Back Hepatitis C

Hepatitis C

Abbott and Enanta Announce First Clinical Trial of Oral HCV Protease Inhibitor ABT-450

The current standard of care for treatment of chronic hepatitis C is combination therapy using pegylated interferon (Pegasys or PegIntron) plus ribavirin. The overall cure rate with this combination in HCV monoinfected patients with genotype 1 HCV is approximately 45%-50%. The success rate is higher for patients with genotype 2 or 3.

Study Shows Treating Prisoners with Hepatitis C is Cost Effective

Chronic hepatitis C is common in U.S. prisons, with prevalence estimates ranging from about 10% to about 30%. A significant proportion of the HCV-infected population passes through the correctional system each year, providing a prime opportunity for diagnosis and treatment.

AASLD 2008: Investigational HCV Protease Inhibitor BI 201335 Exhibits Promising Antiviral Activity

Given the limited efficacy and side effects of interferon-based therapy for chronic hepatitis C virus (HCV) infection -- especially among patients with hard-to-treat HCV genotype 1 -- investigators have explored several small molecule agents (dubbed "STAT-C") that directly target various steps of the viral lifecycle. One such candidate, BI201335, is an HCV NS3 protease inhibitor being developed by Boehringer-Ingelheim. Two posters with results from a Phase 1b study of BI201335 were presented last week at the 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) in San Francisco.

Treatment-naive Patients

Study 1220.2 is a multinational clinical trial evaluating the pharmacokinetics, safety, and antiviral activity of multiple ascending doses of BI201335 monotherapy for 14 days, followed by triple therapy with BI201335 + pegylated interferon + ribavirin for an additional 14 days.

The first analysis looked at 34 treatment-naive patients with genotype 1 chronic hepatitis C in the U.S., France, Germany, and Spain. Most participants (27) were men, all but 1 were white, the mean age was about 49 years, and Metavir fibrosis scores were 0-3.

Participants were randomly assigned to receive placebo or 1 of 4 doses of once-daily BI201335: 20 mg (n=8), 48 mg (n=9), 120 mg (n=9), or 240 mg (n=8). BI201335 was given as monotherapy for 14 days. Patients with less than a 1 log10 decrease in HCV RNA at day 10 had BI201335 discontinued after day 14. Those with at least a 1 log10 decrease at day 10 continued on BI201335, adding 180 mcg/week pegylated interferon alfa-2a (Pegasys) + weight-adjusted ribavirin from day 15 through Day 28.

Results

• A rapid decline in HCV viral load was observed in all patients, with maximal decline 2-4 days after starting BI201335.

• With the exception of 1 patient in the 20 mg group, all participants receiving BI201335 (96.2%) achieved > 2 log10 decline in HCV RNA during the monotherapy period.

• 100% of patients in the 48 mg, 120 mg, and 240 mg BI201335 dose groups achieved > 2.8 log10 drop in HCV viral load during the first few days of monotherapy.

• Median maximal reductions in viral load during the 14-day monotherapy period were 3.0 log10 in the 20 mg arm, 3.6 log10 in the 48 mg arm, 3.7 log10 in the 120 mg arm, and 4.2 log10 in the 240 mg arm, versus no significant change in the placebo group.

• A majority of patients in all dose groups experienced viral load rebound during the first 14 days of monotherapy.

• Population sequencing of the NS3/NS4A protease at baseline and after viral rebound revealed selection of HCV variants previously shown to confer resistance to BI201335 in vitro.

• BI201335 was generally well-tolerated, with no observed dose-dependent increases in adverse events (AEs).

• No patients discontinued treatment during the monotherapy period due to AEs.

• AEs observed while on combination therapy were typical for pegylated interferon + ribavirin.

• Changes in bilirubin were observed with increasing doses of BI 201335.

• One serious AE (asthenia, or muscle weakness) occurred in an individual in the 20 mg dose arm 6 days after starting pegylated interferon + ribavirin.

