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News Review

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The Best in the News on HCV, HBV and HIV/HCV Coinfection from March 15th, 2003 to April 15th, 2003

Alan Franciscus
Editor-in-Chief

March 15th, 2003

PEGASYS® A More Tolerable Treatment for Hepatitis C Patients, Study Reveals. "Health-related quality of life must be considered when selecting a treatment against chronic hepatitis C to ensure adherence to therapy," authors say

Two weeks after initiating treatment with PEGASYS, a new study has found that hepatitis C patients experienced significantly less fatigue, pain, physical and emotional limitations, and had improved vitality compared to patients treated with conventional interferon. Notably, maintaining health-related quality of life during treatment may reduce the risk of early treatment discontinuation. The study is published in the current issue of Pharmacoeconomics.

"We know that many patients do not adhere to their hepatitis C treatment because the side effects are often considered by patients to be more objectionable than the symptoms of the disease," said Dr. Jens Rasenack, the study author and Professor of Medicine in the department of Gastroenterology and Hepatology at the Albert-Ludwigs-University of Freiburg Germany. "The positive impact that PEGASYS has on health-related quality of life makes it more likely that they will complete their treatment and ultimately improve their chances of being cured."

Previous studies have demonstrated that interferon therapy has a negative effect on health-related quality of life (HRQL) during the initial three to six months of therapy. Patients typically experience side effects such as flu-like symptoms, fatigue, lack of energy, body pain and alterations in mood, making it difficult for them to participate in every day activities.

Patients treated with PEGASYS demonstrated significantly better scores in all health areas surveyed compared to those treated with conventional interferon and reported less disabling fatigue. The less disabling fatigue that PEGASYS-treated patient experienced is thought by the study authors "to be attributed to the near-constant and sustained serum levels produced by the weekly dosing regimen of peginterferon alfa-2a (40KD) compared with the peaks and troughs associated with thrice weekly administration of unmodified interferon alfa-2a."

The patients treated with PEGASYS also reported fewer problems with work due to physical or emotional problems and were less likely to report lacking pep or energy, being tired or feeling worn out. These patients were also less likely to report moderate or severe pain that interfered substantially with their work. These benefits continued for at least the first 12 weeks of treatment and in some cases right up to the 48th week of treatment.

The authors note that this analysis further extends the understanding of the documented benefits of PEGASYS' better tolerability. Given that worsening health-related quality of life while on treatment negatively influences compliance, the study authors conclude that "the impact of quality of life should be considered when selecting a treatment against chronic hepatitis C to ensure adherence to treatment."

    About the study
    The health-related quality of life analysis was based on an international multicentre, open-label, randomized dose efficacy and safety study comparing PEGASYS with unmodified interferon alfa-2a. Patients received either the standard dose of PEGASYS (180mcg once weekly) for 48 weeks or conventional interferon (6MIU thrice weekly for 12 weeks followed by 3 MIU thrice weekly for a further 36 weeks). Patients were followed until 72 weeks after the start of treatment. The study was conducted in 36 centres in Australia, Canada, Germany, Mexico, New Zealand, Spain, Switzerland, Taiwan and the United Kingdom and included 531 patients. The results of the study "Peginterferon alfa-2a (40KD) (PEGASYS) improves health-related quality of life outcomes compared with unmodified interferon alfa 2-a in patients with chronic hepatitis C" are published in this month's issue of Pharmacoeconomicsi.

    How quality of life and fatigue were measured Patients' quality of life and levels of fatigue were assessed at 2, 12, 24, 48 and 72 weeks after the start of treatment. Quality of life and fatigue were measured using the internationally recognised Short Form 36 health survey and the Fatigue Severity Scale.

    About hepatitis C
    Chronic hepatitis C is a serious viral infection of the liver and the leading cause of liver damage throughout the world. As many as 3% of the world's population are infected with the hepatitis C virus. Those who develop chronic hepatitis C risk cirrhosis, liver cancer, liver failure and liver transplantation.

    About PEGASYS
    PEGASYS, a new generation hepatitis C therapy that is different by design, provides significant benefit over conventional interferon therapy in patients infected with HCV of all genotypes. The benefits of PEGASYS are derived from its new generation large 40 kilodalton branched-chain polyethylene glycol (PEG) construction, which allows for constant viral suppression. PEGASYS also distributes more readily to the liver (the primary site of infection) than conventional interferon. PEGASYS is the only pegylated interferon available as a ready-to-administer solution. Each weekly subcutaneous injection contains 180mcg of pegylated interferon alfa-2a which is the recommended dose for all patients, regardless of body weight.

    About Roche
    Roche is committed to the viral hepatitis disease area, having first introduced Roferon-A for hepatitis B and then C, followed by PEGASYS in hepatitis C. PEGASYS is also in phase III clinical development for patients infected with the HBV virus. Roche has also launched its own brand of ribavirin, Copegus, to be used in conjunction with Roferon A or PEGASYS. Roche manufactures and sells the Amplicor HCV Test (v2.0) and the Amplicor HCV Monitor Test (v2.0) - two tests used to detect the presence of HCV RNA in a person's blood. The company's commitment to hepatitis is further reinforced by the in-licensing of Levovirin, an alternative antiviral. Levovirin will be studied with the objective of demonstrating superior tolerability over the current standard, ribavirin.
Peginterferon a-2a (40kD) [Pegasys(r)] Improves HR-QOL Outcomes Compared with Unmodified Interferon a-2a [Roferon(r)-A]: In Patients with Chronic Hepatitis C. J Rasenack, S Zeuzem, SV Feinman, EJ Heathcote, M Manns, EM Yoshida, MG Swain, E Gane, M Diago, DA Revicki, A Lin, N Wintfeld, J Green. PharmacoEconomics 2003; 21 (5):341-349. Adis International Limited.

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March 16th, 2003

$50 Million Man: How Schering-Plough's CEO Walked Away a Rich Man with His Board's Blessing-Despite The Company's Tailspin
By David Schwab and Susan Todd

It is a prescription for disaster for any chief executive. You lose a blockbuster product, and its successor flops despite years of research and development.

You agree to pay a record $500 million fine to prevent federal regulators from possibly closing your plants.

You hold closed-door meetings with Wall Street insiders days before you announce an earnings shortfall. The Securities and Exchange Commission launches an investigation to see if some investors were tipped off.

Your share price drops more than 60 percent, to a six-year low. You lose your $1.9 million bonus in back-to-back years. Investors, employees and shareholders are up in arms.

Finally, you abruptly announce your early retirement, without preparing a successor.

For Richard J. Kogan, the CEO at drug maker Schering-Plough Corp., this story of the past two years has a happy ending: He will receive a package valued at $50 million when he leaves the Kenilworth-based drug maker by next month.

