Adding Telaprevir Improves Sustained Response to Pegylated Interferon plus Ribavirin in Genotype 1 Chronic Hepatitis C Patients (PROVE3)

At the 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009) last week in Copenhagen, Denmark, researchers presented data from PROVE3, a Phase 2b study of 453 genotype 1 chronic hepatitis C patients in the U.S. and Europe who did not achieve sustained response with a prior course of pegylated interferon plus ribavirin.

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A Small Proportion of Hepatitis C Patients Develop Liver Cancer despite Sustained Response to Interferon-based Therapy

Over years or decades, chronic hepatitis C virus (HCV) infection can lead to advanced liver disease, including cirrhosis and hepatocellular carcinoma (HCC). Sustained response to interferon-based therapy dramatically reduces the risk of liver disease progression, but does not eliminate it completely, according to 2 recently published studies.

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Adding Boceprevir to PegIntron/Ribavirin Significantly Improves Sustained Virological Response in Chronic Hepatitis C Patients

Combination therapy using pegylated interferon (Pegasys or PegIntron) plus ribavirin -- the current standard of care for chronic hepatitis C virus (HCV) infection -- is associated with numerous side effects and about half the time does not produce a sustained response. In an attempt to improve outcomes, researchers are studying several oral agents that directly target various steps of the HCV lifecycle, an approach known as "STAT-C."

At the 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009) last week in Copenhagen, investigators reported final results from the Phase 2 HCV SPRINT-1 study, which evaluated the safety and efficacy of Schering-Plough's investigational HCV protease inhibitor boceprevir in various combinations with pegylated interferon alfa-2b (PegIntron) plus ribavirin. Hep C drug candidate.

SPRINT-1 included 595 treatment-naive patients with genotype 1 chronic hepatitis C in the U.S., Canada and Europe. Overall, 16% of participants were African-American, 7% had pre-existing liver cirrhosis, 56% had HCV genotype 1a, and 89% had high HCV viral load (> 600,000 IU/mL), all factors associated with poor response to interferon-based therapy.

Boceprevir (800 mg 3 times daily) was evaluated as part of 3 treatment regimens: 

• Lead-in therapy with 1.5 mcg/kg once-weekly pegylated interferon plus 800-1400 mg daily weight-adjusted ribavirin for 4 weeks, followed by the addition of boceprevir for 24 or 44 more weeks (for a total of 28 or 48 weeks of treatment);
• Boceprevir in combination with the same doses of pegylated interferon plus ribavirin, with all 3 drugs taken together for 28 or 48 weeks.
• Boceprevir plus pegylated interferon plus low-dose 400-1000 mg daily weight-adjusted ribavirin for 48 weeks (Part II).

In Part I of the study, the boceprevir regimens were compared against the approved standard of care control regimen of 1.5 mcg/kg once-weekly pegylated interferon plus 800-1400 mg daily weight-adjusted ribavirin, without boceprevir, for 48 weeks.

In Part II, boceprevir plus pegylated interferon plus low-dose ribavirin for 48 weeks was compared against boceprevir plus pegylated interferon plus full-dose ribavirin for 48 weeks.

The rationale for the lead-in period was based on the fact that both pegylated interferon alfa-2b and ribavirin reach steady-state concentrations by week 4, therefore patients had boceprevir added after levels of the other drugs were optimized and HCV viral load was reduced, according to a Schering-Plough press release describing the study findings. This approach may minimize the duration of "functional monotherapy" with the direct antiviral agent, thereby potentially reducing the likelihood of developing resistance.

The primary endpoint of the study was sustained virological response (SVR), or continued undetectable HCV RNA after 24 weeks of post-treatment follow-up.

Use of erythropoietin (EPO) to manage anemia (defined as hemoglobin < 10 g/dL) during treatment was allowed at the discretion of study investigators.
 

