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Hepatitis C

Studies Shed More Light on Acute Hepatitis C among HIV Positive Men in the U.S. and Europe

Since around 2000, clinicians have been reporting outbreaks of apparently sexually transmitted acute hepatitis C virus (HCV) infection among mostly HIV positive men in cities in the U.K. and continental Europe.

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).

 

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.

CROI 2009: Studies from Europe and the U.S. Provide Further Information on Sexual Transmission of Hepatitis C Virus among HIV Positive Men

Starting in 2000, clinicians in several large European cities began reporting clusters of apparently sexually transmitted acute hepatitis C virus (HCV) infection, primarily among HIV positive men who have sex with men (MSM). More recently, similar outbreaks have also been reported in the U.S. In several posters presented at the 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009) last month in Montreal, researchers provided further data on the maturing HIV/HCV epidemics in Europe and the newer outbreaks in the U.S.

Ongoing Epidemic in France

Jade Ghosn and colleagues presented evidence of ongoing sexual transmission of HCV among MSM in France, based on a national survey of acute hepatitis C cases conducted by the French National Institute for Public Health Surveillance in 2006-2007.

The survey included a sample of patients from 115 medical wards across the country, based on the number of HIV and AIDS cases in MSM reported to the National HIV surveillance system. Acute HCV was defined as a positive HCV antibody or HCV RNA within 1 year of a documented negative test.

Complete clinical, biological, and HCV-NS5b genetic sequencing data were available for 32 of the 94 cases meeting the acute HCV definition. The median age at HCV diagnosis was about 40 years and the median time between HIV and HCV diagnosis was 10 years.

Within this group, a majority were receiving combination antiretroviral therapy (ART), 22 had undetectable HIV viral load, and most had a CD4 count above 350 cells/mm3. Most patients were diagnosed with acute HCV due to elevated transaminase (ALT and/or AST) levels during routine HIV-related monitoring.

About two-thirds of these patients (20) had other sexually transmitted diseases (STDs) present at the time of acute HCV diagnosis, including 14 cases of syphilis and 2 cases of lymphogranuloma venereum. A majority reported unprotected anal sex, though just 5 reported "highly at-risk" sexual activities, i.e., fisting. Having undergone surgery or endoscopy was also a significant risk, suggesting "nosocomial" (within a healthcare setting) transmission might possibly play a role.

Half the extensively analyzed patients (16) had HCV genotype 4d, which is generally uncommon in France, and 14 had genotype 1a. Among the 16 genotype 4d viruses, 15 segregated into a single cluster, while among the 14 genotype 1a viruses, 10 segregated into 3 clusters. Furthermore, the 15 clustered genotype 4d viruses isolated in 2006-2007 were closely related to 4d viruses isolated in Paris in 2001-2003, indicating an ongoing epidemic of sexual transmission.

"We show evidence for ongoing sexual transmission of HCV in HIV-infected MSM in France, with an ongoing epidemic transmission of genotype 4d virus in the Parisian area," the investigators concluded. "Our results support the need for regular screening for HCV infection in HIV-infected MSM."

Rapid Rise in Amsterdam

Guido Van Den Berk and colleagues reported a rapid rise in acute hepatitis C cases at OLVG Hospital in Amsterdam, which currently cares for more than 1800 HIV positive patients, about three-quarters of them MSM.

The researchers retrospectively reviewed data on HIV positive MSM identified with HCV coinfection between January 2000 and August 2008. Stored blood samples here tested for HCV antibodies and HCV RNA in an attempt to narrow the potential seroconversion interval.

A total of 49 cases of acute HCV were identified. No cases occurred between 2000 and 2002, 2 cases occurred in 2003, 1 occurred in 2004, 9 occurred in 2005, and 11 occurred in 2006. The number fell to 7 in 2007, but then more than doubled to 20 between January and August 2008 -- accounting for more than 1.5% of all HIV positive MSM seen annually at the hospital.

All but 2 of these patients experienced a marked increase in transaminase levels. About one-third had an HCV seroconversion interval less than 6 months, and approximately another third between 6 months and 1 year, but nearly 15% had an interval between 1 and 2 years, and almost 20% had an interval greater than 2 years.

None of the coinfected patients had any "classical" risk factors for HCV infection such as injection drug use or direct blood exposure in endemic countries, but most did engage in unprotected sex.