"It's a squandering of shareholder wealth, and given the fact he left the company in shambles, it is an utter travesty," said Mike Krensavage, a stock analyst with Raymond James in New York who has followed the company for five years.

A story like this, with an executive reaping tens of millions of dollars, was hardly unusual in the go-go years of the late 1990s, when money was thrown around like confetti. Kogan's goodbye kiss, though, shows the wave of reform that swept through Corporate America last year failed to change one basic truth: Some CEOs still play by rules that don't allow them to fail.

Many investors and compensation experts point the finger at the same target -- a clubby board of directors with ties to Kogan.

Those board members awarded him a rich, long-term contract critics say was excessive, amended it last year to ensure early retirement would provide a handsome reward and now refuse to discuss the decisions they made behind closed doors.

"I think the board has been derelict, and I am not alone in thinking this," said Frank Abella Jr., chief executive of IPG Investment Partners Group in Plainfield, who has advised clients to sell Schering-Plough shares.

The Send-Off
Ordinarily, Schering-Plough's annual meeting next month at the Sheraton at Woodbridge Plaza would be a time for a retiring executive like Kogan to ride triumphantly into the sunset.

After all, in his 20-year run, Kogan, 61, helped turn Schering-Plough into one of the most profitable companies in the pharmaceutical industry. He built one of history's great blockbusters in allergy medicine Claritin and oversaw the introduction of breakthrough medicines in hepatitis C and cholesterol, doubling annual revenues to $10 billion.

Even Krensavage and some of Kogan's other critics concede that during his seven-year tenure as CEO, which began in 1996, he created billions of dollars worth of wealth for investors.

Then Kogan's Midas touch disappeared.

Two years ago, the company revealed the Food and Drug Administration would not approve a newer version of Claritin-which was losing its critical patent protection -- until Schering-Plough fixed serious problems at its plants in New Jersey and Puerto Rico.

One setback after another followed. Just this month, the company announced 2003 profit will fall far short of expectations. Then, last Wednesday, Schering-Plough said the SEC is preparing to charge Kogan with violating rules preventing companies from sharing information with selected analysts and investors.

Kogan, though, will still walk away with one of the richest separation packages in years, according to an analysis by the Corporate Library, a group that promotes corporate reform.

"Investors don't want to see what we call 'pay for failure,'" said Patrick McGurn, senior vice president of the influential Institutional Shareholder Services. ISS advises large institutional investors and pension funds.

"Most fingers point to the CEO," he said. "In reality, they should point to the members of the board."

Kogan, who made his last public comments in July at an analyst meeting in New York, has declined repeated requests for interviews made through a company spokesman. He will leave the board when he retires as CEO.

The 10 other members of the board either declined to answer questions when reached at their homes, referred questions to the company or did not return calls seeking comment.

"This is not something I'd like to get into," said director Donald Miller, reached at his Las Vegas home, before hanging up.

Miller, who sat with Kogan on the board of the Bank of New York for seven years, is chairman of the four-member Schering-Plough compensation committee. The compensation committee recommends to the full board how much top executives should receive in pay, stock grants and bonuses. Compensation committees are supposed to act as independent advocates for shareholders, experts said. That independence, though, can be compromised when members serve on different boards together, setting each other's compensation and forming personal relationships, experts said.

Kiss Me Goodbye
Robert Consalvo, a Schering-Plough spokesman, said the company would not provide information about Kogan's retirement package other than that contained in filings with the SEC. The documents, though, can be difficult to decipher, according to experts who have reviewed them. The $50 million figure, for example, never appears.

Kogan will receive $13 million in severance pay, plus $27 million in a lump-sum payment for his pension and $10 million worth of restricted stock and options, according to figures the company provided in late January.

This is to be paid when he leaves, and comes on top of the $1.4 million in salary he earned last year. Kogan was denied a pay raise and bonus for 2002.

In addition to the cash compensation, Kogan will receive perks comparable to those given other retiring chairmen, including his predecessor, Robert Luciano, according to his six-page retirement agreement dated Nov. 13.

These include an office of his choice within 35 miles of the corporate headquarters in Kenilworth, along with a secretary, plus limited use of the corporate plane.

He will get an automobile and driver, as well as security systems for his $3.8 million home in Short Hills and other unspecified residences. Plus, the company will pay for a security detail for him for a year.

Schering-Plough has not placed a value on these additional perks.

While Schering-Plough will not discuss the specifics of Kogan's retirement package, the company said it had no choice but to honor the terms of the long-term employment contract the board gave him. Kogan's contract has been amended six times since he signed it Sept. 26, 1989.

For Kogan, as with many CEOs, his contract entitled him to a trio of benefits: a severance payment equal to three times his highest salary and bonus over the past three years; upgrades to his pension; and automatic awards of restricted stock and vesting of stock options, notably 368,000 given last year. If Kogan's successor boosts Schering-Plough's share price, these options and stock awards will be worth millions more than their value today.

"Someone should not become rich because of performance that was not acceptable," said Charles Elson, director of the Center for Corporate Governance at the University of Delaware, a leading crusader for reform.

After reviewing Kogan's payout, Graef Crystal, another outspoken critic of boards and a consultant who has helped some companies craft compensation agreements, said: "It illustrates that there are two classes of CEOs in America who get the most money. They are the best-performing CEOs and the worst-performing CEOs, because if your performance is bad enough, you get fired like Kogan and get $50 million."

To be sure, Kogan's package is skewed because it includes a $27 million pension payment. Experts said that is typical for a CEO who has been with a company for a long time.

Kogan, a Bronx native whose first job was selling peanuts at Yankee Stadium, arrived at Schering-Plough in 1982 as an executive vice president. He was named CEO in 1996 and chairman in 1998. He resigned as chairman last November.

Moreover, negotiating severance arrangements with a CEO is tricky for any board, which must consider the effect on Wall Street. No board wants a dispute to erupt. And part of the package is stock awards Kogan had already earned.

The Board Acts
Things didn't necessarily have to end this way.

For one, some CEOs have linked their pay to their performance. Sydney Taurel, the CEO of drug maker Eli Lilly & Co., volunteered to take $1 in salary for 2002, it was revealed last week. Kogan has not given up any benefits he is entitled to, according to Consalvo, the company spokesman.

In addition, Schering-Plough's board did not always appear to act as if its hands were tied.

The company's annual proxy statement, for example, revealed the board retained an independent compensation consultant and an outside attorney to negotiate the terms of last November's retirement agreement.

Consalvo said the negotiations only involved logistics, such as when Kogan would leave, and not money.

