Exposure to Ribavirin Predicts EVR and SVR in Patients With HCV Genotype 1
Exposure to Ribavirin Predicts EVR and SVR in Patients With HCV Genotype 1
Background: The impact of reduced drug exposure on outcomes in patients with chronic hepatitis C has not been determined in routine clinical practice.
Aim: To examine the impact of exposure to peginterferon alfa-2a and ribavirin on early virological response (EVR) and sustained virological response (SVR) in treatment-nave patients with HCV genotype 1 infection enrolled in a large expanded access programme.
Methods: Eight hundred and ninety-one patients treated for 48 weeks with an initial ribavirin dose of 800 or 1000/1200 mg/day were evaluated. Ribavirin 1000 mg/day (<75 kg) or 1200 mg/day (≥75 kg) and peginterferon alfa-2a 180 μg/week were considered optimal. The impact of reduced drug exposure (expressed as a percentage of optimal) on EVR and SVR was evaluated.
Results: Mean ribavirin exposure in week 0-12 was 70% and 96% in patients assigned to ribavirin 800 and 1000/1200 mg/day, respectively. EVR and SVR rates were lower in patients assigned to ribavirin 800 than 1000/1200 mg/day (EVR, 75% vs. 84%, respectively, P < 0.001; SVR, 45% vs. 54%, respectively, P = 0.011). Furthermore, there was a strong correlation between achievement of EVR and SVR and ribavirin dose over the first 12 weeks expressed either as absolute dose or proportion of optimal dose received (P < 0.001 for both).
Conclusions: Ribavirin exposure to week 12 is significantly associated with EVR and SVR in genotype 1 patients. Maintenance of an optimal ribavirin dose is the most important modifiable factor during combination therapy for chronic hepatitis C.
The combination of pegylated interferon plus ribavirin is the treatment of choice for chronic hepatitis C. On the basis of results from a randomized multicentre trial, guidelines recommend that patients infected with hepatitis C virus (HCV) genotype 1 should be treated for a total of 48 weeks with a regimen that includes ribavirin at a daily dose of 1000 or 1200 mg/day.
Ribavirin can cause dose-dependent haemolytic anaemia and pegylated interferon can cause flu-like symptoms, both of which may result in fatigue and adversely affect patients' quality of life and adherence. Anaemia is managed by temporary or permanent reductions in the dose of ribavirin. Likewise, dose modifications of pegylated interferon may be required to manage adverse events or laboratory abnormalities. For this reason, patients often receive less than the recommended optimal drug doses.
Patients who fail to achieve an early virological response (EVR) by week 12 of combination therapy are highly unlikely to achieve an SVR. For this reason, treatment guidelines recommend that treatment be discontinued in patients who do not achieve an EVR.
Analyses of large randomized trials suggest that exposure to ribavirin is a significant predictor of SVR. In the first such analysis by McHutchison et al., maintenance of 80% exposure to pegylated interferon alfa-2b and ribavirin was shown to enhance SVR rates in genotype 1 patients. In contrast to these findings in the highly controlled environment of a randomized clinical trial, the exact impact of reduced drug exposure to treatment on EVR and SVR has not been determined in routine clinical practice.
The PEGASYS expanded access programme (EAP) is a large multicentre programme in which more than 2000 patients with chronic hepatitis C were treated in diverse settings including tertiary academic medical centres and community gastroenterology practices across Canada. The overall results suggest that SVR rates achieved in pivotal trials can be replicated in routine clinical practice.
We examined the relationship between exposure to peginterferon alfa-2a and ribavirin, as continuous variables, and the probability of SVR in treatment-nave, genotype 1 patients enrolled in the EAP.
Background: The impact of reduced drug exposure on outcomes in patients with chronic hepatitis C has not been determined in routine clinical practice.
Aim: To examine the impact of exposure to peginterferon alfa-2a and ribavirin on early virological response (EVR) and sustained virological response (SVR) in treatment-nave patients with HCV genotype 1 infection enrolled in a large expanded access programme.
Methods: Eight hundred and ninety-one patients treated for 48 weeks with an initial ribavirin dose of 800 or 1000/1200 mg/day were evaluated. Ribavirin 1000 mg/day (<75 kg) or 1200 mg/day (≥75 kg) and peginterferon alfa-2a 180 μg/week were considered optimal. The impact of reduced drug exposure (expressed as a percentage of optimal) on EVR and SVR was evaluated.
Results: Mean ribavirin exposure in week 0-12 was 70% and 96% in patients assigned to ribavirin 800 and 1000/1200 mg/day, respectively. EVR and SVR rates were lower in patients assigned to ribavirin 800 than 1000/1200 mg/day (EVR, 75% vs. 84%, respectively, P < 0.001; SVR, 45% vs. 54%, respectively, P = 0.011). Furthermore, there was a strong correlation between achievement of EVR and SVR and ribavirin dose over the first 12 weeks expressed either as absolute dose or proportion of optimal dose received (P < 0.001 for both).
Conclusions: Ribavirin exposure to week 12 is significantly associated with EVR and SVR in genotype 1 patients. Maintenance of an optimal ribavirin dose is the most important modifiable factor during combination therapy for chronic hepatitis C.
The combination of pegylated interferon plus ribavirin is the treatment of choice for chronic hepatitis C. On the basis of results from a randomized multicentre trial, guidelines recommend that patients infected with hepatitis C virus (HCV) genotype 1 should be treated for a total of 48 weeks with a regimen that includes ribavirin at a daily dose of 1000 or 1200 mg/day.
Ribavirin can cause dose-dependent haemolytic anaemia and pegylated interferon can cause flu-like symptoms, both of which may result in fatigue and adversely affect patients' quality of life and adherence. Anaemia is managed by temporary or permanent reductions in the dose of ribavirin. Likewise, dose modifications of pegylated interferon may be required to manage adverse events or laboratory abnormalities. For this reason, patients often receive less than the recommended optimal drug doses.
Patients who fail to achieve an early virological response (EVR) by week 12 of combination therapy are highly unlikely to achieve an SVR. For this reason, treatment guidelines recommend that treatment be discontinued in patients who do not achieve an EVR.
Analyses of large randomized trials suggest that exposure to ribavirin is a significant predictor of SVR. In the first such analysis by McHutchison et al., maintenance of 80% exposure to pegylated interferon alfa-2b and ribavirin was shown to enhance SVR rates in genotype 1 patients. In contrast to these findings in the highly controlled environment of a randomized clinical trial, the exact impact of reduced drug exposure to treatment on EVR and SVR has not been determined in routine clinical practice.
The PEGASYS expanded access programme (EAP) is a large multicentre programme in which more than 2000 patients with chronic hepatitis C were treated in diverse settings including tertiary academic medical centres and community gastroenterology practices across Canada. The overall results suggest that SVR rates achieved in pivotal trials can be replicated in routine clinical practice.
We examined the relationship between exposure to peginterferon alfa-2a and ribavirin, as continuous variables, and the probability of SVR in treatment-nave, genotype 1 patients enrolled in the EAP.