In conclusion, the investigators stated, "BI 201335 as monotherapy for 14 days followed by combination with [pegylated interferon + ribavirin] for [an] additional 14 days was well tolerated, and induced a strong and rapid antiviral response."

"The results support further study of BI201335 as a once-daily potent antiviral for treatment-naive HCV patients," they added.

Medizinische Hochschule Hannover Zentrum Innere Medizin, Hannover, Germany; Hopital Saint Joseph, Marseille, France; Hopital Pitie Salpetriere, Paris, France; California Pacific Medical Center Research Institute, San Francisco, CA; Charité Berlin Campus Virchow-Klinikum, Berlin, Germany; Hopital Hotel Dieu, Lyon, France; Central Texas Clinical Research, Austin, TX; Hopital Cochin, Paris, France; Boehringer Ingelheim Pharma, Ridgefield, CT; Hospital Universitario Puerta de Hierro, Madrid, Spain.

Treatment-experienced Patients

Study 1220.2 also included a cohort of 19 treatment-experienced patients with genotype 1 chronic hepatitis C who experienced confirmed virological failure (< 2 log reduction in HCV RNA from baseline) during or after previous combination therapy with approved doses of pegylated interferon + ribavirin. Here, too, a majority of participants were men, all were white, and the mean age was 49 years.

This part of the study was open-label, and all patients received BI201335 at doses of 48, 120, or 480 mg once-daily in combination with standard doses of Pegasys + ribavirin for 28 days (none received monotherapy or 20 mg BI201335).

Results

• Here again, a rapid dose-related decline in HCV RNA was observed in all patients.

• All participants treated with BI201335 + pegylated interferon + ribavirin achieved > 2 log10 decline in HCV viral load.

• Median maximal declines in HCV RNA during 28-day combination therapy were 4.8 log10 in the 48 mg arm, 5.2 log10 in the 120 mg arm, and 5.3 log10 in the 240 mg arm.

• 2 of 6 patients (33%) in the 48 mg group and 1 of 7 (14%) in the 120 mg group experienced virological rebound during the first 28 days of triple combination therapy.

• In these patients, sequencing of the NS3/4A protease revealed variants with known BI201335 resistance mutations.

• No viral rebound during treatment was seen in the 240 mg dose arm, and 5 of 6 patients (83%) in this group had HCV RNA < 25 IU/mL at day 28.

• Again, BI201335 was well-tolerated and no serious drug-related AEs were observed.

• AEs were typical for pegylated interferon + ribavirin.

• 1 participant discontinued treatment due to anxiety.

"BI201335 given once-daily in combination therapy with [pegylated interferon + ribavirin] for 28 days was well tolerated, and induced a strong and rapid antiviral response," the researchers concluded. "The results support further study of BI201335 as a potent protease inhibitor for [pegylated interferon + ribavirin] treatment-experienced HCV patients."

Medizinische Hochschule Hannover Zentrum Innere Medizin, Hannover, Germany; Hopital Saint Joseph, Marseille, France; Hopital Pitie Salpetriere, Paris, France; I. Med. Klinik und Poliklinik, Mainz, Germany; Universitätsklinikum Düsseldorf, Düsseldorf, Germany; Hopital Cochin, Paris, France; California Pacific Medical Center Research Institute, San Francisco, CA; Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT.

11/11/08

References

MP Manns, M Bourliere, Y Benhamou, and others. Safety and antiviral activity of BI201335, a new HCV NS3 protease inhibitor, in treatment-naive patients with chronic hepatitis C genotype-1 infection given as monotherapy and in combination with Peginterferon alfa 2a (P) and Ribavirin (R). 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1849.

MP Manns, M Bourliere, Y Benhamou, and others. Safety and antiviral activity of BI201335, a new HCV NS3 protease inhibitor, in combination therapy with Peginterferon alfa 2a (P) and Ribavirin (R) for 28 days in P+R treatment-experienced patients with chronic hepatitis C genotype-1 infection. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1882.