Just a few months earlier, on May 15, the board had amended Kogan's employment agreement for the sixth time. The changes spelled out that if the board asked Kogan to retire early, the company would pay him the most generous of benefits-those typically extended to a CEO who is fired for no cause or who is forced out by a merger.

Asked why the board amended the agreement, Consalvo said: "You can see what it says. That is a board decision, and as a matter of policy, the company does not comment on board deliberations."

The amendment was signed three weeks after Kogan was berated by angry investors at the company's annual shareholder meeting.

At the time, the six-member committee that set his pay package was short-handed.

Two committee members had resigned the previous month, including its chairman, James Wood, the retired chairman of A&P. A third member, Pat Russo, had just taken over as CEO of Lucent, whose revival remains one of the biggest challenges in Corporate America.

The three other members had some of the deepest connections to Kogan: Miller, a former vice president of employee relations at Dow Jones & Co.; Richard Osborne, the board member with the longest tenure, who sits on the prestigious Council on Foreign Relations along with Kogan and would take over as chairman; and Hans Becherer, the retired chairman of Deere & Co., who had the second-longest tenure on the board.

Gift That Keeps Giving
Under the contract, the board could not get rid of Kogan without paying these benefits unless it fired him "for cause." For Kogan, as with most CEOs, that essentially boils down to conviction of "a felony involving moral turpitude," a fairly standard definition, experts said.

"It is not bad performance," said Alan Johnson, an expert in executive compensation who runs his own firm in New York. "It's not the way you or I define it. "It is weird."

John Coffee, a professor at Columbia Law School and an expert on securities law, said even charges by the SEC would not be enough to prevent a CEO from collecting on his contract.

Paul Hodgson, a senior research associate at The Corporate Library, said CEOs of Fortune 500 companies rarely leave for anything other than "good cause." "I can't remember in the last two or three years anybody ever not receiving anything, and there are plenty of people who screwed up," he said.

Kogan was one of the highest-paid CEOs in the drug industry, earning nearly $100 million combined from 1998 to 2001.

His three-year employment contract, which runs 27 pages, contained a number of features critics contend are excessive. These include automatic vesting of restricted stock awards-which normally are kept in reserve for up to five years to entice key executives to stay-and two automatic contract extensions of two years apiece.

Even if the board had allowed Kogan's contract to expire last December, Kogan would get the full package of benefits due to the automatic extensions.

"This contract never ends," Crystal said. "It's the gift that keeps on giving."

Abella, the CEO at IPG Investment Partners, said part of the problem might have stemmed from the difficulties two members of the board faced with their own companies.

Russo, Lucent's CEO, was trying to reverse the tide of red ink swamping the telecom equipment maker, while David Komansky, the chairman at Merrill Lynch, was in the middle of a power struggle that ultimately led to his impending departure from the securities firm. (Merrill Lynch provides investment banking services to Schering-Plough.)

They were "preoccupied with their own problems," Abella said.

A spokeswoman for Russo declined to comment. And Tim Cobb, a spokesman for Komansky, said, "He doesn't want to talk to you about it."

Shareholders will have a chance to voice their opinions about Kogan's severance package at the annual meeting next month in Woodbridge. But Kogan is supposed to step down by then, or possibly earlier if the board names his successor, widely anticipated to be Fred Hassan, Pharmacia's CEO.

Kogan's send-off has upset some investors like Rick Bayan, a freelance writer in Philadelphia.

"I was outraged," Bayan said. "He is being rewarded for it with the money shareholders have invested in the company."

Bayan's late father was an industrial microbiologist for Schering-Plough in Union from 1967 until 1995. Bayan owns about 600 shares, down from 2,200.

"Corporate boards have emerged as almost a miniature, totalitarian states," he said. "They are not accountable to anybody."

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March 19th, 2003

HCV Seen Sporadically in Semen of the HIV Coinfected

Hepatitis C virus (HCV) appears intermittently in the semen of men coinfected with HIV-1, but as yet there is no clear predictor of such occurrences, French researchers report in the March issue of the Journal of Medical Virology (J Med Virol 2003;69:344-349).

Dr. Christopher Pasquier of Hopital Purpan, Toulouse, and colleagues note that although HCV is usually transmitted by means of blood, HCV has recently been detected in semen. This, they point out, could mean that infected men "may transmit HCV during medically assisted procreation or sexual intercourse."

To determine which factors might be associated with the appearance of HCV, the researchers studied 35 men who were coinfected with HCV and HIV and were enrolled in a medically assisted procreation program for HIV serodiscordant couples.

Examination of paired blood and semen samples showed that HCV RNA appeared sporadically in the semen of 9 (25.7%) of the subjects. However, no correlation was found with factors such as HCV viral load, age, duration of HIV infection, HIV treatment, HIV viral load or CD4+ cell count.

These findings, which lend weight to French safety requirements, the investigators conclude, underline the importance of a "systematic search for HCV RNA in semen and the use of processed spermatozoa in assisted medical procreation of infertile HCV discordant couples."

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March 21st, 2003

HCV Genotype 6 Is More Responsive to Therapy than Genotype 1
By Brian Boyle, MD, hivandhepatitis.com

Hepatitis C virus (HCV) is a significant cause of chronic hepatitis which frequently progresses to cirrhosis or hepatocellular carcinoma. HCV has 6 distinct genotypes, labeled (understandably) 1 through 6.

While a significant amount of research has been conducted on genotypes 1-4, little is known about the treatment of genotype 6, which is uncommon in the United States but occurs with higher frequency in several Asian countries, including China, Vietnam and Thailand.

In a study published in The Journal of Infectious Diseases, researchers in Hong Kong investigated the treatment of HCV genotype 6 with interferon and ribavirin. The prospective study enrolled 40 patients with chronic HCV, 16 and 24 of who had genotype 6 and 1, respectively. The patients were treated with subcutaneous recombinant interferon a-2b and ribavirin for 12 months.

Of the 40 enrolled patients, an end-of-treatment response was detected in 12 (75%) patients with genotype 6 and in 10 (41.6%) patients with genotype 1 (P = .05). A sustained virological response (SVR) was present in 10 (62.5%) patients with genotype 6 and in 7 (29.2%) patients with genotype 1 (P = .04).

The authors conclude, "HCV genotype 6 has a better response to IFN treatment than HCV genotype 1 and is associated with a significantly higher SVR. A higher dose of IFN does not seem to increase the SVR rate in Chinese patients with genotype 1. Future trials should be performed to determine whether 6 months of combination therapy is adequate for patients with genotype 6."

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March 23rd, 2003

Lawmakers Pushing For Oversight of Inmates' Health

There are competing views about how best to deliver health care services inside New York's sprawling prison system to inmates suffering from potentially fatal chronic diseases.

