Advances being made in the treatment of hepatitis

CHICAGO, IL (June 2, 2009) – Researchers are making great strides in the development of new treatments for hepatitis and in confirming the effectiveness of current treatments, according to several studies being presented at Digestive Disease Week^® 2009 (DDW^®).

"Only about half of the patients infected with hepatitis B and C respond to currently used treatments," said Nicholas J. Shaheen, MD, MPH, AGAF, University of North Carolina School of Medicine. "Research is needed to identify which treatments may effectively help these patients who progress to liver failure, which often leads to liver transplants and significant health care costs."

Hepatitis is an inflammation of the liver that usually produces swelling, tenderness and sometimes permanent damage. Hepatitis B can be spread from mother to child at birth or soon after and through sexual contact, contaminated blood transfusions and needles. Hepatitis C, the most common form of viral hepatitis, can be spread through blood transfusions and contaminated needles, but for a substantial number of patients, the cause is unknown. Both forms of viral hepatitis may lead to cirrhosis, or scarring, of the liver.

DDW is the largest international gathering of physicians and researchers in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery.

Two year follow-up data from this ongoing trial demonstrate that hepatitis B (HBV) patients with persistent viremia (presence of virus of blood) while receiving adefovir dipivoxil (ADV) therapy may be safely and effectively switched to tenofovir disoproxil fumarate (TDF), either as monotherapy or in combination therapy with emtricitabine (FTC/TDF). In this study, 105 patients were randomized to treatment with TDF (53) or FTC/TDF (52); all were on ADV at the time of enrollment and 57 percent had prior or current lamivudine (LAM) experience. Using a sensitive assay for detection, 41 percent of the patients had LAM- or ADV- associated resistance mutations at baseline. A switch from blinded therapy (TDF or FTC/TDF) to open-label FTC/TDF was made if HBV DNA levels exceeded 400 copies/mL after 24 weeks on therapy.

At week 96, HBV DNA levels were suppressed to less than 400 copies/mL in 89 percent and 83 percent of subjects randomized to initial therapy with TDF and FTC/TDF, respectively, under an intent to treat (missing=failure) analysis. In other words, two years after starting therapy with TDF or FTC/TDF, 86 percent of all participants who entered the study with a prior suboptimal response to ADV, had achieved HBV DNA suppression. When considering "switch-failure," 63 percent and 75 percent of subjects randomized to initial therapy with TDF and FTC/TDF, respectively, had HBV DNA levels suppressed to less than 400 copies/mL by week 96. The presence of adefovir or lamivudine resistance mutations at baseline had no impact on the response to therapy. Eight patients discontinued through week 96, none due to adverse events. In ongoing HBV resistance surveillance in this trial, as well as in the TDF for HBV pivotal trials, no TDF resistance has been observed.

"These data expand upon the safety and efficacy findings from the TDF hepatitis B pivotal trials," said David Oldach, MD, director of clinical research at Gilead Sciences, Inc. "Tenofovir disoproxil fumarate has demonstrated consistent efficacy across a broad range of chronic hepatitis B patients, including patients with preexisting resistance mutations or prior suboptimal response to adefovir dipivoxil, patients with cirrhosis, and patients with any of the major HBV genotypes. An additional very promising finding in the registrational trial among HBeAg positive patients has been hepatitis B surface antigen loss, occurring in 3 percent of TDF recipients in one year and 6 percent in two years time."

Continued Dr. Oldach, "The data to be presented review outcomes from the first two years of a three and a half year study. While we cannot predict future treatment outcomes, we hope and expect that the participants will continue to receive durable benefit from this therapy."

Dr. Oldach will present these data on Monday, June 1 at 11:45 a.m. CDT in Room S105, McCormick Place.

Interferon or peginterferon with or without ribavirin (IFNTx) should be the standard treatment for patients with hepatitis C (HCV), according to a study presented by researchers from the Virginia Commonwealth University Medical Center, Richmond, VA. HCV patients who achieved sustained virologic response, including those with cirrhosis, resolved fibrosis. After five years, liver histology returned to normal in most patients without pre-existing cirrhosis. Additionally, IFNTx reduced the rate of histologic progression over five years compared to no treatment, even in patients with no fibrosis, or scarring.

"The use of interferon or peginterferon for the treatment of patients with hepatitis C can have a dramatic improvement on the histology of the disease, including the disappearance of cirrhosis," summarized Richard Sterling, MD, MSc, Professor of Medicine, Virginia Commonwealth University, and a study co-investigator. "The results of our study show that in patients who respond to treatment, the use of interferon or peginterferon in addition to ribavirin is very effective."

