A few years ago, hepatitis physicians got excited about the approval of the first direct-acting antiviral agents (DAA) for hepatitis C virus (HCV) therapy, the NS3/4A protease inhibitors boceprevir and telaprevir. In treatment-naive patients, an approximate 30% increase in sustained virologic response (SVR) rates was achieved with the addition of either boceprevir or telaprevir to the long-standing standard of care, peginterferon and ribavirin. In treatment-experienced patients, the response rates for virologic relapsers were excellent, but they were a good deal lower for previous peginterferon/ribavirin partial and null responders, particularly those with more advanced liver disease. The discussion was fierce as to whether or not previous null responders with advanced fibrosis or cirrhosis should be treated with these regimens, given that SVR rates in this population were only approximately 15%. Data from the real-world CUPIC cohort study in cirrhotic patients recently reminded us that interferon-based therapies have the potential to be dangerous and are associated with a high incidence of morbidity and mortality in patients with specific risk factors, including serum albumin < 3.5 g/dL and/or platelets < 100,000 cells/mm3.
Although only 10% to 20% of previously untreated patients and relapsers experienced virologic failure on first-generation protease inhibitors, the rate of virologic breakthrough and relapse was much higher in patients with cirrhosis and a previous partial or null response to peginterferon and ribavirin. The latter patients continue to have an urgent indication for therapy, but what can we offer?
The majority of patients who developed virologic failure on first-generation protease inhibitors selected for resistance associated variants (RAVs). Early studies showed that a proportion of RAVs reverted back to wild-type variants (faster for HCV genotype 1b than for genotype 1a isolates) most likely due to lower replication fitness of the RAVs compared with wild-type variants. In theory, patients with apparent disappearance of RAVs could be retreated with protease inhibitors in combination with peginterferon and ribavirin and perhaps a second DAA. This concept has never been investigated in larger clinical trials, although small case series supported its general plausibility. Treatment guidelines from the AASLD/IDSA recommend that patients in whom previous treatment with boceprevir or telaprevir has failed should not be retreated with peginterferon/ribavirin plus a protease inhibitor, however, given the shortage of data supporting this approach.
My Approaches Now and In the Future
An approach I have used for patients who did not respond to triple therapy with a first-generation protease inhibitor is retreatment with peginterferon and ribavirin in combination with an agent from a different class of DAA. The combination of peginterferon and ribavirin with the nucleoside polymerase inhibitor sofosbuvir seems like an attractive option given its current clinical availability. However, this treatment strategy has not been formally investigated in large clinical studies of genotype 1 patients; indeed the NEUTRINO study that evaluated peginterferon/ribavirin plus sofosbuvir for genotype 1 infection did not enroll any treatment-experienced patients. This treatment strategy was recently evaluated by Pol and colleagues in a small trial in 80 patients who did not respond to treatment with peginterferon/ribavirin plus an investigational protease inhibitor with or without 1 or 2 additional DAAs. However, the data from this study are not yet fully published. Despite the presence of multiple resistance associated variants at baseline, the overall SVR12 rate among 50 evaluable patients was 74%. In my limited personal experience, the NEUTRINO-like approach (peginterferon, ribavirin, and sofosbuvir for 12 weeks) works well in patients who did not respond to boceprevir- or telaprevir-based triple therapy, and this approach is recommended in the AASLD/IDSA guidelines. Another strategy recommended in the AASLD/IDSA guidelines for this population is sofosbuvir for 12 weeks plus peginterferon and ribavirin for 24 weeks, whereas sofosbuvir plus ribavirin for 24 weeks or peginterferon, ribavirin, and sofosbuvir for 24 weeks are included as alternative approaches. None of these strategies, however, has been formally evaluated in large clinical trials.
New Retreatment Strategies Presented at EASL
Exciting data on the use of all-oral treatment for the management of patients who did not achieve SVR during protease inhibitor therapy have emerged during the past year. In a phase II study first presented at EASL 2013, patients who failed triple therapy with a protease inhibitor were retreated with only 2 DAAs (sofosbuvir and the NS5A inhibitor daclatasvir) with or without ribavirin, but without peginterferon, for 24 weeks. In this retreatment study, all patients receiving the ribavirin-free regimen and 95% of those who received 2 DAAs plus ribavirin achieved SVR12. The efficacy of this approach was confirmed in a recent phase III study presented at the 2014 EASL meeting, ION-2, where patients who failed previous peginterferon/ribavirin with or without a protease inhibitor were retreated with sofosbuvir and a different NS5A inhibitor, ledipasvir, with or without ribavirin for 12 or 24 weeks. SVR rates in this study exceeded 94%. Clearly, with these data, interferon-free retreatment strategies with a potent nucleoside polymerase inhibitor and an NS5A inhibitor will be the preferred option for patients failing protease inhibitor–containing triple therapy, whenever these drugs are accessible.
Your Thoughts?
I’m interested to hear about your own approach to managing patients who have failed boceprevir- or telaprevir-containing regimens, given the recent data presented at EASL 2014. What is your preferred strategy in this setting? Please use the comments section below to provide your insights.