Corrections officials maintain that what they are doing works, and point to the dramatic decline of AIDS-related deaths and tuberculosis outbreaks in prisons in the past decade.

However, prison reform advocates contend that the prison system exists in a vacuum with little oversight. The result, they say, is that inmates receive inconsistent care depending on where they are locked up.

"The picture is a very uneven one," Robert Gangi, executive director of the Correctional Association of New York, said of the state's prisons.

"There's been significant improvements over the last decade but very serious problems remain," Gangi said.

One issue is that the state Department of Correctional Services maintains virtual control over every aspect of prison life, including the delivery of medical care to inmates. For years, advocates and some Democratic state lawmakers have unsuccessfully pushed for the state Health Department to extend its control to prison infirmaries so that they are subject to the same quality control standards as civilian health facilities.

Currently, the state Commission of Corrections, a watchdog group over state prisons and local jails, is charged with establishing minimum health care standards. But advocates want more, favoring an agency that focuses solely on medical care delivery to oversee inmates' health.

New York corrections officials dispute claims that inmates receive substandard medical care. "They receive care that is at least as good as what people receive on the outside," corrections spokesman James Flateau said.

He said every inmate upon entering prison is screened for TB and hepatitis C and can voluntarily request to be tested for HIV, the virus that causes AIDS.

Roughly 67,000 inmates are spread out in 70 prisons across the state and some 29,000 inmates are released to the community each year. Critics say health safeguards need to be in place so that sick inmates don't pose a public health hazard when they are released.

About 15 percent of inmates are infected with hepatitis C, a viral disease that attacks the liver and about 9 percent are positive for HIV, according to prison officials.

Since Gov. George Pataki took office in 1995, the state's spending on medical care for prisoners increased more than 50 percent, from $149 million to $229 million in the current year's budget, Flateau said.

The federal Centers for Disease Control and Prevention estimate that of the more than 4 million Americans with chronic hepatitis C infections, 39 percent once were in prison. Health experts say the disease is commonly spread among inmates through intravenous drug use, unprotected sex and sharing of items like razors.

About 1 percent of inmates with hepatitis C infections in New York are receiving treatment, advocates and prison officials say. Advocates believe that number should be higher, but corrections officials insist that all those who qualify for treatment receive it.

Unlike hepatitis A and B, there is no vaccine against hepatitis C. Treatment involves a combination of the drugs interferon and ribavirin, which can cost up to $25,000 annually to administer.

Some inmates are temporarily ineligible for treatment because of past drug use or preexisting medical conditions. In other cases, CDC guidelines advise that the year-long anti-viral treatment regimen should not be started if there is less than a year remaining on an inmates' sentence.

Last month, a package of bills passed the Assembly Health Committee that would extend state Department of Health oversight to reviewing AIDS and hepatitis C care in prison health care facilities.

"We have an obligation to provide them professional health care services," said committee chairman Assemblyman Richard Gottfried, a Manhattan Democrat.

The bills also would mandate that the corrections commissioner develop and implement programs for guards and inmates in every facility to prevent the spread of HIV, hepatitis C and sexually transmitted diseases.

Similar efforts to pass the bills in the past have failed, mainly because the bills lacked a majority sponsor in the Republican-dominated Senate.

In a seven-year period, the number of AIDS-related deaths dropped more than 90 percent, from 258 deaths in 1995 to 18 in 2002, according to prison officials. They credit the introduction of a cocktail of anti-viral drugs and the expansion of a voluntary HIV testing program that enabled some 20,000 inmates to undergo anonymous testing and counseling in the late 1990s.

The state also made great strides in containing the number of active TB infections in prisons, Flateau said. The number of inmates with active TB dropped 95 percent since 1991, when the resurgence of the illness was first documented nationwide.

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March 25th, 2003

Adefovir Dipivoxil Improved Liver Abnormalities in Patients with Chronic Hepatitis B

According to a study published in The New England Journal of Medicine, treatment of serum hepatitis B e antigen(HBeAg)negative chronic hepatitis patients with adefovir dipivoxil may reduce injury to the liver.

HBeAg-negative chronic hepatitis B is usually a progressive disease causing hepatic injury that can result in cirrhosis and hepatocellular carcinoma. The disease is characterized by persistent or intermittent hepatitis B (HBV) replication, severe inflammation of the liver, and progressive fibrosis (reactive formation of fibrous tissue). Remission is rare; the majority of patients with HBeAg-negative chronic hepatitis B are likely to require long-term therapy.

The goal of therapy for patients with HBeAg-negative chronic hepatitis B is to slow or stop the progression of HBV-associated hepatic (liver) injury. However, the treatments that exist for HBeAg-negative chronic hepatitis B are not optimally effective or tolerable. Interferon alfa is antiviral and can induce remission in patients. However, long term treatment with interferon alfa is problematic because of side effects and the need for administration by injection. Lamivudine suppresses HBV replication in HBeAg-negative patients. Furthermore, it is well-tolerated and orally administered. However, long-term treatment is compromised by the development of drug resistance.

Adefovir dipivoxil is an orally administered drug with potent activity against the polymerase (enzyme) activity of several viruses. Treatment of hepatitis B with adefovir dipivoxil has been found to be safe, with few side effects and no drug resistance reported.

A trial conducted at 32 sites around the world investigated the safety and effectiveness of a 48 week treatment with adefovir dipivoxil in 185 patients. Patients received either 10 milligrams of adefovir dipivoxil per day or placebo (inactive substance). Results showed an improvement in liver abnormalities, an anti-viral effect, and normalization of alanine aminotransferase levels, an enzyme that is often elevated in hepatitis B patients. The antiviral effect was evidenced by a rapid decrease in serum HBV DNA levels that began with the therapy and continued throughout the 48 weeks. Serum HBV DNA levels were below the lower limit of detection in 51% of the patients given adefovir dipivoxil, as compared with 0% in the placebo group.

Adefovir dipivoxil was also well tolerated. None of the patients withdrew from the study because of side effects attributable to treatment with adefovir dipivoxil. Overall, side effects for the adefovir dipivoxil group were similar to those found in the placebo group.

Finally, results showed an absence of resistance mutations during 48 weeks of therapy. This is a particularly important advantage since the majority of patients with HBeAg-negative chronic hepatitis B will require long-term therapy.

The researchers concluded that adefovir dipivoxil appears to be an effective treatment for patients with HBeAg-negative chronic hepatitis B. However, further clinical trials are necessary in order to confirm these findings. Patients may wish to speak with their physician about participating in a clinical trial with adefovir dipivoxil.

