Wednesday, March 30, 2011

Boceprevir; Difficult Hepatitis C Type Responds to Novel Protease Inhibitor

 From the New England Journal of Medicine.

Boceprevir for Untreated Chronic HCV Genotype 1 Infection
F. Poordad and Others

Boceprevir for Previously Treated Chronic HCV Genotype 1 Infection
B.R. Bacon and Others

Posted by John Staples • March 30th, 2011
A Better Way to Unbind Prometheus? Boceprevir for the Treatment of Chronic Hepatitis C Infection
What do Mickey Mantle, Evel Knievel, and Pamela Anderson have in common? Infamy, certainly, but all three are also reported to have battled chronic hepatitis C virus (HCV) infection. And they aren’t alone: Including a sizable list of celebrities, it is estimated that 160 million people worldwide have the disease, putting them at risk of hepatic cirrhosis, hepatocellular carcinoma, and death. Current treatments with peginterferon plus ribavirin are poorly tolerated and result in sustained virologic response (SVR) rates below 50% in HCV genotype 1 infection. Some patients feel like the mythical Prometheus, their hands bound as they helplessly watch the virus ravage their liver day after day. Can anything more reliably loosen these chains?.... continue reading...

Related; Boceprevir; New Drugs for Hepatitis C on the Horizon

Difficult HCV Type Responds to Novel Protease Inhibitor

By Michael Smith, North American Correspondent, MedPage Today

Published: March 30, 2011

Reviewed by Zalman S. Agus, MD; Emeritus Professor

University of Pennsylvania School of Medicine.

Action Points

Note that rates of sustained virologic response associated with peginterferon–ribavirin therapy, the current treatment of choice for chronic infection with hepatitis C virus, remain below 50%.

Note that in these two studies, the addition of boceprevir, an experimental oral HCV-protease inhibitor, significantly improved response rates in both previously untreated and treated groups of patients.

Note that anemia is a significant concern with the use of this drug and may require the addition of erythropoietin.

In both untreated and previously treated hepatitis C patients, an investigational drug improved outcomes in a hard-to-treat type of the disease, researchers reported.

The drug -- boceprevir (Victrelis) -- significantly improved rates of sustained virologic response when added to standard therapy, compared with the standard therapy alone, according to two clinical trials reported in the March 31 issue of the New England Journal of Medicine.

Boceprevir is a protease inhibitor that directly targets genotype 1 of the virus -- one of two in clinical development -- and is the leading edge of a "new era of therapy for hepatitis C," according to Donald Jensen, MD, of the University of Chicago Medical Center, who contributed an editorial commenting on the studies in the same issue of the journal.

Jensen said that the protease inhibitors are a major advance in therapy for genotype 1 hepatitis C, which until now has relied on boosting the immune system, rather than attacking the virus directly. The drugs have little effect on other genotypes of hepatitis C.

The two industry-sponsored randomized, placebo-controlled trials had similar designs and were conducted by overlapping teams of investigators.

All patients had a four-week lead-in with peginterferon alfa-2b and ribavirin, the standard treatment. Then, in the control group, a placebo was added for another 44 weeks of treatment.

In a second group, treatment was guided by response: boceprevir was added for 24 weeks and if patients had detectable hepatitis C RNA between weeks eight and 24, the drug was continued for another 20 weeks.

Finally, a third group got boceprevir, combined with the standard therapy, for 48 weeks.

The endpoint for both studies was the proportion of patients who achieved a sustained virologic response, defined as undetectable hepatitis C RNA levels for 24 weeks after the end of therapy.

Among treatment naive patients in the so-called SPRINT-2 trial, the results were significantly better than placebo in both boceprevir arms, according to Fred Poordad, MD, of Cedars-Sinai Medical Center in Los Angeles, and colleagues.

In the cohort of 938 patients who were not black, they reported, 40% of those in the control group had a sustained virologic response.

On the other hand, the rate was 67% in the response-guided arm, and 68% in the fixed treatment arm -- both different at P<0.001 from the control group.

The 159 black patients were analyzed separately because blacks usually don't do as well when treated with standard therapy, the researchers noted.

In that cohort, 23% of the control patients had a sustained virologic response, compared with 42% in the response-guided arm and 53% in the fixed treatment arm. The differences from controls were significant at P=0.04 and P=0.004, respectively.