Researchers conducted a longitudinal cohort study to evaluate the use of IFNTx on liver histology in patients with chronic HCV. Seven hundred and fifty five patients underwent liver biopsy and received a single course of IFNTx or no treatment. Of these patients, 230 were followed for five years without additional treatment (41 patients declined treatment and 189 received IFNTx without obtaining sustained virologic response) before undergoing a repeat liver biopsy. An additional 102 patients who received IFNTx and obtained sustained virologic response (SVR) underwent liver biopsy after five years.

There were no significant differences in worsening of inflammation or fibrosis scores between those who did not undergo treatment or did not have an SVR. Factors associated with fibrosis progression were change in total inflammation and increase in piecemeal necrosis (interface hepatitis) on second biopsy and presence of interface hepatitis on baseline biopsy. Conversely, the 102 patients who achieved SVR had a significant reduction in fibrosis score; 73 percent of patients who had portal fibrosis on their first biopsy showed no evidence of scarring on the second biopsy, while 20 percent showed no change with treatment. Of the patients with bridging fibrosis on first biopsy (52 percent of the cohort with SVR), 35 percent had no scarring on the second biopsy, 23 percent had portal scarring, 38 percent remained unchanged and 4 percent had cirrhosis, which investigators believe could be a sampling error. For patients with cirrhosis on first biopsy (19 percent of the cohort with SVR), 50 percent had improved on second biopsy — 10 percent had no scarring, 10 percent had portal scarring and 30 percent had improved to bridging fibrosis. African American participants and patients with genotype 1 experienced less sustained virologic responses, which has been shown through other research.

Dr. Mitchell Shiffman will present these data on Sunday, May 31 at 8:30 a.m. CDT in Room 9B-16, McCormick Place.

For the first time, researchers have shown that patients with hepatitis C (HCV) genotype 1 who do not respond to standard treatment can obtain a sustained virologic response using a combination regimen of telaprevir (T) plus peginterferon-alfa-2a (P) ± ribavirin (R). About 70 percent of patients who had relapsed on previous HCV treatment experienced sustained virologic response and about 40 percent of patients who previously had not responded to treatments experienced sustained virologic response. Patients who had not responded to previous treatments needed to undergo 48 weeks of treatment with T/PR. The sustained virologic response rate was significantly higher in all treatment groups receiving T/PR regimens compared with those receiving placebo plus PR48.

"This is a very important and unique trial," said Adrian M. Di Bisceglie MD, FACP, chairman of the department of internal medicine and chief of hepatology at the Saint Louis University School of Medicine, and lead investigator of the study. "Since a large majority of hepatitis C patients do not experience a sustained response to current treatments, it is necessary to identify new drugs and treatment regimens to help better the chances of patients clearing the disease from their systems. The results of this trial bring us closer to understanding how to do that."

In the PROVE3 study, 453 patients were randomized to receive T/PR for12 weeks followed by PR for 12 weeks (T12/PR24); T/PR for 24 weeks followed by PR for 24 weeks (T24/PR48); T/P for 24 weeks (T24/P24); or placebo/PR for 24 weeks, then PR for 24 weeks. Of the participants, 235 (52 percent) completed their assigned treatments. Many of the patients included in the intent-to-treat analysis had baseline characteristics know to be associated with poor response to treatment, including 196 (43 percent) with cirrhosis or bridging fibrosis, 418 (92 percent) with baseline serum HCV RNA ≥ 800,000 IU/mL, and 40 (9 percent) were African American.

The general safety profile of T12/PR24 compared with T24/PR28 was similar to that observed in treatment naïve patients. Patients in the T12/PR24 or T24/PR48 group experienced greater frequency of fatigue, nausea, headache, rash, pruritus, diarrhea, anemia, insomnia, fever, hair loss and chills thank those treated with placebo followed by PR48. Of those patients discontinuing treatment due to adverse events, 11 (10 percent) were in the T12/PR24 group, 29 (25 percent) were in the T24/PR48 group, 10 (9 percent) were in the T24/P24 and five (4 percent) were in the placebo plus RP48 group.

"We are continuing to study these treatment combinations in a phase III trial, which is currently underway," said Dr. Di Bisceglie. "We hope to identify the optimal duration of treatment of telaprevir to ensure HCV patients have the best opportunity of clearing the disease from their system to obtain a sustained virologic response."

Approximately 80 percent of HCV patients in the U.S. have genotype 1, and approximately 50 percent of patients with HCV do not respond to current treatments.

This study was funded by Vertex Pharmaceuticals.

Dr. Di Bisceglie will present these data on Tuesday, June 2 at 2:15 p.m. CDT in Room E451B, McCormick Place.

Digestive Disease Week^® 2009 (DDW^®) is the largest international gathering of physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery. Jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE) and the Society for Surgery of the Alimentary Tract (SSAT), DDW takes place May 30 – June 4, 2009 in Chicago, IL. The meeting showcases more than 5,000 abstracts and hundreds of lectures on the latest advances in GI research, medicine and technology.