LiverHope

Bristol Compound Potent Against Hepatitis C

Early stage compound knocks down virus in one dose

Drug may be powerful addition in hepatitis C cocktail

By Julie Steenhuysen

CHICAGO, April 21, 2010 (Reuters) - An experimental Bristol-Myers Squibb compound called BMS-790052 is proving to be the most potent yet at treating hepatitis C, an infection poorly treated with existing drugs, company researchers said on Wednesday.

An early, phase I safety study of the compound found it was highly effective at blocking the protein NS5A, a new target that might provide one more weapon against a virus that can quickly develop resistance.

"A lot like HIV, it is anticipated that a combination of at least three drugs will be required to prevent the emergence of resistance," said Bristol-Myers Squibb's Dr. Nicholas Meanwell, who worked on the study published in the journal Nature.

"We are targeting a different protein. This will provide a unique resistance profile," Dr. Meanwell said in a telephone interview.

Hepatitis damages the liver, causing chronic liver problems, liver cancer, cirrhosis and death. It is the leading cause of liver disease worldwide, affecting an estimated 4 million people in the United States alone and 170 million worldwide.

Typical treatment involves 48 weeks of interferon plus the antiviral drug ribavirin. The combination works in only about half of all patients, and some develop such taxing side effects that they have to stop.

The Bristol-Myers compound works differently than a new class of drugs called protease inhibitors being developed by Merck's Schering-Plough division and Vertex Pharmaceuticals Inc.

Dr. Meanwell said BMS-790052 helps inhibit the hepatitis C virus from replicating.

In a phase 1 trial, infected patients who got a single 100 milligram dose of the compound saw their viral load drop by more than 99.9% within 24 hours. The reduction was sustained for 120 hours, according to the report.

Early results of a phase II study presented last week at the European Association for the Study of the Liver in Vienna were also promising. Seven out of eight patients who got the highest dose of the drug had undetectable levels of the virus. The eighth patient had stopped taking the drug for a while.

"It's got potency and effectiveness in a single dose that is unmatched by anything else," Dr. Meanwell said.

He said the findings are very early, but the hope is that the compound could be used in a cocktail of drugs to keep the virus from developing resistance long enough for patients to clear the disease.

NEW YORK (Reuters Health) Apr 16, 2010 - Liver biopsy complication rates are low at experienced centers -- although as might be expected, lower platelet counts are associated with higher risk of bleeding, according to a multicenter study.

"It is our belief that liver biopsies, at least among persons with advanced but otherwise compensated chronic hepatitis C, can be undertaken reasonably safely, but should not be done when the platelet count is less than 60,000," lead author Dr. Leonard B. Seeff told Reuters Health by email.

several reasons," Dr. Seeff said. "First, there is a developing belief that some noninvasive procedures might offer almost as much information as performing a liver biopsy, a view not universally shared. Second, there are concerns that the procedure has potential for causing side effects that include bleeding and, rarely, even death."

Nevertheless, biopsies are necessary to diagnose certain conditions, and as Dr. Seeff and his colleagues point out, liver histology is a mandatory endpoint in clinical trials of therapies for liver disease.

In their April 16th online paper in Clinical Gastroenterology and Hepatology, the researchers report on 2740 percutaneous liver biopsies performed at 10 centers in the U.S. All were done in patients with advanced chronic hepatitis C who were enrolled in the HALT-C trial of peginterferon alfa-2a maintenance therapy.

There were no biopsy-associated deaths, but 63 patients (2.3%) had complications. Complications were serious in 1.1%. About half of the serious complications involved bleeding, about a quarter involved severe pain. Other severe complications included gallbladder puncture, hypotension, pneumothorax, and syncope. Most of the non-serious complications involved transient pain at the biopsy site.

The bleeding rate was higher when platelet counts were 60,000/mm 3 or less and when patients had an international normalized ratio (INR) of 1.3 or more. However, no patient with an INR above 1.5 had bleeding.

"There was not much difference in the frequencies (of adverse events) among the various participating centers," continued Dr. Seeff, "nor were there significant differences based upon operator experience, the type of needle used, or the use of ultrasound guidance."

However, he and his colleagues point out, biopsies were done "largely by experienced hepatologists in outpatient facilities, mostly under ultrasonic guidance" with conscious sedation and most often with a cutting needle.

Although it's uncertain whether these findings would also apply to patients with other liver diseases, in these patients at least, "despite their advanced chronic liver disease," biopsy was "safe and well tolerated," the researchers conclude.