Meanwhile, a team led by Bruce Bacon, MD, of the Saint Louis University School of Medicine in St. Louis, Mo., conducted the so-called HCV RESPOND-2 trial among 438 patients previously treated with standard therapy.

Patients in the study had either failed to achieve a sustained virologic response on peginterferon and ribavirin or had reached that goal but relapsed.

Bacon and colleagues reported that the rate of sustained virologic response among patients in the control group was 21%, compared with 59% among patients getting response-guided therapy and 66% among those getting fixed duration treatment.

Both differences were significant at P<0.001.

Among patients who had never responded to therapy, the rates were 7% in the control group, 40% in the response-guided arm, and 52% in the fixed-duration boceprevir group.

Among those who had responded but relapsed, the comparable rates were 29%, 69%, and 75%, respectively, Bacon and colleagues reported.

One of the most common adverse effects of the drug was anemia, seen in both studies, and more than 40% of patients needed erythropoietin for up to 150 days.

Indeed, in the HCV RESPOND-2 trial, more than 8% of patients in the fixed-duration boceprevir group had a reduction in the hemoglobin level to less than 8.0 gm per deciliter, and 9% required blood transfusions, the researchers reported.

"This rate of anemia poses concerns," argued editorial writer Jensen, since without erythropoietin it could require adjusting the dosages of boceprevir, ribavirin, or both -- possibly reducing the rates of sustained virologic response.

Both studies were sponsored by Schering-Plough (now Merck).

Poordad reported financial links with Merck, Vertex, Abbott, Gilead, Achillion, Genentech, and Tibotec.

Bacon reported financial links with Gilead, Three Rivers Pharmaceuticals, Valeant, Vertex, Human Genome Sciences, Roche, Bristol-Myers Squibb, Wyeth, Romark Laboratories, Schering-Plough (now part of Merck), Novartis, and Isis.

In both cases, several authors reported being employed by or holding equity in the company.

Jensen reported financial links with Abbott, Boehringer-Ingelheim, BMS, Genentech/Roche, Roche Global, Merck, Pharmasset, Pfizer, Tibotec, Vertex, GlobeImmune, Medscape, Projects in Knowledge, Simpson Health Care, Focus Medical Communications, WebMD, and Practice Point Communications.

Primary source: New England Journal of Medicine

Source reference:

Poordad F, et al "Boceprevir for untreated chronic HCV genotype 1 infection" N Engl J Med 2011; 364: 1195-206.
Additional source: New England Journal of Medicine

Source reference:

Bacon BR, et al "Boceprevir for previously treated chronic HCV genotype 1 infection" N Engl J Med 2011; 364: 1207-1217.
Additional source: New England Journal of Medicine
Source reference:
Jensen DM "A new era of hepatitis C therapy begins" N Engl J Med 2011; 364: 1272-1274.

From EurekAlert

Public release date: 30-Mar-2011
Contact: Maria


Henry Ford Health System

Drug cocktail offers new hope for hepatitis C patients

A three-drug cocktail can eliminate the hepatitis C virus in patients far more effectively than the current two-drug regimen, according to researchers at Henry Ford Hospital.

"This study represents a remarkable advance and a potential cure for people with hepatitis C who have not responded to previous therapy," says co-author Stuart C. Gordon, M.D., section chief for the Division of Hepatology at Henry Ford Hospital.

"We will soon have a new standard of treatment for hepatitis C patients," says Dr. Gordon. "This study ushers in a new era of drug development that will provide a host of antiviral agents to treat hepatitis C, and we are now witnessing dramatic and rapid advances in how we will be able to treat these patients."

The results of the global study are in the March 31 issue of The New England Journal of Medicine.

At least 3.2 million Americans are infected with hepatitis C, a chronic viral disease affecting the liver. The Centers for Disease Control and Prevention estimates that more than 12,000 people die each year of liver disease and liver cancer associated with the hepatitis C virus.

Most people who are infected with hepatitis C remain without symptoms for years. When symptoms of advanced liver disease do occur, it is often too late to offer the current treatment regimens. The infection may lead to scarring of the liver (cirrhosis), liver cancer or the need for liver transplant.