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Results

• In the 28-week and 48-week boceprevir/pegylated interferon/ribavirin triple-therapy arms with no lead-in period, SVR rates were 54% (58 of 107 patients) and 67% (69 of 103 patients), respectively. 
• In Part I of the study, response rates were improved in the arms with a 4-week pegylated interferon/ribavirin lead-in period before starting boceprevir.
• The 4-week pegylated interferon/ribavirin lead-in followed by 44 weeks of triple combination therapy produced an SVR rate of 75% (77 of 103 patients), compared with 38% in the standard of care control arm (39 of 104 patients) (P < 0.0001). 
• The SVR rate was 56% (58 of 103 patients) using the 4-week pegylated interferon/ribavirin lead-in period followed by 24 weeks of triple combination therapy (P = 0.005 vs standard of care).
• In the lead-in arms, 64% of all patients achieved rapid virologic response (RVR), defined as undetectable HCV RNA 4 weeks after adding boceprevir.
• Among patients in the lead-in arms who achieved RVR, SVR rates were 94% using the 48-week regimen and 82% using the 28-week regimen.
• In Part II of the study, the SVR rate for the triple-combination regimen with low-dose ribavirin was 36% (21 of 59 patients). 
• The low-dose ribavirin regimen was associated with an increased risk of viral breakthrough during treatment and a higher relapse rate after the end of treatment, resulting in a lower SVR rate.
• Overall, triple-combination therapy was well tolerated.
• In Part I of the study, 9%-19% of participants in the boceprevir arms discontinued therapy due to adverse events, compared with 8% in the standard of care control arm. 
• Fewer patients in the 28-week and 48-week lead-in arms discontinued treatment due to viral breakthrough (4% and 5%, respectively, vs 7% and 12% with no lead-in).
• The most common adverse events reported in the boceprevir arms were fatigue, anemia, nausea, and headache. 
• The incidence of skin adverse events (rash or pruritus [itching]) was similar in the boceprevir and standard of care arms.
• About one-half of patients in the boceprevir arms and about one-third in the standard therapy arm developed anemia during treatment.
• 39%-51% of patients in the boceprevir combination arms and 26% in the standard of care control arm used EPO.
• Participants who developed anemia had a greater likelihood of achieving SVR than those without anemia.

"Both 28 and 48 week boceprevir regimens significantly increased SVR with very low relapse rates in 48 week regimens," the investigators concluded. "However, low dose ribavirin with PegIntron and boceprevir was associated with increased viral breakthrough, relapse and lower efficacy. In contrast, pegylated interferon/ribavirin lead-in prior to boceprevir substantially increased SVR and reduced viral breakthrough."

"These results are very exciting and provide important insights to help further define response guided therapy using a pegylated interferon/ribavirin lead-in boceprevir regimen with peginterferon and ribavirin backbone treatment," stated lead investigator Paul Kwo, MD, in the Schering-Plough press release. "Building on these results, the boceprevir Phase III clinical program individualizes treatment based on response, utilizing RVR criteria at week 4 of boceprevir treatment to determine overall duration of therapy. Based on the RVR rate seen in this Phase II study, we are hopeful that the majority of patients can be treated with 28 weeks of therapy."

Patient enrollment has been completed in 2 ongoing randomized, double-blind, placebo-controlled registration studies evaluating boceprevir in combination with PegIntron and ribavirin: HCV SPRINT-2 in treatment-naive patients and HCV RESPOND-2 in treatment-experienced relapsers and non-responders.

Indiana University School of Medicine, Indianapolis, IN; Alamo Medical Research, San Antonio, TX; Mount Vernon Endoscopy Center, Alexandria, VA; Center for Liver Diseases, University of Miami Miller School of Medicine, Miami, FL; Baylor College of Medicine, Houston, TX; Indianapolis Gastroenterology Research Foundation, Indianapolis, IN; Digestive Care/South Florida Center of Gastroenterology, Wellington, FL; Liver Specialists of Texas, Houston, TX; Henry Ford Health Systems, Detroit, MI; Digestive Disease Associates, Baltimore, MD; University of California-Davis Medical Center, Sacramento, CA; Liver & Intestinal Research Center, Vancouver, BC, Canada; Weill Cornell Medical College, New York, NY; Digestive Healthcare of Georgia, Atlanta, GA; Schering-Plough Research Institute, Kenilworth, NJ.

4/28/09

Reference
P Kwo, E Lawitz, J McCone, and others. HCV SPRINT-1 Final Results: SVR 24 from a Phase 2 Study of Boceprevir Plus PegIntron (Peginterferon Alfa-2b)/Ribavirin in Treatment-Naive Subjects with Genotype-1 Chronic Hepatitis C. 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark. April 22-26, 2009. Abstract 4.

