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AASLD 2012: Patients with Cirrhosis Can Respond Well to Boceprevir or Telaprevir with Careful Monitoring

Real-world experience in the French early-access CUPIC study shows that hepatitis C patients with advanced liver damage can achieve good response to interferon-based triple-therapy including boceprevir (Victrelis) or telaprevir (Incivek), although adverse events are common, according to a presentation at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2012) last month in Boston.

Over years or decades, people with chronic hepatitis C virus (HCV) infection can develop advanced liver disease including cirrhosis or hepatocellular carcinoma. While people with serious liver damage are most urgently in need of treatment, they do not respond as well to interferon-based therapy and are more susceptible to severe side effects.

Pivotal trials of new drugs typically do not include the most difficult-to-treat patient groups, both because pharmaceutical companies want their candidates to perform as well as possible, and because people with advanced disease are most likely to experience safety problems.

Such individuals may be able to access new treatments through early and expanded access programs that run alongside controlled clinical trials, however. In France, early access is available through the Temporary Authorization for Use, or ATU, program while drugs are awaiting marketing authorization.

CUPIC (ANRS CO20), under the auspices of the French National Agency for Research on AIDS and Viral Hepatitis, is a national multicenter observational study in the ATU setting of compassionate use of HCV protease inhibitors for hepatitis C patients with cirrhosis who were non-responders to prior interferon-based therapy.

Christophe Hézode From Hôpital Henri Mondor in Paris presented findings from a 16-week analysis of nearly 500 CUPIC participants who were treated with boceprevir or telaprevir plus pegylated interferon and ribavirin.

The Phase 3 SPRINT-2 and RESPOND-2 trials showed that people receiving triple therapy with boceprevir had more anemia and dysgeusia (odd taste sensations) than those on pegylated interferon/ribavirin alone. The ADVANCE, ILLUMINATE, and REALIZE trials likewise found that telaprevir recipients were more likely to experience anemia, rash, and pruritus (itching). However, Hezode noted, these studies included only a small number of people with liver cirrhosis -- 115 total in the boceprevir trials and 247 in the telaprevir trials.

Between February 2011 and April 2012, a total of 674 treatment-experienced hepatitis C patients with cirrhosis were enrolled in the CUPIC cohort at 56 sites throughout France. The present analysis included 497 participants:

• 205 patients who received 800 mg boceprevir every 8 hours plus pegylated interferon alfa-2b (PegIntron) and 800-1400 mg/day weight adjusted ribavirin for 48 weeks, with a 4-week interferon/ribavirin lead-in before starting boceprevir.
• 292 patients who received 750 mg telaprevir every 8 hours plus pegylated interferon alfa-2a (Pegasys) and 1000-1200 mg/day weight adjusted ribavirin for 12 weeks, followed by interferon/ribavirin alone through week 48.

A majority of participants (68%) were men and the mean age was 57 years. About half had HCV subtype 1b, 30%-40% had harder-to-treat subtype 1a, and the rest had other genotypes. About two-thirds had high baseline HCV viral load (>800,000 IU/mL). At baseline they had normal hemoglobin levels (nearly 15 g/dL) and platelet counts (mean of approximately 150,000/mm³). Participants had compensated cirrhosis; most had Child-Pugh class A liver function (the least severe level) and MELD scores below 10.  

Results

Boceprevir Efficacy:

• Only 2% of boceprevir recipients experienced rapid virological response (RVR) at 4 weeks in an intent-to-treat analysis.
• Response rates rose to 38% by 8 weeks, 55% at 12 weeks, and 58% at 16 weeks.
• In a per-protocol or as-treated analysis, the corresponding rates were 3%, 42%, 64%, and 77%, respectively.

Telaprevir Efficacy:

• Telaprevir proved more effective overall in reducing HCV viral load.
• At 4 weeks the RVR rate was 55% in an intent-to-treat analysis.
• Response rates rose to 80% by 8 weeks and 79% at 12 weeks, but fell back to 67% at 16 weeks.
• In a per-protocol analysis, response rates remained high at 58%, 92%, 93%, and 92%, respectively.

Boceprevir Safety:

• 33% of boceprevir recipients experienced serious adverse events.
• 26% stopped treatment prematurely.
• 7% stopped early did so due to adverse events.
• 1 patient died, 6 experienced hepatic decompensation, and 5 had serious (grade 3/4) infections.
• None developed severe rash or kidney failure.
• 23% developed grade 2 anemia (hemoglobin 8.0-9.0 g/dL), 4% developed grade 3/4 anemia (hemoglobin < 8.0 g/dL), 46% used erythropoietin (EPO), 6% received blood transfusions, and 11% had ribavirin dose reductions.
• 1% developed grade 3, and 3% developed grade 4 thrombocytopenia (low platelet count).
• 5% developed grade 3, and 2% developed grade 4 neutropenia (low white blood cell count).

Telaprevir Safety:

• Telaprevir was less well-tolerated overall.
• 45% of telaprevir recipients experienced serious adverse events.
• 23% stopped treatment prematurely.
• 15% did so due to adverse events.
• 5 patients died, 6 experienced hepatic decompensation, and 19 had grade 3/4 infections.
• 14 (5%) developed severe rash and 5 experienced kidney failure.
• 19% developed grade 2 anemia, 12% developed grade 3/4 anemia, 54% used EPO, 16% received transfusions, and 13% had ribavirin dose reductions.
• About 10% developed grade 3, and 3% developed grade 4 thrombocytopenia.
• Only 2% developed grade 3, and less than 1% developed grade 4 neutropenia.

Risk Factors:

• In a multivariate analysis, significant predictors of severe complications including death, severe infection, or decompensation included:

o   Low platelet level (< 100,000/mm³) at baseline: odds ratio 3.1, or 3-fold higher risk;

o   Low serum albumin (< 35 g/L) at baseline: odds ratios 6.3, or 6 times higher risk.

• Predictors of severe anemia or need for blood transfusion included:

o   Female sex: odds ratio 2.2, or double the risk;

o   Age 65 years or older: odds ratio 3.0;

o   Low hemoglobin level at baseline: odds ratio 5.3.

Based on these findings, the CUPIC investigators concluded, "In this large cohort of compensated cirrhotic patients, the safety profile of telaprevir or boceprevir in triple combination was poor as compared with Phase 3 trials" -- with increased rates of serious adverse events and more difficult management of anemia -- "but associated with high rates of on-treatment virologic response."

The risk/benefit ratio should be assessed for treatment-experienced cirrhotic individuals with low platelet or serum albumin levels, and "these patients should be treated on a case-by-case basis due to high risk to develop severe complications," they added. Cirrhotic treatment-experienced patients without predictors of severe complications "should be treated but cautiously and carefully monitored."

12/4/12

Reference

C Hezode, C Dorival, F Zoulim, et al. Safety and efficacy of telaprevir or boceprevir in combination with peginterferon alfa/ribavirin, in 497 cirrhotic non responders. Week 16 analysis of the French early access program (ANRS CO20-CUPIC) in real-life setting. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 51.