Among 46 cases in which HCV genotype was determined, 35 patients (76%) had genotype 1, 1 each (2.2%) had genotypes 2 and 3, and 9 (20%) had genotype 4.

"Our study confirmed a marked increase in the occurrence of acute HCV starting from 2003 and escalating in 2008, and mostly involving HCV genotypes with a poor response to therapy," the investigators concluded. "In the absence of classical risk factors, HCV has become a sexually transmitted disease in HIV-infected MSM. Efforts to contain this epidemic should be started rapidly."

Risk Factors in New York vs the U.K.

Researchers at Mt. Sinai Hospital and School of Medicine in New York City were among the first to report an outbreak of apparently sexually transmitted HCV among MSM in the U.S.

Sarah Fishman and colleagues undertook an analysis comparing characteristics and risk behaviors among HIV positive men with acute hepatitis C in New York and in the United Kingdom, where the first European cases were reported.

The researchers used the Danta risk factor questionnaire, developed by Mark Danta of St. Vincent's Hospital in Sydney and Royal Free and University College Medical School in London, who authored some of the earliest reports on the current acute hepatitis C epidemic. The questionnaire was administered to 21 HIV positive MSM with acute HCV infection in New York, and their responses were compared to previously published responses from 60 U.K. men.

The men involved in both the New York and U.K. were relatively older (median 40 and 36 years, respectively) than the average age of clients typically seen at STD clinics. The youngest affected men were 29 in New York and 24 in the U.K., while the oldest were 49 and 58, respectively. In both groups, the median CD4 count was above 500 cells/mm3 and similar proportions were on HAART.

The median duration of HIV infection among the New York men was 8 years, compared with 4 years in the U.K. In both outbreaks, however, some men had been infected with HIV for less than 1 year when they became coinfected with HCV.

In the 12 months prior to study enrollment, the New York men reported less fisting than the U.K. men (33% vs 73% for active; 24% vs 57% for receptive); even more striking, U.K. men were nearly 6 times more likely to report active fisting in a group sex setting (12% vs 67%), though the difference was not so great for getting fisted in a group setting (29% vs 56%). A majority of men in both New York and the U.K. had had both active (65% vs 85%) and receptive (77% vs 94%) unprotected anal intercourse in a group setting.

New York men were significantly more likely to use condoms while performing and receiving oral sex (which has not previously been reported as a major risk factor for HCV transmission). Approximately half as many New Yorkers as U.K. men reported a lifetime history of STDs (38% vs 85%), in particular non-specific urethritis.

In both groups, direct blood-to-blood (parenteral) exposure could not account for most cases of acute HCV. Although significantly more men in New York had a history of injection drug use, this only reached 24%, compared with just 3% in the U.K. Use of non-injection recreational drugs was significantly more common among the U.K. men -- including ketamine ("Special K"; 24% vs 80%), non-crack cocaine (38% vs 77%), LSD (0% vs 33%), and ecstasy (38% vs 80%). The New York men, however, reported more sharing of implements for drug smoking (48% vs 20%) and drug injection (15% vs 2%).

"HCV transmission among HIV-infected [MSM] is not the result of adolescent risk taking, rather transmission is occurring primarily in men over the age of 35 years," the investigators concluded. "This demographic feature raises the possibility that older age may be a risk factor for sexual transmission of HCV, as previously reported. The greater use of non-injection recreational drugs in the U.K. cases was a notable finding."

Liver Disease Progression

The Mt. Sinai team also presented the latest data on liver disease progression and treatment response in HIV positive individuals with acute HCV infection.

Daniel Fierer first reported at the 2007 CROI that HIV positive MSM with acute hepatitis C showed evidence of unusually rapid and severe liver fibrosis, which typically develops much later in the course of HCV infection. He followed up with similar findings at the 2008 CROI and published further data in the September 1, 2008 issue of the Journal of Infectious Diseases,

As of this report, the investigators had enrolled 45 HIV positive MSM with acute hepatitis C, defined as newly identified HCV antibody seropositivity with either ALT elevation, >1 log HCV viral load fluctuation, or high clinical suspicion. The median age was 40 years, the median CD4 count was 525 cells/mm3, and 94% had HIV viral load < 400 copies/mL; 89% had HCv genotype 1 (this cohort overlaps with the New York group described above).