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March 26th, 2003

Schering-Plough, Teva, Geneva in Hepatitis C Deal

Schering-Plough Corp.said it will license hepatitis C drug ribavirin to Teva Pharmaceutical Industries Inc. and Geneva Pharmaceuticals Inc., settling patent litigation.

Generic drug makers Teva and Geneva, a unit of Novartis AG are both seeking to make copycat versions of the anti-viral drug, marketed by Schering under the brand name Rebetol as part of a two-drug combination that includes Schering interferon drug PEG-Intron.

Sales of Rebetol totaled $865 million last year. The agreement does not affect patent litigation between the generic drug makers and Ribapharm Inc. which developed ribavirin, and its parent ICN Pharmaceuticals Inc.

In a statement, Teva said the Ribapharm litigation prohibits U.S. Food and Drug Administration approval of its generic ribavirin product until expiration of a 30-month stay or a court ruling on the patent case-whichever comes first.

The Ribapharm suit is scheduled for trial on June 2 and summary judgment motions are pending, Teva said.

Under the Schering-Plough deal, the company granted Teva and Geneva nonexclusive rights to ribavirin patents and in return the generics pay Schering-Plough a royalty, which was not specified.

Last month, Schering reached a similar settlement of ribavirin patent litigation with Three Rivers Pharmaceuticals LLC, which is also seeking FDA approval for a generic form of the drug.

Schering has acknowledged that it might face generic competition for the drug in 2003, when its earnings are expected to drop about 30 percent from 2002.

Ribavirin and PEG-Intron are also expected to face competition from similar dual-therapy drugs made by Swiss drug company Roche Holding AG

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Novartis Bolsters Portfolio, Winks At Roche
By Carey Sargent

Sending another warning shot across the bows of its rival Roche AG (Z.ROC), Swiss drugs firm Novartis AG said it'll pay $255 million for a majority stake in U.S. company Idenix Pharmaceuticals Inc.

The proposed purchase bolsters Novartis' late-stage pipeline and gives it a potential foothold in the Hepatitis market, which it reckons could be worth about $6 billion a year. But this also looks like another step in preparations for marriage to reluctant bride Roche Holding AG, in which it already holds a 32.7 percent stake. Roche has already laid claim to the Hepatitis market and has great hopes for its new Hep C drug Pegasys.

Idenix' pipeline is focused on Hepatitis. Novartis' move into this new disease field follows its buy last week of experimental incontinence drug darifenacin from Pfizer Inc. Roche is developing drugs in that field too.

"Obviously our first objective was to strengthen our late-stage pipeline, but whatever we do also needs to make sense in case Novartis and Roche were to get together," Thomas Ebeling, Novartis' drugs chief told Dow Jones Newswires.

Analysts have mixed opinions about the deal. They don't know much about Idenix's drug candidates as they're at a very early development stage.

Much of Novartis' payment for the stake is dependent on the successful regulatory application of a Hepatitis C drug candidate, but some analysts still think the price is a bit steep.

"It's difficult to determine the quality of the drug candidates that Novartis would be licensing as details aren't yet available," said WestLB Panmure analyst Michael King.

Pictet analysts added that right now, it's "difficult to see this deal as other than expensive, in an area where Novartis has no current presence."

At 1112 GMT, Novartis shares were up 0.1% at CHF52.30 while the overall market was up 0.7%.

Novartis may not have a current presence in the Hepatitis market, but it's upbeat about the prospects.

"It's a big market that could reach $6 billion in the mid-term, and there's currently a high unmet need," Ebeling said.

"The side-effects of current treatments are pretty severe, and there's not a lot of competition out there-it's not like the market for cardiovascular disease."

The Hepatitis C market is more attractive than Hepatitis B. Unlike Hep B, there's no immunization for Hep C so the market for drugs to treat that disease in the developed world is more limited. The main markets for Hep B drugs are in Asia.

Novartis' Ebeling said the Hep C drug could have blockbuster potential: "If the profile is good, it could achieve blockbuster sales, but it's still very, very early to tell."

The drug is still in early stage testing, and years away from a possible regulatory filing.

The Hep C project "does look very interesting," Pictet analysts said.

"If successful, such a drug would challenge the alpha-interferons in the large and growing Hepatitis C market, but (the molecule) is still at a very early stage of development."

Ebeling said though it could be that the drug will be used in combination with the current standard of treatment.

"I think that it can work in addition to interferon and ribavirin, but we'll also look into use as a monotherapy," Ebeling said.

Ebeling said he thinks that Hepatitis C could be treated with a cocktail of drugs in the future, much like HIV, another viral disease. Current treatments like Roche's combination treatment Pegasys and Copegus involve a mix of interferon and ribavirin.

Idenix is also developing two drugs to treat Hep B. One is in late-stage testing, and Ebeling said it could be filed for regulatory approval in 2006. But he added it would be very difficult to achieve blockbuster sales with a Hep B drug.

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March 30th, 2003

Surgeon Declines Safety Advice: LI Doctor with Hepatitis C Still Opening, Closing Chests
By Roni Rabin

A prominent Manhasset heart surgeon who infected patients with blood-borne hepatitis C continues to open and close patients' chest cavities, hospital officials said, despite being advised the procedures place patients at risk.

Heart surgeons are most likely to sustain injuries or puncture their gloves at the very beginning of the operation, when they cut through the breastbone, or at the conclusion, when they use wire to sew the sternum back together. But a North Shore University Hospital-Manhasset spokesman said other surgeons are not available to step in and assist Dr. Michael Hall at the start and end of surgery, and that Hall, who has hepatitis C, prefers to complete the procedure himself.

State officials have said Hall almost certainly infected three and possibly more patients with the illness during previous surgeries. Hospital spokesman Terry Lynam emphasized that no new infections are known to have occurred since Hall implemented new precautions - including wearing double layers of latex gloves - to prevent needle sticks and cuts that could transmit the virus.

"Dr. Hall's patients, all of whom consent in writing to have him as their surgeon with full knowledge of his health status, insist, or at least prefer, that he be present and perform as much of the procedure as possible," Lynam said. "The hospital does not have a large enough surgical staff to have someone step in and do the closing. It's not Mass. General."

Hall did not return phone calls.

Hall, one of the top-ranked cardiac surgeons in the state, has continued to operate since state officials disclosed the cluster of infections last year, but he is required to inform patients of his condition and to warn them of a slight risk of hepatitis C infection during surgery. The virus can cause long-term liver damage, cirrhosis and cancer.

State health investigators were never able to figure out exactly how the virus was transmitted to patients from the surgeon, but the infections presumably occurred when Hall stuck or nicked himself and bled into an open surgical wound.

