Alimentary Pharmacology & Therapeutics
Early View (Online Version of Record published before inclusion in an issue)
Adding ribavirin to newer DAA regimens does not affect SVR rates in HCV genotype 1 infected persons: results from ERCHIVES
Adding ribavirin to newer DAA regimens does not affect SVR rates in HCV genotype 1 infected persons: results from ERCHIVES
A. A. Butt1,2,3,*, P. Yan1, K. Marks3, O. S. Shaikh1,4, K. E. Sherman5
Version of Record online: 26 JUL 2016
DOI: 10.1111/apt.13748Background
Ribavirin is a key component of several hepatitis C virus (HCV) treatment regimens. However, its utility in combination with newer directly acting anti-viral agents regimens is unclear.
Aim
To determine the SVR rates with paritaprevir/ritonavir/ombitasvir/dasabuvir (PrOD) regimen ± ribavirin and compare this with sofosbuvir/simeprevir and sofosbuvir/ledipasvir regimens.
Methods
We used Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES), a well-established national cohort of HCV-infected Veterans to identify HCV genotype 1 infected persons initiated on the above regimens. We excluded those with HIV coinfection, positive HBsAg and missing HCV RNA.
Results
We identified 1235 persons on PrOD (75.5% ribavirin), 1254 on sofosbuvir/simeprevir (16.9% ribavirin) and 4247 on sofosbuvir/ledipasvir (23.3% ribavirin). Among HCV genotype 1a infected persons, ribavirin was prescribed to 99.2% on PrOD, 18.2% on sofosbuvir/simeprevir and 23.3% on sofosbuvir/ledipasvir. The SVR rates ranged from 92.6% to 100% regardless of the treatment regimen, presence of cirrhosis or HCV subtype, except in PrOD group without ribavirin, HCV genotype 1a without cirrhosis (SVR 80%, N = 5). There were minor, clinically insignificant differences in SVR rates in those treated with or without ribavirin in each of the treatment groups, regardless of presence of cirrhosis at baseline. In multivariable logistic regression analysis, ribavirin use was not associated with achieving SVR in any group.
Conclusions
In HCV genotype 1 infected persons, PrOD, sofosbuvir/simeprevir and sofosbuvir/ledipasvir regimens, are associated with high rates of SVR in actual clinical settings, which are comparable to clinical trials results (except PrOD genotype 1a with cirrhosis where the number was too small). The benefit of adding ribavirin to these regimens in the ERCHIVES treated cohort is not established.
Discussion Only
Aim
To determine the SVR rates with paritaprevir/ritonavir/ombitasvir/dasabuvir (PrOD) regimen ± ribavirin and compare this with sofosbuvir/simeprevir and sofosbuvir/ledipasvir regimens.
Methods
We used Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES), a well-established national cohort of HCV-infected Veterans to identify HCV genotype 1 infected persons initiated on the above regimens. We excluded those with HIV coinfection, positive HBsAg and missing HCV RNA.
Results
We identified 1235 persons on PrOD (75.5% ribavirin), 1254 on sofosbuvir/simeprevir (16.9% ribavirin) and 4247 on sofosbuvir/ledipasvir (23.3% ribavirin). Among HCV genotype 1a infected persons, ribavirin was prescribed to 99.2% on PrOD, 18.2% on sofosbuvir/simeprevir and 23.3% on sofosbuvir/ledipasvir. The SVR rates ranged from 92.6% to 100% regardless of the treatment regimen, presence of cirrhosis or HCV subtype, except in PrOD group without ribavirin, HCV genotype 1a without cirrhosis (SVR 80%, N = 5). There were minor, clinically insignificant differences in SVR rates in those treated with or without ribavirin in each of the treatment groups, regardless of presence of cirrhosis at baseline. In multivariable logistic regression analysis, ribavirin use was not associated with achieving SVR in any group.
Conclusions
In HCV genotype 1 infected persons, PrOD, sofosbuvir/simeprevir and sofosbuvir/ledipasvir regimens, are associated with high rates of SVR in actual clinical settings, which are comparable to clinical trials results (except PrOD genotype 1a with cirrhosis where the number was too small). The benefit of adding ribavirin to these regimens in the ERCHIVES treated cohort is not established.