The virus was previously spread through contact with infected blood products before 1990, and often via injection drug use or the sharing of straws during the use of cocaine. Among immigrants to the U.S. from Asian, African, Middle Eastern and Eastern European countries, the virus may have been transmitted via the use of non-sterile glass syringes used for vaccination purposes.

There is currently no vaccine for hepatitis C.

In the study, researchers randomly assigned patients to one of three groups. In all three groups, patients received peginterferon and ribavirin (the current standard of care) for four weeks. A control group (group 1) continued to receive only peginterferon–ribavirin for 44 additional weeks; group 2 received boceprevir plus peginterferon–ribavirin for 32 weeks, and patients with a detectable hepatitis C virus level at treatment week 8 received placebo plus peginterferon–ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon–ribavirin for 44 weeks.

Boceprevir is a protease inhibitor, a new class of direct-acting antiviral agent that specifically targets and inhibits the replication of the hepatitis C virus.

Results showed the rate of sustained virologic response (loss of the virus) was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%).

Among patients with an undetectable hepatitis C virus level at treatment week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. A sustained virologic response generally translates into a long-term eradication of virus, or cure.

"We can conclude that boceprevir, when added to peginterferon and ribavirin, leads to high rates of sustained virologic response in difficult-to-treat patients," explains Dr. Gordon.

In an accompanying article in the same issue of The New England Journal of Medicine, treatment of previously untreated hepatitis C patients with the same three-drug cocktail likewise showed significantly higher response rates than the current two drug regimen.
The study was funded by Schering-Plough (now Merck).

Contact: Carrie Bebermeyer

Saint Louis University

Game changer: Hepatitis C drug may revolutionize treatment

Saint Louis University investigator reports findings in New England Journal of Medicine

ST. LOUIS – The drug boceprevir helps cure hard-to-treat hepatitis C, says Saint Louis University investigator Bruce R. Bacon, M.D., author of the March 31 New England Journal of Medicine article detailing the study's findings. The results, which were first reported at the 61st annual meeting of the American Association for the Study of Liver Disease's last November, offer a brighter outlook for patients who have not responded to standard treatment.

Bacon, who is professor of internal medicine at Saint Louis University School of Medicine and co-principal investigator of the HCV RESPOND-2 study, studied the protease inhibitor boceprevir and found that it significantly increased the number of patients whose blood had undetectable levels of the virus.

"These findings are especially significant for patients who don't respond to initial treatment," said Bacon. "When the hepatitis C virus is not eliminated, debilitating fatigue and more serious problems can follow."

Hepatitis C is caused by a virus that is transmitted by contact with blood. The infection may initially be asymptomatic, but for patients who develop chronic hepatitis C infection, inflammation of the liver may develop, leading to fibrosis and cirrhosis (scarring of the liver), as well as other complications including liver cancer and death.

The prognosis varies for patients with chronic hepatitis C. With the current standard therapy, about half fully recover after an initial course of peginterferon and ribavirin anti-viral therapy that may last from six months to a year.

The remaining patients, known as non-responders, may improve with initial treatment but the virus is not eliminated, or may not respond to treatment at all. For this group, the only current option is to re-treat patients with the same or similar drugs, which increases the likelihood of severe treatment side-effects. In addition, researchers have found that the success of treatment depends on the major strain, or genotype, of hepatitis C that a patient has.

The HCV RESPOND-2 study looked at 403 patients with chronic hepatitis C infections with genotype one, the most difficult strain of the virus to treat, who still had significant levels of the virus after being treated with peginterferon and ribavirin, the standard hepatitis C treatment.

"These results are very exciting," Bacon said. "In this study, boceprevir helped cure significantly more patients in 36 weeks of therapy than did treatment with peginterferon and ribavirin alone."

A second study, HCV SPRINT-2, examined patients with hepatitis C with genotype one who had not yet been treated with the standard treatment. They, too, responded well to the drug.

Bacon calls the progress made in treating hepatitis C remarkable.

"We've gone from the discovery of the virus in 1989 to where we are now, 22 years later, when we have the ability to cure a large majority of those with hepatitis C," Bacon said. "It's a true success story."

"Drugs like boceprevir are going to revolutionize care of those with hepatitis C."

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