Several published studies of other heart surgeons who transmitted hepatitis C to patients said the transmissions most probably occurred during the sternal closure. And a 1988 study in the medical journal The Lancet said 40 percent of cardiac surgeons punctured their gloves during the sternal closure, compared to 12 percent during the actual procedure.

Closing the sternum after surgery typically involves threading wires through holes in the breastbone and then tying them. The wires can apparently slice through latex gloves.

The state health department initially advised the surgeon to modify his technique and either defer the closure to a colleague or assistant or adopt an alternative method of closing the chest, using clamps, which are les

s likely to injure the surgeon. But the state reversed its recommendation after a nationally respected cardiac surgeon hired by North Shore evaluated his surgical technique, saying it was "exemplary," and that it carried "a very low risk" of viral transmission.

"The operative conduct . . . reflects efficient and appropriate technical maneuvers" that "minimize the likelihood of sharp object penetration of the surgeon" that could lead to transmission, said the Aug. 15, 2002, report by Duke University Medical Center professor of surgery Dr. Robert H. Jones. Jones serves on the New York State Cardiac Advisory Committee, which has ranked Hall as one of the state's top heart surgeons in recent years.

Jones' report, however, includes a recommendation that Hall consider deferring the opening and closing of the chest to a colleague.

"This would remove the risk of blood-borne infection from [Hall] to the patient during the sternal opening and closing . . . when needle punctures of personnel are most common," Jones wrote.

A year earlier, in August 2001, Dr. Barbara Wallace, who heads the state's bureau of communicable disease control, had made the same recommendation in a letter to North Shore's infection control director, Dr. Bruce Farber. In it, she wrote that Hall should modify his surgery by "deferring the closure . . . to another member of the surgical team" or "using clamps rather than wire to close the chest cavity."

That same August, Stan F. Kondracki, the state's regional epidemiology program manager, wrote an e-mail to Miriam Alter, at the U.S. Centers for Disease Control and Prevention, and said that in light of the recent discovery of the surgeon's infection, "We are developing interim control measures such as . . . having someone else open and close the chest cavity." In parentheses, it added "surgeon feels most likely time for puncture through the glove is when surgical wires are used for closure."

State epidemiologists who observed Hall operate on the same day as Jones' visit, last Aug. 14, also raised the subject, under the heading of "areas for improvement." Dr. Stephanie Noviello and Rachel Stricof said Hall occasionally left suture needles dangling and tied sutures with needles attached, and noted that he placed his fingers near the exit point of the needle when wiring the sternum.

"He forced the sternal wire needles off and then tied the wires off himself, which may pose an increased risk of exposure," according to their reports, obtained under the Freedom of Information Act.

In a recent telephone interview, Jones said his suggestions were mere recommendations and that it would be inappropriate for him to tell another surgeon how to "run his team."

He said it was common practice for cardiac surgeons at academic medical centers to ask an assistant surgeon or surgeon in training to open and close the patient, and that he rarely opens and closes his own patients, usually deferring to a doctor in training.

But, Jones said, Hall did not want to do so.

"He likes to stay with the patient until the very end, and that's fine," Jones said. "He thinks the disadvantage of letting someone else do it outweighs the advantage of eliminating any very, very remote chance that he's going to injure himself.

"Everything in medicine is a risk-benefit ratio," Jones said. "That's the surgeon's call."

Several months after Jones' visit, North Shore's senior vice president for quality management, Yosef D. Dlugacz, appealed to the state to condone Hall's closing of his patients, citing Jones' report and Hall's low rate of post-operative complications with the closure.

State officials agreed.

"Our epidemiologists made recommendations with the caveat that a cardiac surgeon would review them," state health spokeswoman Kristine Smith said. "We believe the patient is at less risk if [Hall] does the closure . . . due to his low sternal wound complication rate."

Smith said state officials believe Hall is taking appropriate precautions, including using blunt needles to penetrate through the sternum during the closing, and announcing sharp instruments in the operating room.

"We feel they are following the necessary procedures," Smith said. She added, "The informed consent is obviously the most essential change."

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March 31st, 2003

Infergen and Actimmune Combination Produces Synergistic Antiviral Effects In Preclinical Models of Hepatitis C

InterMune, Inc. today announced that Lawrence Blatt, Ph.D., InterMune's Vice President of Biopharmacology Research and Researcher at the Scripps Clinic in La Jolla, Calif., presented a review of the Company's recent research on the antiviral effects of its novel interferons, Infergen(R) (interferon alfacon-1) and Actimmune(R) (interferon-gamma 1b), at the Cytokines and Beyond conference in San Diego. Dr. Blatt is a distinguished researcher in the field of hepatology, credited with leading the development of consensus interferon.

The highlight of Dr. Blatt's presentation was the important finding of synergistic antiviral effects of combination use of Infergen and interferon gamma-1b in cell-based models of hepatitis C virus (HCV).

"The fact that combination use of Infergen and interferon gamma-1b produced synergistic antiviral effects (i.e., significantly more potent than additive effect of the drugs) in cell-based models of HCV is extremely exciting," said Dr. Blatt. "We look forward to further studying the combination of these two interferons to determine whether better antiviral effects in patients with this difficult-to-treat disease are possible and because this could lead to a new treatment paradigm for hepatitis C. InterMune is continuing our innovative leadership in bio-optimizing and improving upon our interferon therapies through our applied research programs in an effort to design our future clinical research programs."

Dr. Blatt presented results of several recent cell-based studies on the combination of Infergen and interferon gamma-1b that utilized model systems for HCV. Co-administration of interferon gamma-1b and Infergen significantly reduced the concentration of HCV replicons by up to 100-fold, delivering significantly higher potency than either drug alone.

"This applied research program ideally represents InterMune's core strategy to expand the uses of and indications for our approved products, such as Infergen and Actimmune," said Scott Harkonen, InterMune's President and CEO. "These encouraging data support further research of this combination for the treatment of hepatitis C infection. InterMune is now among the companies at the forefront of research and development in hepatitis C and liver diseases. We are very excited about the multiple opportunities we have in our pipeline, which include our marketed product Infergen, our PEG-Infergen (pegylated interferon alfacon-1) in Phase I clinical trials for HCV, and several other earlier-stage applied research and development programs."

    About Infergen for Hepatitis C
    Infergen is a bioengineered type I interferon alpha indicated for treatment of adult patients with chronic hepatitis C infections. Infergen is the only interferon alpha with data in the label regarding use in patients following relapse or non-response to treatment with certain previous treatments. Physicians and patients can obtain additional information about Infergen, including the product's safety profile by visiting http://www.infergen.com including the black box warning for all the interferon alphas.