ROCKVILLE, Md. – April 30, 2010 - The FDA heard public testimony Friday on establishing a compassionate use program that would allow severely ill hepatitis C (HCV) patients access to investigational, direct-acting antiviral agents.

One of the current treatments for HCV -- pegylated interferon alfa-2a and ribavirin (Rebetol) -- is highly toxic with a response rate of about 50%, clinical data show. That number is much lower in real-world cases, according to a number of physicians who testified during the public hearing.

The FDA understands current treatment options are not good enough, an official said. "Current control of hepatitis C is not working," said Peter Lurie, MD, of the FDA's Office of the Commissioner.

Friday's meeting was called in response to a petition by groups seeking access to the drugs for individuals often excluded from clinical trials.

Clinical trials are only open to a small subset of real-world HCV patients, noted Diana Sylvestre, MD, who treats HCV-infected intravenous drug users in the San Francisco area. Yet, there are many HCV patients who cannot tolerate current treatments, she said.

Her patients are rarely accepted into clinical trials, she said, because of their drug use, comorbidities, and mental illnesses.

Other patient populations who might benefit from expanded access include those with cirrhosis, HIV, or hemophilia; those awaiting transplant or post-transplant patients who have a recurrence of HCV; and African Americans and Hispanics.

Several physicians urged special consideration for minority patients, who are disproportionately left out of clinical trials. A recent study confirmed that members of ethnic minorities do not fare as well as expected with current HCV treatments.

The FDA instituted compassionate use programs in the 1970s and such drugs as Herceptin, Avastin, and Tarceva have all been made available before formal FDA approval under an expanded access protocol.

One major expanded access program involved breakthrough HIV therapies in the '90s. "Anecdotally, the results were so striking," said Jeffrey Murray, MD, deputy director of the FDA's antiviral products division. "They did save lives."

Murray noted that the FDA is working on a guidance document on the use of direct-acting antiviral agents, which should be released sometime this year. If approved, an expanded access program could be applied to several novel HCV treatments currently in clinical trials.

One of the most advanced is the protease inhibitor telaprevir from Vertex and Johnson & Johnson.

Results from a phase II trial showed that when telaprevir was added to pegylated interferon alfa-2a and ribavirin among patients who hadn't responded to treatment, the virus was significantly more likely to be eradicated.

The legislation is in two parts: the first step would end the right of the next of kin to challenge the decisions of their dead or dying relatives to donate their organs.

In a second measure, which is far more contentious, people would have to indicate in official documents — their driver’s licenses, most commonly — that they specifically don’t want to donate organs. If the box is not checked, it is presumed the person wants to donate.

What are the ethical and practical issues involved in changing the law? Is a “presumed consent” system an effective way to increase the number of organs available, and thus save lives, or will it deter public support for donation?

Admitting that we don't feel well takes a great deal of courage. We live in a society that prizes beauty, strength, and productivity, and there is a great deal of shame and self-blame that comes with not living up to that ideal. More often than not, when someone asks us how we are, we're likely to say "just fine" and change the subject.

Our discomfort is compounded when our symptoms are largely invisible. When Jeri, herself chronically ill, is not feeling well, she often gets the rash on her face that is characteristic of lupus. "I get nice rosy cheeks and I do look better," Jeri says. "I tell people I feel awful, and they say, 'You look wonderful.'"

Looking good and feeling bad creates a number of dilemmas for those of us with chronic, invisible illnesses. How much and to whom do we tell that we are sick? What do we say when someone asks us how we are, or tells us how great we look?

At one point in my journey of chronic illness, I would likely have said there was a one-size-fits-all answer to these questions, and it would have been to tell everyone you know everything you know, and make sure they understand it. But whether it's a growing sense of maturity about my illness or a decreasing lack of energy, or some fateful convergence of the two, I no longer feel compelled to explain myself to people I meet on the street. When we accept the fact that we're sick, it's less important that everyone else does, too.

Certainly, those relationships that are most important to us require special care and attention, and in my April column, I'll share some tips for improving communication and strengthening our ties to spouses, parents, children, and best friends. In the balance of this column, I'll share my current thinking about how much, or how little, to reveal in the checkout line at the grocery store, during coffee hour at church, or around the water cooler at the office.

With people we have known for a long time, it can be hard to hide a change in our health or unnecessary to do so. But with newer friends or passing acquaintances, we sometimes struggle with the question of when to say we have a chronic illness and how much detail to reveal. On the one hand, we may feel that if we withhold information, we won't be able to develop a deeper relationship. But on the other hand, we have very little way of knowing how someone will respond to the reality that we're sick.