ICAAC 2008: Blood Lipid Levels and Insulin Resistance Predict Response to Interferon-based Therapy in HIV-HCV Coinfected Patients

Response to interferon-based therapy for chronic hepatitis C virus (HCV) infection varies widely across individuals, but tends to be poorer in people with HIV-HCV coinfection. Some factors associated with better response are well established -- including having HCV genotypes 2 or 3 (rather than 1 or 4) and a low baseline HCV viral load -- but others have been less extensively studied.

As reported at the 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008) in late October, Paola Nasta and colleagues analyzed the association between baseline metabolic parameters and response rates in 96 HIV-HCV coinfected individuals undergoing hepatitis C treatment with pegylated interferon plus ribavirin.

Most (83%) were men, the median age was 43 years, 54% had HCV genotypes 1 or 4, 58% had advanced liver fibrosis (Metavir stage F3-F4), and 29% had cirrhosis. Nearly 90% were on HAART, three-quarters of them using a protease- inhibitor (PI)-based regimen.

The investigators assessed rapid virological response (RVR; undetectable HCV RNA at week 4 of treatment), early virological response (EVR) at week 12, and sustained virological response (SVR; continued undetectable HCV 24 weeks after completing therapy).

Fasting total cholesterol, LDL ("bad") and HDL ("good") cholesterol, and triglycerides levels were measured in all patients at baseline. To assess insulin resistance, the researchers determined HOMA-IR scores.

Results

• 62% achieved EVR (39% and 91% for the respective genotype groups);

• In a multivariate analysis, genotype was a predictor for RVR, EVR, and SVR.

• LDL level was only a significant factor for RVR.

• Baseline HCV RNA < 400,000 IU/mL was an additional predictor for SVR.

"Metabolic parameters are key factors to predict RVR, EVR, and SVR in HIV-HCV coinfected subjects treated with [pegylated interferon/ribavirin]," the researchers concluded.

They added that their analysis "suggest[s] a direct role" for hypertriglyceridemia (elevated triglycerides), and a possible impact of HAART-related metabolic impairment on response to hepatitis C treatment.

Inst. of Infectious and Tropical Diseases, Univ. of Brescia, Brescia, Italy.

12/9/08

Reference

P Nasta, G Gatti, G Cologni, and others. Triglycerides, LDL Cholesterol and HOMA Score Predict the Virological Response in HIV/HCV Co-infected Patients Treated with PegInterferon alfa2a/Ribavirin (PegIFN/RBV). 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008). Washington, DC. October 25-28, 2008. Abstract H-2318.

24 Weeks of Pegylated Interferon plus Ribavirin May Be Sufficient for Selected Genotype 1/4 Chronic Hepatitis C Patients with Rapid Response

Given the side effects and cost of interferon-based therapy for chronic hepatitis C virus (HCV) infection, researchers continue to explore shorter treatment durations, especially for individuals who respond rapidly after starting therapy.

The current standard of care is 24 weeks of pegylated interferon plus ribavirin for chronic hepatitis C patients with HCV genotypes 2 or 3, while those with hard-to-treat genotypes 1 or 4 are treated for 48 weeks. Many experts recommend longer therapy for individuals with HIV-HCV coinfection.

In a study described in the August 2008 issue of Gastroenterology, Peter Ferenci and colleagues from Austria aimed to determine whether 24 weeks might be adequate for patients with HCV genotype 1 or 4 who achieve rapid virological response (RVR), or undetectable after 4 weeks of therapy.

The study initially included 516 genotype 1 or 4 patients treated with 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus 1000-1200 mg/day weight-based ribavirin. Participants who did not achieve RVR (HCV RNA < 50 copies/mL) at week 4 were randomly assigned to receive 48 or 72 weeks of treatment (this part of the study was ongoing at the time of the report).

