Expert Commentary
Paul J. Pockros, MD
Posting Date: December 19, 2011
Head, Division of Gastroenterology/Hepatology
Director, SC Liver Research Consortium
Clinical Director of Research, Scripps Translational Science Institute
The Scripps Clinic
La Jolla, California
Editor’s note: In this edition of Journal Options Hepatitis, we feature the 5 pivotal phase III studies that led to the approval in 2011 of boceprevir and telaprevir for the treatment of chronic hepatitis C. Each commentary in this series addresses a key issue or question of clinical relevance related to the use of these agents in clinical practice.
Patients with cirrhosis or advanced fibrosis due to hepatitis C virus (HCV) are a particularly challenging group to treat with combination therapy that includes 1 of the currently approved direct-acting antivirals (DAA), boceprevir or telaprevir. Patients with decompensated cirrhosis have the greatest need for curative therapy; however, these individuals were not studied in the pivotal trials of boceprevir and telaprevir and are not included in the prescribing information for either drug; therefore, there is significant risk associated with treating this group of patients in the absence of experience or guidelines.[1-3] Although patients with compensated cirrhosis were included in the phase III trials of both telaprevir and boceprevir, the number of these patients is too small on which to base treatment decisions with confidence. Furthermore, patients with cirrhosis who failed previous therapy—individuals comprising a significant proportion of our current patient population—do not respond as well as others to triple therapy and will often develop protease inhibitor–resistant variants at the time of treatment failure.[4]
So how should clinicians go about implementing telaprevir and boceprevir as treatment in patients with advanced fibrosis or cirrhosis? Here I describe what we know about telaprevir and boceprevir in patients with advanced liver disease based on data from the pivotal clinical trials, along with how my colleagues and I currently go about treating these individuals in clinical practice.
Compensated Cirrhosis
Implementing Telaprevir and Boceprevir
The combined data for patients with compensated cirrhosis in all 3 phase III trials of telaprevir revealed an overall sustained virologic response (SVR) rate of 62%, and combined data in fixed-duration and response-guided arms for boceprevir demonstrated an SVR rate of 48%, rates which are certainly high enough to warrant treating compensated cirrhosis.[5-9] Notably, the addition of IL28B testing does not provide sufficient specificity to aid in predicting which cases are likely to fail treatment, and thus we do not use this routinely in my practice for cirrhotic patients.[10,11]
Data from the REALIZE trial showed much lower SVR rates with telaprevir-based therapy among previous null responders to peginterferon/ribavirin with cirrhosis (14%) or bridging fibrosis (30%).[7] Similar data are not available for boceprevir because of the exclusion of null responders in the RESPOND-2 trial.[9] Subanalysis of the arm from REALIZE that received 4 weeks of lead-in treatment with peginterferon/ribavirin before addition of telaprevir indicated that a < 1 log10 IU/mL decrease in HCV RNA at Week 4 was associated with treatment failure in patients with compensated cirrhosis, whereas a ≥ 1 log10 IU/mL decrease in HCV RNA was associated with SVR in approximately 50%.[12] Although it is not recommended in the prescribing information for telaprevir, based on these findings, my colleagues and I routinely employ a 4-week peginterferon/ribavirin lead-in for all null responder patients with advanced liver fibrosis, and we do not initiate telaprevir until the HCV RNA value at Week 4 has been reviewed. For treatment-experienced patients lacking interferon sensitivity, we defer therapy for future clinical trials of quadruple therapy or interferon-free regimens (eg, daclatasvir, asunaprevir, and peginterferon/ribavirin; PSI-7977 plus ribavirin; others).[13]
Similarly, when planning to use boceprevir in patients with compensated cirrhosis, my colleagues and I implement the 4-week peginterferon/ribavirin lead-in phase, as indicated in the boceprevir prescribing information.[2] We wait to see the HCV RNA results at Week 4 before deciding whether to expose patients to boceprevir. If patients do not have at least a 1-log10 reduction in HCV RNA from baseline, we defer therapy or enroll patients in clinical trials. Other experts follow the recommendations in the prescribing information and continue therapy until the 12-week futility rule evaluation point and use response at this time point to determine whether treatment should be continued.
Duration of Therapy
Although we have no published data regarding the benefit of extending peginterferon/ribavirin therapy to 48 weeks in cirrhotic patients who achieve an extended rapid virologic response (ie, undetectable HCV RNA at Weeks 4 and 12) on telaprevir/peginterferon/ribavirin, the telaprevir prescribing information provides a small amount of data on this issue. Of 30 patients with cirrhosis who achieved an extended rapid virologic response, 67% (12 of 18) attained SVR when the duration of peginterferon/ribavirin was shortened to 24 weeks, and 92% (11 of 12) attained SVR when peginterferon/ribavirin was administered for the full 48 weeks.[1] These are very small numbers on which to base treatment decisions, and we need more robust studies in cirrhotics to evaluate the duration of peginterferon/ribavirin therapy when combined with telaprevir. Because these data are not yet available, I administer peginterferon/ribavirin for the full 48 weeks in cirrhotic patients if they can tolerate it; I shorten therapy to 24 weeks if they cannot.