Discussion Only
Full Text Article Available @ Alimentary Pharmacology & Therapeutics
In this large national observational study of HCV infected persons in actual clinical settings, ribavirin use was not associated with any clinically meaningful differences in SVR rates among patients treated with newer DAA regimens. Presence of cirrhosis at baseline, HCV subtype and prior treatment status did not affect these results. Number of HCV genotype 1a infected persons treated with PrOD (without ribavirin) was too small to make any conclusions in this group (n = 6).
Our study demonstrates that treatment for HCV infection with newer oral regimens is associated with high SVR rates in actual clinical settings, and that these rates are comparable to those seen in clinical trials.[23] We have previously shown that treatment with sofosbuvir-based regimens in actual clinical settings is associated with SVR rates similar to clinical trials,[8] and this study provides similar assurance with PrOD regimen in similar settings. To our knowledge, this is among the first and largest study with data from actual clinical settings, that compares the three commonly used newer DAA agents.
Ribavirin was considered an important part of the treatment regimen with pegylated interferon and first generation DAAs. However, its role in all-oral regimens of newer DAAs is less clear. In one recent trial, virological failure was more common without ribavirin than with ribavirin among HCV genotype 1a infected patients but not among those with genotype 1b infection.[10] In another trial, ledipasvir + sofosbuvir + ribavirin for 12 weeks and ledipasvir + sofosbuvir without ribavirin for 24 weeks provided similar SVR12 rates in previous nonresponders with HCV genotype 1 and compensated cirrhosis.[24] Use of ribavirin is associated with significant haematological toxicity and drug–drug interactions, and it is a highly teratogenic agent.[25, 26] In a recent analysis of 1952 patients enrolled in phase III ION clinical trials, treatment-related adverse events were observed in 71% of patients treated with RBV, but in only 45% of patients treated without RBV.[26] While most adverse events were mild in severity and not associated with treatment discontinuation, there is some cost and risk to adding ribavirin to the regimen. Regimens without ribavirin are attractive in such settings.
The strongest and most consistent predictor of achieving SVR was duration of treatment. This is not surprising, and is consistent with numerous previous studies which have assessed patients treated in actual clinical settings.[8, 9] Future studies should assess the role of treatment adherence upon virological outcomes in these patients. Presence of cirrhosis at baseline was associated with a numerically large reduction in SVR rates (37% lower SVR rates for PrOD, 44% for sofosbuvir/simeprevir, 53% for sofosbuvir/ledipasvir), though this did not reach statistical significance in the PrOD group.
The newer treatment regimens remain associated with a low rate of adverse haematological adverse events.[27] Although anaemia was more common in those who received ribavirin, severe (grade 3/4) anaemia remains uncommon overall. In previous studies, we have shown that haematological parameters revert towards baseline after completion of treatment, providing some reassurance regarding the safety of these regimens.[9]
While our study provides new and important clinical information about newer DAA regimens derived from a well-established national database, there are certain limitations that need to be addressed when analysing administrative databases. The information in such databases is collected as part of routine clinical care, and is thus not always collected at rigorously defined time-points during the course of treatment. Given this is an observational study and not a randomized study of ribavirin use, confounding by indication is of concern. Persons who received ribavirin may have been harder to treat; however, in multivariate analysis controlling for these baseline predictors did not reveal a benefit of ribavirin use. Laboratory testing was performed at different laboratories, and subtle differences in results may affect overall results. Definition of cirrhosis was based on a non-invasive clinical marker (FIB-4 score), which was based on routine laboratory testing which may have been performed at different time-points prior to baseline. Number of persons in HCV genotype 1a PrOD group was too small (n = 6) to make any conclusions, and clinical trials data suggest that adding ribavirin in genotype 1a patients may be of some benefit.[10] We also did not analyse the role of resistance associated mutations upon virological response rates.
In conclusion, in HCV genotype 1 infected persons, PrOD, sofosbuvir/simeprevir and sofosbuvir/ledipasvir regimens are associated with high rates of SVR in actual clinical settings, which are comparable to those achieved in clinical trials (except PrOD genotype 1a with cirrhosis where number was too small). Addition of ribavirin to the regimen does not appear to enhance SVR rates in a clinically meaningful way, with the caveat that the number of persons in HCV genotype 1a PrOD group was too small to make any conclusions.