Although only 10% to 20% of previously untreated patients and relapsers experienced virologic failure on first-generation protease inhibitors, the rate of virologic breakthrough and relapse was much higher in patients with cirrhosis and a previous partial or null response to peginterferon and ribavirin. The latter patients continue to have an urgent indication for therapy, but what can we offer?
The majority of patients who developed virologic failure on first-generation protease inhibitors selected for resistance associated variants (RAVs). Early studies showed that a proportion of RAVs reverted back to wild-type variants (faster for HCV genotype 1b than for genotype 1a isolates) most likely due to lower replication fitness of the RAVs compared with wild-type variants. In theory, patients with apparent disappearance of RAVs could be retreated with protease inhibitors in combination with peginterferon and ribavirin and perhaps a second DAA. This concept has never been investigated in larger clinical trials, although small case series supported its general plausibility. Treatment guidelines from the AASLD/IDSA recommend that patients in whom previous treatment with boceprevir or telaprevir has failed should not be retreated with peginterferon/ribavirin plus a protease inhibitor, however, given the shortage of data supporting this approach.
My Approaches Now and In the Future
An approach I have used for patients who did not respond to triple therapy with a first-generation protease inhibitor is retreatment with peginterferon and ribavirin in combination with an agent from a different class of DAA. The combination of peginterferon and ribavirin with the nucleoside polymerase inhibitor sofosbuvir seems like an attractive option given its current clinical availability. However, this treatment strategy has not been formally investigated in large clinical studies of genotype 1 patients; indeed the NEUTRINO study that evaluated peginterferon/ribavirin plus sofosbuvir for genotype 1 infection did not enroll any treatment-experienced patients. This treatment strategy was recently evaluated by Pol and colleagues in a small trial in 80 patients who did not respond to treatment with peginterferon/ribavirin plus an investigational protease inhibitor with or without 1 or 2 additional DAAs. However, the data from this study are not yet fully published. Despite the presence of multiple resistance associated variants at baseline, the overall SVR12 rate among 50 evaluable patients was 74%. In my limited personal experience, the NEUTRINO-like approach (peginterferon, ribavirin, and sofosbuvir for 12 weeks) works well in patients who did not respond to boceprevir- or telaprevir-based triple therapy, and this approach is recommended in the AASLD/IDSA guidelines. Another strategy recommended in the AASLD/IDSA guidelines for this population is sofosbuvir for 12 weeks plus peginterferon and ribavirin for 24 weeks, whereas sofosbuvir plus ribavirin for 24 weeks or peginterferon, ribavirin, and sofosbuvir for 24 weeks are included as alternative approaches. None of these strategies, however, has been formally evaluated in large clinical trials.
New Retreatment Strategies Presented at EASL
Exciting data on the use of all-oral treatment for the management of patients who did not achieve SVR during protease inhibitor therapy have emerged during the past year. In a phase II study first presented at EASL 2013, patients who failed triple therapy with a protease inhibitor were retreated with only 2 DAAs (sofosbuvir and the NS5A inhibitor daclatasvir) with or without ribavirin, but without peginterferon, for 24 weeks. In this retreatment study, all patients receiving the ribavirin-free regimen and 95% of those who received 2 DAAs plus ribavirin achieved SVR12. The efficacy of this approach was confirmed in a recent phase III study presented at the 2014 EASL meeting, ION-2, where patients who failed previous peginterferon/ribavirin with or without a protease inhibitor were retreated with sofosbuvir and a different NS5A inhibitor, ledipasvir, with or without ribavirin for 12 or 24 weeks. SVR rates in this study exceeded 94%. Clearly, with these data, interferon-free retreatment strategies with a potent nucleoside polymerase inhibitor and an NS5A inhibitor will be the preferred option for patients failing protease inhibitor–containing triple therapy, whenever these drugs are accessible.
Your Thoughts?
I’m interested to hear about your own approach to managing patients who have failed boceprevir- or telaprevir-containing regimens, given the recent data presented at EASL 2014. What is your preferred strategy in this setting? Please use the comments section below to provide your insights.
Topics: HCV - Treatment
New This Month: Clinical Thoughts
Post-EASL Update: What Is the Role of Treatment Guidelines in the Current HCV Era?
New This Month: Clinical Thoughts
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With the new era of HCV therapies comes a new era in clinical guidelines; although there is certainly overlap, the major guidelines serve different but important roles.
Post-EASL Update: Reconsidering Whether to Treat Genotype 1 HCV Patients or Wait for All-Oral Therapy
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Following the presentation of phase III data on new all-oral regimens for genotype 1 HCV at EASL, which patients might wait for the approval of new therapies and which should be treated now?
Treating HBV Patients With Cirrhosis: The Need for Vigilant HCC Screening
Treating HBV Patients With Cirrhosis: The Need for Vigilant HCC Screening
Antiviral therapy can dramatically improve liver histology, even in cirrhotic patients, but it remains critical to screen patients with suppressed viral load for hepatocellular carcinoma.
Clinical Care Options
Clinical Care Options
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