With regard to boceprevir, the prescribing information clearly indicates that patients with compensated cirrhosis should receive 4 weeks of peginterferon/ribavirin followed by 44 weeks of boceprevir in combination with peginterferon/ribavirin.[2] This is based on data from clinical trials that clearly show a benefit of fixed-duration rather than response-guided therapy in this population.[2] Although the numbers are again small, among treatment-naive cirrhotic patients, SVR rates were 42% (10 of 24) with a fixed-duration 48-week regimen vs 31% (5 of 16) when response-guided therapy was employed. Among treatment-naive individuals, SVR rates were 77% (17 of 22) and 35% (6 of 17), respectively, with fixed vs response-guided therapy. Thus, when treating with boceprevir, I administer the recommended 48 weeks of peginterferon/ribavirin in cirrhotic patients if they can tolerate it. If the patient is unable to tolerate 48 weeks of peginterferon plus ribavirin, we push duration as long as possible to that point, but at least 24 weeks. It is expected that shortened durations of therapy would compromise efficacy.
Dosing
No dosage adjustment of boceprevir is recommended for patients with mild, moderate, or severe hepatic impairment.[2] Dose modification of telaprevir is not required when it is administered to patients with mild hepatic impairment (Child-Pugh A, score 5-6), although a 15% reduction in steady-state exposure was observed in HCV-negative subjects with mild hepatic impairment compared with healthy subjects.[1] When my colleagues and I treat patients with compensated cirrhosis with telaprevir, we do not adjust the telaprevir dosage. However, when treating patients with compensated cirrhosis with either protease inhibitor, we monitor weekly for expected reductions in white and red blood cell counts, and we implement higher thresholds for reducing the dosage of peginterferon or ribavirin when declines in absolute neutrophil count and hemoglobin occur. Specifically, we will normally dose-reduce ribavirin for hemoglobin levels < 10 g/dL and peginterferon for an absolute neutrophil count < 500.For more information on anemia management, see the accompanying commentary by Brian Pearlman.
Decompensated Cirrhosis
Telaprevir is not recommended for use in patients with moderate or severe hepatic impairment (Child-Pugh B or C, score ≥ 7).[1] My colleagues and I have selected a few patients with a prior history of a single decompensation event (eg, a remote history of variceal bleeding followed by stability and low Model of End-Stage Liver Disease scores for years) to undergo triple therapy with telaprevir/peginterferon/ribavirin. This was done only after patients completed a transplant evaluation and were approved and/or listed. Thus far, 3 of 6 patients have decompensated (1 from hepatic encephalopathy, 2 because of new-onset ascites with spontaneous bacterial peritonitis), likely due to the peginterferon component of the regimen. All 3 patients were hospitalized and treatment was stopped; all recovered.
The safety and efficacy of boceprevir have not been studied in patients with decompensated cirrhosis, and the poor safety and tolerability of peginterferon/ribavirin in patients with decompensated cirrhosis remains a contraindication to treatment in this population.[8,9] My colleagues and I have not yet treated patients with decompensated cirrhosis with boceprevir. However, the data in cirrhotics in the pivotal trials of boceprevir were equally as good as those with telaprevir, so we are currently beginning to start patients on this regimen.
To date, treatment with protease inhibitor–based therapy in decompensated cirrhotics cannot be recommended outside of centers highly experienced in the management of this patient population.
Please review the remaining 4 commentaries in this series on the use of boceprevir and telaprevir in clinical practice:
- To review strategies for management of telaprevir-associated rash and anorectal symptoms, click here.
- For a better understanding of futility rules and their importance with boceprevir and telaprevir, click here.
- To review the impact of the occurrence and management of anemia with boceprevir and telaprevir, click here.
- To review rules for following response-guided therapy guidelines with telaprevir and boceprevir, click here.
References
1. Incivek [package insert]. Cambridge, Mass: Vertex Pharmaceuticals Inc.; 2011.
2. Victrelis [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2011.
3. Ghany MG, Nelson DR, Strader DB, et al. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54:1433-1444.
4. Pockros PJ. Drugs in development for viral hepatitis: care and caution. Drugs. 2011;71:263-271.
5. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405-2416.
6. Sherman KE, Flamm SL, Afdhal NH, et al. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med. 2011;365:1014-1024.
7. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364:2417-2428.
8. Poordad F, McCone J, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-1206.
9. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1207-1217.
10. Pol S, Aerssens J, Zeuzem S, et al. Similar SVR rates in IL28B CC, CT or TT prior relapser, partial- or null-responder patients treated with telaprevir/peginterferon/ribavirin: retrospective analysis of the REALIZE study. J Hepatol. 2011;54(suppl 1):S6.
11. Poordad F, Bronowicki JP, Gordon SC, et al. IL28B polymorphism predicts virologic response in patients with hepatitis C genotype 1 treated with boceprevir (BOC) combination therapy. Program and abstracts of the 46th Annual Meeting of the European Association for the Study of the Liver; March 30 - April 3, 2011; Berlin, Germany. Abstract 12.
12. Zeuzem S, Foster GR, Andreone P, et al. Different likelihood of achieving SVR on a telaprevir-containing regimen among null responders, partial responders and relapsers irrespective of similar responses after a peginterferon/ribavirin 4-week lead-in phase: REALIZE study subanalysis. Hepatology. 2011;54(suppl):986A.
13. Lok A, Gardiner D, Lawitz E, et al. Quadruple therapy with BMS-790052, BMS-650032 and PEG-IFN/RBV for 24 weeks results in 100% SVR12 in HCV genotype 1 null responders. J Hepatol. 2011;54(suppl 1):S536.
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