Other Source
Schering-Plough. Final Results of Boceprevir Phase II HCV Sprint-1 Study Showed Significantly Higher SVR Rates Compared to Standard of Care in Treatment-Naive Genotype 1 Hepatitis C Patients. Press release. April 23, 2009.

Long-term Maintenance Interferon Does Not Prevent Hepatocellular Carcinoma among Chronic Hepatitis C Patients in HALT-C Study

Current standard therapy for chronic hepatitis C virus (HCV) infection using pegylated interferon plus ribavirin produces a sustained virological response (SVR) in about half of treated patients, and researchers have explored other therapies that might slow, halt, or even reverse liver fibrosis progression and reduce the risk of cirrhosis and hepatocellular carcinoma (HCC) in people who do not clear the virus.

The HALT-C trial was designed to assess whether long-term, low-dose pegylated interferon maintenance monotherapy would improve outcomes in this population. While an interim analysis indicated that low-dose interferon produced improvements in ALT levels, HCV viral load, and necroinflammation, the study's primary analysis found no benefit with regard to reduced liver disease progression after 3.5 years.

HALT-C researchers also conducted several secondary analyses looking at specific aspects of disease progression. In the present study, published in the January 2009 issue of Gastroenterology, Anna Lok from the University of Michigan Medical Center and colleagues analyzed the HCC incidence rate and risk factors among HALT-C participants. (Results from a shorter duration of follow-up were previously presented at the April 2008 annual meeting of the European Association for the Study of the Liver [EASL]).

Briefly, HALT-C included more than 1000 participants with chronic hepatitis C and bridging fibrosis (Ishak stages F3-F4; 59%) or cirrhosis (stages F5-F6; 41%) at baseline. Those who did not achieve sustained response to standard combination therapy with pegylated interferon plus ribavirin were randomly assigned to receive either low-dose (90 mcg per week) pegylated interferon alfa-2a (Pegasys) monotherapy for 3.5 years or else no ongoing treatment. Most study participants (71%) were men, the mean age was 50 years, and 72% were white.

Results

• Over a median 4.6 years of follow-up (maximum 6.7 years), 48 out of 1005 patients (4.8%) developed HCC
• The cumulative 5-year HCC incidence rate was similar in the maintenance therapy and untreated observation arms, at 5.4% and 5.0%, respectively (P = 0.78).
• As expected, HCC was more likely to occur in patients with cirrhosis than in those with bridging fibrosis (7.0% vs 4.1%, respectively; P = .08).
• However, HCC developed in 8 patients (17%) whose serial biopsy specimens showed only simple (non-bridging) fibrosis.
• In a multivariate analysis, a model including older age, black race, lower platelet count, higher alkaline phosphatase level, presence of esophageal varices, and tobacco smoking was developed to predict the risk of HCC.
• Over 5 years, the researchers calculated that the expected rate of HCC would be < 1% for patients the model classified as low-risk, about 5% for those classified as intermediate-risk, and approximately 20% for those considered high-risk.

Based on these results, the study investigators concluded, "We found that maintenance peginterferon did not reduce the incidence of HCC in the HALT-C cohort. Baseline clinical and laboratory features predicted risk for HCC."

In an accompanying editorial, Morris Sherman from the University of Toronto presented an overview of HCC epidemiology in individuals with chronic hepatitis C.

He noted that the incidence HCC was "unexpectedly high" in HALT-C participants who had advanced fibrosis but not yet cirrhosis. Until this report, he wrote, "HCC developing in a noncirrhotic hepatitis C patient was considered uncommon."

The HALT-C findings led to an algorithm that can identify patients at greatest risk who can then be targeted for surveillance. But, Sherman stated, "the intensity of surveillance in the United States has to increase to a level that exists elsewhere in the world before HCC surveillance will result in mortality reduction."

Recent data suggest that regular surveillance (e.g., with ultrasonography) every 6 months is associated with better survival than every 12 months, since the shorter interval improves the chances of detecting small tumors at an earlier, more treatable stage.

3/17/09

Reference

AS Lok, LB Seeff, TR Morgan, and others. Incidence of Hepatocellular Carcinoma and Associated Risk Factors in Hepatitis C-Related Advanced Liver Disease. Gastroenterology 136(1): 138-148. January 2009. (Abstract).