, further progress was made with the advent of pegylated IFNs (PEG-IFNs). Two PEG-IFNs are currently available; PEG-IFN-α2a with a large, branched PEG moiety, administered at a fixed dose of 180 µg/week, and PEG-IFN-α2b, with a small, linear PEG structure, administered at a dose of 1.5 µg/kg/week.
Today's standard therapy is based on a weekly injection of PEG-IFN-α2a or -α2b and daily administration of RBV (800-1200 mg/day, adjusted for bodyweight) for 24 weeks (HCV genotypes 2 or 3) or 48 weeks (HCV genotypes 1 or 4) (Figure 1). The combination of PEG-IFN and RBV yielded SVR rates of over 50% for the first time.
(Enlarge Image)
Figure 1.
Standard treatment of chronic hepatitis C.
PEG-IFN: Pegylated interferon; RBV: Ribavirin.
Data from [70].
Several studies have highlighted the fact that the successful management of HCV-infected patients is related to the initial starting dose, the duration of therapy and the need to maintain adequate RBV exposure by minimizing RBV dose reductions whenever possible.
Many patients will either fail to respond to standard treatment or will have major side effects. Hence, the prediction of nonresponse (NR) before initiating a treatment is an attractive idea. Gene expression profiling studies are a promising approach to understanding altered molecular pathways in relation to disease outcome and response to treatment in chronic hepatitis C. Since genetic profiling is not widely available, attention has focused on the rapid virological response (RVR; defined as the achievement of an undetectable viral load after 4 weeks of treatment) and the early virological response (EVR; defined as a log 2 reduction in HCV RNA after 12 weeks of treatment) (Figure 2). Indeed, mathematical modeling and statistical analyses have revealed that the drop in HCV RNA levels in response to IFN-based therapy is bi- or possibly tri-phasic. An early study showed that the third phase of viral decay was significantly faster in patients treated with a combination of PEG-IFN-α2a plus RBV, compared with PEG-IFN-α2a alone. This third phase of viral decay may represent a delayed, treatment-induced inflation of infected cell loss. Virus-, host- or treatment-related factors (especially HCV genotype, patient ethnicity, steatosis, cirrhosis status and BMI) have been shown to influence these important kinetic parameters.
(Enlarge Image)
Figure 2.
Different types of responses to pegylated IFN-α and ribavirin. Sustained virological response: plasma hepatits C virus (HCV) RNA-negative 24 weeks after cessation of treatment. Relapse: the reappearance of HCV RNA in the plasma after therapy is discontinued. Rapid virological response: HCV RNA-negative after 1 month of treatment. Early virological response: greater than 2 log decrease in HCV RNA titer, compared with baseline. Nonresponse: failure to decrease the plasma HCV RNA titer after 24 weeks of treatment.
EVR: Early virological response; RVR: Rapid virological response; SVR: Sustained virological response.
Optimizing the standard of care may be an effective strategy for improving outcomes over the next few years.
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