Each time I told someone I was writing a book about chronic illness and they wanted to know why I was interested in the topic, I held my breath. When I admit that I have health problems, I feel as if I am walking out on a limb that might break without warning. I've been pleasantly surprised to discover that by acknowledging my own limitations, I've opened the door for others to share their health problems, or those of their relatives or friends. You'd be amazed at how many of us are dealing, rather successfully, with ongoing health problems!

In general, however, I think how much we reveal depends on the nature of the relationship; my best friend knows the intimate details of my health problems, but casual acquaintances may only know that I rarely make evening commitments. When I tell business associates that I have chronic health problems, I do so in the broadest of terms, and I try to sound as healthy as I can when I say it! While we might feel that the more sick we seem, the more sympathy and respect we'll command, I think it really works the other way around. I've never had a client question me when I state simply, and without further explanation, that I choose to limit long-distance travel because of health problems. Yet I know instinctively that they don't want to hear about my aches and pains.

I hope that some of the following specific tips, garnered both from my own experience and from what others tell me, will help you through some of the awkward situations we all encounter.

Most of us have developed a standard answer to the question, "How are you?"; and I don't think we're being dishonest to use it in social situations. My response, "Hanging in there," some days translates to "by the skin of my teeth," but it works on good days, as well.

When someone tells you that you look great, even though you feel awful, a simple and heartfelt "thank you" is always an appropriate response. After all, looking good while feeling bad takes talent!

When someone says that it's hard to believe you're sick, you might acknowledge that even you struggle with the disparity between how you feel and how you look. Try saying something like, "Yes, it's even hard for me to understand how I can feel so bad when I look so well." This disarms your critics and creates common ground.

If you are no longer working because of health problems, and someone asks you what you do, try borrowing a page from Mirielle, who has fibromyalgia. "As little as I can," is her cheery response.

Above all, save the limited energy you have to help those who are most important to you understand how you feel. When people tell Angela, who has multiple sclerosis, that she sleeps too much, her reaction depends on the source. To those friends she thinks will understand, she explains why she takes a nap every day. "For the most part," Angela says, "I just laugh it off and say that some of us are lazier than others."

April 16, 2010 - A jury has been seated to hear the first civil trial stemming from Southern Nevada's hepatitis C outbreak.

Jury selection, which started Monday, wrapped up Thursday afternoon with the final selection of eight jurors and four alternates.

Opening statements in the case will begin 9 a.m. Monday, April 19, 2010, before District Judge Jessie Walsh.

Henry Chanin, 61, and his wife, Lorraine, are suing Teva Parenteral Medicines Inc. and Baxter Healthcare Corp., the maker and distributor of propofol, the anesthetic linked to the hepatitis C outbreak.

Henry Chanin was infected with hepatitis C during a June 2006 colonoscopy at the Desert Shadow Endoscopy Center, a sister clinic of the Endoscopy Center of Southern Nevada.

Public health investigators blamed the outbreak on nurse anesthetists who reused single-dose vials of propofol between patients at the clinics.

Chanin's lawsuit alleges the drug companies made and sold the clinics 50-milliliter vials of the milky liquid, which is five times the amount needed for a typical colonoscopy. The larger vials induced medical workers to reuse the vials between patients instead of throwing out the unused anesthetic, Chanin's lawyers say.

February 24, 2010 - Research has shown that people with chronic hepatitis C are at greater risk for cardiovascular disease, possibly due to metabolic disturbances.

As described in the January 2010 Journal of Clinical Virology, M. Boddi and colleagues from Italy looked for HCV genetic material and evidence of viral replication in atherosclerosis plaques from chronic hepatitis C patients with ischemic heart disease (heart damage due to lack of oxygen).

Atherosclerosis is an inflammatory process in which plaques of cholesterol, immune cells, scar tissue, and other material accumulate in artery walls, which can rupture and develop clots. In addition to narrowing the arteries, pieces of material can break off and block blood vessels, leading to heart attack or stroke.

The researchers found HCV RNA in seven carotid artery (blood vessels in the neck that supply the brain) plaque samples from HCV antibody positive people, but not in the nine plaque samples from HCV antibody negative individuals. Three people had HCV genetic material in carotid plaques despite having undetectable plasma viral load.

“The novel finding of HCV RNA sequences in plaque tissue strongly suggests an active local infection,” the study authors concluded. “This in turn makes it conceivable that the virus may exert local action in carotid atherosclerosis.”

Source: HEPATITIS JOURNAL REVIEW: A Bi-Monthly Publication of the Hepatitis Support Project