In this large national observational study of HCV infected persons in actual clinical settings, ribavirin use was not associated with any clinically meaningful differences in SVR rates among patients treated with newer DAA regimens. Presence of cirrhosis at baseline, HCV subtype and prior treatment status did not affect these results. Number of HCV genotype 1a infected persons treated with PrOD (without ribavirin) was too small to make any conclusions in this group (n = 6).
Our study demonstrates that treatment for HCV infection with newer oral regimens is associated with high SVR rates in actual clinical settings, and that these rates are comparable to those seen in clinical trials.[23] We have previously shown that treatment with sofosbuvir-based regimens in actual clinical settings is associated with SVR rates similar to clinical trials,[8] and this study provides similar assurance with PrOD regimen in similar settings. To our knowledge, this is among the first and largest study with data from actual clinical settings, that compares the three commonly used newer DAA agents.
Ribavirin was considered an important part of the treatment regimen with pegylated interferon and first generation DAAs. However, its role in all-oral regimens of newer DAAs is less clear. In one recent trial, virological failure was more common without ribavirin than with ribavirin among HCV genotype 1a infected patients but not among those with genotype 1b infection.[10] In another trial, ledipasvir + sofosbuvir + ribavirin for 12 weeks and ledipasvir + sofosbuvir without ribavirin for 24 weeks provided similar SVR12 rates in previous nonresponders with HCV genotype 1 and compensated cirrhosis.[24] Use of ribavirin is associated with significant haematological toxicity and drug–drug interactions, and it is a highly teratogenic agent.[25, 26] In a recent analysis of 1952 patients enrolled in phase III ION clinical trials, treatment-related adverse events were observed in 71% of patients treated with RBV, but in only 45% of patients treated without RBV.[26] While most adverse events were mild in severity and not associated with treatment discontinuation, there is some cost and risk to adding ribavirin to the regimen. Regimens without ribavirin are attractive in such settings.
The strongest and most consistent predictor of achieving SVR was duration of treatment. This is not surprising, and is consistent with numerous previous studies which have assessed patients treated in actual clinical settings.[8, 9] Future studies should assess the role of treatment adherence upon virological outcomes in these patients. Presence of cirrhosis at baseline was associated with a numerically large reduction in SVR rates (37% lower SVR rates for PrOD, 44% for sofosbuvir/simeprevir, 53% for sofosbuvir/ledipasvir), though this did not reach statistical significance in the PrOD group.
The newer treatment regimens remain associated with a low rate of adverse haematological adverse events.[27] Although anaemia was more common in those who received ribavirin, severe (grade 3/4) anaemia remains uncommon overall. In previous studies, we have shown that haematological parameters revert towards baseline after completion of treatment, providing some reassurance regarding the safety of these regimens.[9]
While our study provides new and important clinical information about newer DAA regimens derived from a well-established national database, there are certain limitations that need to be addressed when analysing administrative databases. The information in such databases is collected as part of routine clinical care, and is thus not always collected at rigorously defined time-points during the course of treatment. Given this is an observational study and not a randomized study of ribavirin use, confounding by indication is of concern. Persons who received ribavirin may have been harder to treat; however, in multivariate analysis controlling for these baseline predictors did not reveal a benefit of ribavirin use. Laboratory testing was performed at different laboratories, and subtle differences in results may affect overall results. Definition of cirrhosis was based on a non-invasive clinical marker (FIB-4 score), which was based on routine laboratory testing which may have been performed at different time-points prior to baseline. Number of persons in HCV genotype 1a PrOD group was too small (n = 6) to make any conclusions, and clinical trials data suggest that adding ribavirin in genotype 1a patients may be of some benefit.[10] We also did not analyse the role of resistance associated mutations upon virological response rates.
In conclusion, in HCV genotype 1 infected persons, PrOD, sofosbuvir/simeprevir and sofosbuvir/ledipasvir regimens are associated with high rates of SVR in actual clinical settings, which are comparable to those achieved in clinical trials (except PrOD genotype 1a with cirrhosis where number was too small). Addition of ribavirin to the regimen does not appear to enhance SVR rates in a clinically meaningful way, with the caveat that the number of persons in HCV genotype 1a PrOD group was too small to make any conclusions.
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