Just 4 patients (9%) spontaneously cleared HCV infection -- lower than the 25% or so typically seen in studies of HIV negative people with acute hepatitis C. Of the remainder, 15 started hepatitis C therapy, all with pegylated interferon plus ribavirin, while 20 refused or deferred treatment and 6 were still being evaluated.

Of the 10 patients who completed a 24-week post-treatment follow-up period, 8 achieved sustained virological response (SVR) while 2 were non-responders (others are still undergoing treatment).

For 24 participants, liver biopsies were performed a median of 4 months after the first identified ALT elevation. Within this group, 1 patient (4%) had stage 3 fibrosis (using the 0-4 Scheuer scale), 18 (75%) had stage 2, 3 (13%) had stage 1, and 2 (8%) had stage 0.

In a case-control study of 21 matched HCV infected/HCV-uninfected pairs, significant risk factors for HCV infection were unprotected receptive anal intercourse with or without ejaculation (P = 0.03-0.04), unprotected receptive oral sex with ejaculation (P = 0.03), use of sex toys (P = 0.03), sex while high on drugs (P = 0.01), and use of marijuana (P = 0.04). Interestingly, in this analysis getting fisted was not a risk factor, while active fisting was associated with a slightly higher risk that did not reach statistical significance.

"Acquisition of HCV infection in the outbreak of acute HCV infection in HIV-infected MSM in New York City is associated with receptive, unprotected sex and results in early and rapid progression of liver fibrosis," the researchers concluded, confirming their earlier findings.

"Treatment is highly successful when initiated in the acute phase but many do not receive prompt treatment, missing the opportunity to prevent further progression of the already significant liver fibrosis," they continued.

"We therefore recommend at least quarterly ALT and yearly HCV testing for all HIV-infected MSM and rapid referral to an HCV treatment expert upon suspicion of HCV" they added. "Promotion of safe sex and decreased drug use is also warranted."

Screening in 6 U.S. Cities

Finally, Karen Hoover with the Centers for Disease Control and Prevention (CDC) and colleagues estimated the proportion of HIV positive MSM receiving care at 8 HIV clinics who were ever screened for hepatitis A virus (HAV), hepatitis B virus (HBV), or HCV.

HIV management guidelines have consistently recommended that HIV positive individuals should be screened for HBV, which can be prevented with a vaccine if a person is unexposed; there is also a vaccine for HAV, but not for HCV. Despite the mounting evidence that HCV is sexually transmitted among HIV positive MSM, screening is not yet routine.

The present analysis looked at medical record of 1607 patients who made approximately 12,000 visits to 8 clinics in 6 cities (Atlanta, Chicago, Los Angeles, Miami, New York, and San Francisco) since 1998.

The investigators found that while just 45% of the men had been tested for HAV and 48% for HCV, the rate for HBV was much higher, at 89%.

"Screening for HBV and HAV infection and vaccination of susceptible persons are important preventive services in the management of HIV-infected persons," the researchers concluded. "Screening for HBV and HCV infection and evaluation of those persons with chronic infection is important to identify those who require treatment and may be at risk for progressive liver disease."

3/10/09

References

J Ghosn, C Larsen,L Piroth, and others. Evidence for Ongoing Epidemic Sexual Transmission of HCV (2006 to 2007) among HIV-1-infected Men who Have Sex with Men: France. 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009). Montreal, Canada. February 8-11, 2009. Abstract 800.

G Van Den Berk, W Blok, H Barends, and others. Rapid Rise of Acute HCV Cases among HIV-1-infected Men Who Have Sex with Men, Amsterdam. CROI 2009. Abstract 804.

S Fishman, K Childs, D Dieterich, and others. Age and Risky Behaviors of HIV-infected Men with Acute HCV Infection in New York City Are Similar, but not Identical, to those in a European Outbreak. CROI 2009. Abstract 801.

D Fierer, S Fishman, A Uriel, and others. Characterization of an Outbreak of Acute HCV Infection in HIV-infected Men in New York City. CROI 2009. Abstract 802.

K Hoover, K Workowski, S Follansbee, and others. Hepatitis Screening of HIV-infected Men Who Have Sex with Men: 8 US Clinics. CROI 2009. Abstract 803.

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.

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.

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.

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.