    Hepatitis C is a liver disease caused by hepatitis C virus found in the blood of infected individuals. It is the most common form of hepatitis infection in North America and Europe. According to the National Center for Infectious Diseases, an estimated 3.9 million (1.8%) Americans have been infected by hepatitis C virus, and 2.7 million of these patients are chronically infected. If not detected and treated, hepatitis C may lead to chronic liver disease, including liver cancer, and ranks second to alcoholism as a cause of cirrhosis. Hepatitis C causes an estimated 8,000 to 10,000 deaths annually in the United States.

    About Interferon gamma-1b
    Interferon gamma is a naturally occurring protein that stimulates the immune system. InterMune markets interferon gamma-1b for the treatment of two life-threatening congenital diseases: chronic granulomatous disease and severe, malignant osteopetrosis. InterMune is also conducting a Phase III study of interferon gamma-1b in ovarian cancer and a Phase II study of interferon gamma-1b for the treatment of severe liver fibrosis, or cirrhosis, caused by hepatitis C virus (HCV). Physicians and patients can obtain additional information about interferon gamma 1-b, including the product's safety profile, by visiting http://www.actimmune.com

    About InterMune
    InterMune is a commercially driven biopharmaceutical company focused on the marketing, development and applied research of life-saving therapies for pulmonary disease, infectious disease and cancer. For additional information about InterMune, please visit www.intermune.com.

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HCV RNA in the Semen of Patients with Chronic HCV Infection
hivandhepatitis.com

The prevalence of HCV infection in Egypt approximates 12%. The role of sexual intercourse in transmitting HCV remains controversial. The aim of the current Egyptian study was to detect HCV RNA in semen of chronic HCV-infected patients.

Seminal plasma was tested for HCV RNA in 40 married patients with chronic HCV infection (all had positive HCV RNA in their sera) using a nested reverse transcription PCR assay with commercial kits for amplification and detection of HCV RNA (Purescript, Gentra Systems, Minneapolis, USA). Semen was tested for the presence of PCR inhibitors to identify patients with false negative results.

10 patients (25%) had HCV RNA in their semen (seminal plasma was positive while round cells and motile spermatozoa were negative for HCV RNA). Three out of the 10 wives of these 10 patients had HCV RNA in serum.

Duration of marriage was significantly longer in HCV positive wives compared to non-infected wives. Serum HCV RNA levels were significantly higher in patients with positive semen samples than in patients with negative semen samples (mean ± SD 1, 695, 539±1, 348, 002 vs 241, 860±338, 504 copies /ml, p <0.001).

Conclusion: HCV RNA can be detected in the semen of patients with high blood viral load. They may transmit the infection to their wives and the risk of transmission increases proportionately with duration of marriage.

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April 1st, 2003

Progenics Pharmaceuticals Discovers the First Liver-Specific Receptor for Hepatitis C Virus

Receptor may reveal how HCV infects the liver and provide a new therapeutic drug target-Scientists from Progenics Pharmaceuticals may have solved a longstanding riddle concerning hepatitis C disease: How does the virus target the liver for infection? Researchers today reported discovering the first-ever liver-specific receptor, called L-SIGN, for hepatitis C virus (HCV). The Company also reported the identification of specific inhibitors, including a monoclonal antibody, that blocked HCV from binding to the L-SIGN receptor. Preventing HCV from binding L-SIGN on liver cells represents a new and targeted strategy for treating this serious disease. The studies are reported in a paper published today in the Proceedings of the National Academy of Sciences USA. The publication is scheduled to be available online this week in the PNAS Early Edition at http://www.pnas.org/.

"In recent years, various cellular receptors for HCV have been proposed, but until now, none had been found that occurred specifically in the liver and was capable of binding with HCV," said the paper's senior author William C. Olson, Ph.D., Progenics' Vice President of Research and Development. "As we reported in today's PNAS article, L-SIGN efficiently binds and captures naturally occurring hepatitis C virus particles. We further demonstrated that L-SIGN binds to a viral protein called E2 that is present on the surface of the HCV particle. L-SIGN is found on specialized liver cells that form a barrier between the bloodstream and the surrounding liver tissue. These cells are the first to contact HCV as it enters the liver via the bloodstream. Thus, L-SIGN is uniquely positioned to capture blood-borne virus and concentrate it in the liver, thereby potentially facilitating initial and subsequent rounds of infection."

HCV infection afflicts nearly 3% of the world's population and causes serious liver disease, including cirrhosis and cancer. No vaccine is available to prevent new infections. Current therapies are largely non-specific, effective in only about half of all cases, and have a high relapse rate. New treatment strategies are urgently needed to combat this debilitating disease.

"The L-SIGN receptor is abundantly expressed on endothelial cells of the liver and binds to the envelope glycoprotein E2 of HCV," explained Tatjana Dragic, Ph.D., Assistant Professor of Microbiology and Immunology, Albert Einstein College of Medicine and co-author of the manuscript. "Viruses often make use of cellular receptors to target a specific tissue for infection. For example, the human immunodeficiency virus (HIV) targets the CD4 receptor on immune system cells. As the first step of viral entry, the HIV glycoprotein gp120 attaches to cellular CD4. HCV's E2 glycoprotein may serve as the functional equivalent of HIV gp120. Our paper shows that E2 bound to the L-SIGN receptor as a potential means of targeting the liver. The research further demonstrated that HCV bound to a related receptor, known as DC-SIGN, that is expressed on dendritic cells, which are specialized cells of the immune system. L-SIGN and DC-SIGN are also expressed in placental tissue, and thus the findings may also explain why HCV is readily passed from mothers to their newborn children."

"Our previous discoveries of the cellular receptors utilized by HIV have translated directly into novel therapeutic agents, and we are eager to leverage this expertise for HCV therapy," added Dr. Olson. "We have shown that HCV binding to L-SIGN can be blocked in the laboratory using specific inhibitors, including monoclonal antibodies. In addition, HCV appears to bind L-SIGN at a site different from that of its natural ligand (ICAM-3), which is a protein that mediates adhesion between cells. Thus, it may be possible to block HCV without blocking the natural activity of L-SIGN. These findings provide proof-of-concept for targeted therapy. Our current goals are to develop increasingly potent and drug-like inhibitors while concurrently exploring the role of L-SIGN in natural infection."