Among those who did achieve RVR, the investigators analyzed rates of sustained virological response (SVR), or continued undetectable HCV viral load 24 weeks after completion of therapy.

Results

• 150 of the 516 patients (26%) achieved RVR.

• 143 of the 150 completed 24 weeks of treatment.

• The overall SVR rate in this subgroup was 80.4%:

• 78.8% for genotype 1;
• 86.7% for genotype 4.

• The following factors were predictive of RVR:

• younger age;
• lower body fat;
• low baseline HCV RNA (< 400,000 IU/mL);
• HCV genotype 4 rather than 1.

• However, once a person had achieved RVR, no baseline factors significantly predicted SVR.

• Treatment was well tolerated overall.

Based on these findings, the investigators concluded, "This prospective study confirms that a 24-week regimen of peginterferon alfa-2a plus ribavirin 1000-1200 mg/day is appropriate in genotype 1 and 4 patients with a low baseline HCV RNA level who achieve an RVR by week 4 of therapy."

Medical University, Vienna, Austria; Kaiser-Franz-Josef-Spital, Vienna, Austria; Wilhelminenspital, Vienna, Austria; Elisabethinen Hospital, Linz, Austria; Hospital Hietzing, Vienna, Austria; Medical University, Graz, Austria; Rudolfshospital, Vienna, Austria; LKH Hörgas-Enzenbach, Gratwein, Austria; Krankenhaus, Oberndorf, Austria; Roche Austria, Vienna, Austria.

10/14/08

Reference
P Ferenci, H Laferl, TM Scherzer, and others. Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1 and 4 patients with rapid virological response. Gastroenterology 135(2): 451-458. August 2008. (Abstract).

 

Nitazoxanide Enhances Anti-HCV Activity of Pegylated interferon/ribavirin and STAT-C Agents

Studies presented at the recent 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) in San Francisco looked at adding nitazoxanide (Alinia) to pegylated interferon and to novel directly-targeted "STAT-C" agents in the development pipeline.

Combination Therapy with Investigational HCV Polymerase Inhibitor R7128 Produces Rapid Response in Patients with Genotype 2/3 HCV

Due to the limited efficacy and side effects of standard hepatitis C therapy using pegylated interferon (Pegasys or PegIntron) plus ribavirin, researchers are studying several oral agents that directly target various steps of the hepatitis C virus (HCV) lifecycle. One such agent, Pharmasset's R7128 (a prodrug of the nucleoside analog HCV polymerase inhibitor PSI-6130) is currently in Phase 1 clinical trials, in combination with Pegasys plus ribavirin. In August, the company reported preliminary data from a cohort of patients with hard-to-treat HCV genotype 1. This week, Pharmasset reported early results from a subgroup of participants with easier-to-treat genotypes 2 or 3.

AASLD 2008: Canadian POWeR Study Finds Patients with Advanced Liver Disease Respond Poorly to Pegylated Interferon plus Ribavirin

It is well established that chronic hepatitis C patients with advanced liver fibrosis or cirrhosis respond poorly to interferon-based therapy, but this group has the most urgent need for effective treatment. The Canadian POWeR program evaluated the impact of advanced fibrosis or cirrhosis on sustained virological response (SVR) rates in treatment-naive genotype 1 chronic hepatitis C patients treated with pegylated interferon plus ribavirin in "real-life" clinical settings between 2000 and 2007. Results were reported at the recent 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) in San Francisco.

Older Donor Liver Grafts May Be Suitable for Chronic Hepatitis C Patients Requiring Transplantation

Liver transplantation is the only effective treatment for end-stage liver failure due to chronic hepatitis C virus (HCV) infection, but the availability of the procedure is severely hampered by the shortage of donor organs. Surgeons have traditionally preferred to use livers from young donors, but increasing the age of acceptable donors could significantly expand the available liver supply.