    Company Profile
    Progenics Pharmaceuticals, Inc. of Tarrytown, NY, is a biopharmaceutical company focusing on the development and commercialization of innovative therapeutic products to treat the unmet medical needs of patients with debilitating conditions and life-threatening diseases. The Company applies its expertise in immunology and molecular biology to develop biopharmaceuticals to fight viral diseases, such as human immunodeficiency virus (HIV) infection, and cancers, including malignant melanoma and prostate cancer. In symptom management and supportive care, therapies are being developed to provide patients with an improved quality of life. Progenics' most clinically advanced product is methylnaltrexone, a compound in phase-3 clinical testing that is designed to block the debilitating side effects of opioid analgesics without interfering with pain palliation. The Company is conducting multi-dose phase-2 clinical trials with its lead HIV product, PRO 542, a viral-entry inhibitor and is in preclinical development with PRO 140 and other follow-on product candidates in HIV infection. The Company is developing cancer immunotherapies based on PSMA (prostate-specific membrane antigen) technology and currently is conducting phase-1 clinical studies of a therapeutic prostate cancer vaccine. GMK is a cancer vaccine in phase-3 clinical trials for the treatment of malignant melanoma.

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Durability of Serologic Response after Lamivudine Treatment

Most HBeAg responses achieved during lamivudine therapy are durable, and most responders experience prolonged clinical benefit, find researchers in the April issue of Hepatology (Hepatology 2003; 37(4): 748-55).

In this study, an international team of researchers assessed the durability of serologic responses following lamivudine treatment. They studied 40 subjects with chronic hepatitis B and hepatitis B e antigen (HBeAg) seroconversion following treatment.

Patient follow-up began a median of 4.3 months after completion of therapy in previous trials.

The team tested for HBeAg and hepatitis B surface antigen (HBsAg), hepatitis B virus (HBV) DNA, and alanine aminotransferase (ALT). They measured these at months 2, 4, 6, 9, and 12 of year 1, and every 6 months thereafter.

3-year durability of HBeAg seroconversion was 64%.

The researchers found that after a median of 36.6 months of follow-up, HBeAg seroconversion was demonstrated at the last visit by 77% of the patients.

In a post hoc analysis which included 65 patients with HBeAg seroconversion, the team found that 3-year durability of HBeAg seroconversion was 64%. This was measured from the time immediately after discontinuing lamivudine therapy.

They also identified 23% of patients as HBsAg negative at the last assessment.

Furthermore, 74% of patients with baseline undetectable HBV DNA and normal ALT maintained these responses at the last visit.

In addition, 20% were retreated for reappearance of HBV markers. The team determined that 7 out of 8 patients showed biochemical and/or virologic improvement, which included regained HBeAg seroconversion in 2.

No safety issues of concern emerged.

Dr Jules Dienstag's team concluded, "Most HBeAg responses achieved during lamivudine therapy were durable, and most responders experienced prolonged clinical benefit after HBeAg seroconversion and subsequent discontinuation of lamivudine".

"Lamivudine retreatment for reappearance of hepatitis B markers can achieve resumption of viral suppression."

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April 2nd, 2003

Biochemical Markers Accurately Predict Significant Fibrosis
hivandhepatitis.com

Liver biopsy remains the gold standard for assessing hepatitis C virus (HCV)-related liver injury, including inflammation and fibrosis. Liver biopsy is an invasive procedure, however, and even in the best hands is associated with a low rate of complications including bleeding and infection.

In a study published in AIDS, investigators attempted to determine whether an algorithm could be constructed that estimated the degree of liver injury incurred by the patient using non-invasive markers. The study was a cross-sectional, cohort study in a French tertiary-care hospital that enrolled 130 HIV/HCV-co-infected patients with a liver biopsy and serum available for the laboratories.

The investigators found that a non-invasive index of biochemical markers accurately predicted fibrosis in HIV/HCV-co-infected individuals. The use of a five-marker index (including bilirubin, GGT, haptoglobin, apolipoprotein A1, and a2-macroglobulin).was able to distinguish, with a relatively high degree of accuracy, between clinically important outcomes.

Using certain statistically-derived cut-offs, the five-marker index had a positive predictive value for septal fibrosis of 86% and a negative predictive value of 93%. If biopsy was restricted to patients with scores in an intermediate range (i.e., those with suboptimal predictive values), the use of the five-marker index could potentially reduce the indication the need for liver biopsy by 55%, with 89% accuracy.

The authors conclude, "An index including five biochemical markers accurately predicts significant fibrosis in patients with HIV/HCV co-infection, and may substantially reduce the necessity for liver biopsy." If these data are confirmed in larger trials, it may be possible to avoid liver biopsy in a number of HIV/HCV co-infected certain patients.

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April 3rd, 2003

Metabasis Therapeutics Announces the Commencement of Clinical Testing Of Hepavir B in Patients with Hepatitis B

Metabasis Therapeutics, Inc. (Metabasis) announced today that Ribapharm, Inc., (Ribapharm) has begun clinical testing of Hepavir B, an orally active, liver-specific prodrug of the proven antiviral agent adefovir. Hepavir B was developed by Metabasis and licensed to Ribapharm in October 2001. Ribapharm filed an IND in October 2002, which was subsequently allowed by the United States Food and Drug Administration.

Hepavir B was developed using Metabasis proprietary HepDirect(TM) Technology, a broadly applicable prodrug technology that results in the production of the active drug specifically in the liver. By enabling higher drug concentrations in the liver and minimizing exposure to non-liver tissues, HepDirect prodrugs may improve efficacy, reduce toxicity and thus improve the treatment of liver and liver-related diseases. Adefovir, the active ingredient of Hepavir B, has proven to be an effective drug for the treatment of patients with chronic hepatitis B. However, studies have shown that accumulation of the drug in the kidney results in dose limiting renal toxicity. The HepDirect Technology is designed to change the biodistribution of the active form of adefovir and thereby result in an improved therapy. Preclinical studies show that the HepDirect prodrug of adefovir, Hepavir B, achieves significantly higher levels of the active form in the liver and lower levels in the kidney resulting in an overall 10- to 50-fold increase in liver targeting. Metabasis believes that this redistribution of the drug will allow for more optimal dosing and therefore a more efficacious drug with improved safety.

Dr. Paul Laikind, Chairman, President and CEO of Metabasis stated, "We are very pleased with the progress made in the development of Hepavir B. Ribapharm previously announced that it had successfully completed a Phase 1 trial with the drug. This was important both for the continued development of Hepavir B but also because it marked the first clinical experience with our liver-specific prodrug technology, HepDirect. The recent initiation of studies in patients infected with the hepatitis B virus marks another important milestone in the development of the drug.

Dr. Mark Erion, Executive Vice President of Research and Development said, "The success to date with Hepavir B further demonstrates the potential of the HepDirect Technology for developing new and improved drugs for the treatment of liver and liver-related diseases. Based on the preclinical experience, the high liver specificity provided by the HepDirect Technology should minimize systemic exposure and lead to an overall improvement in the therapeutic index of the drug. The second HepDirect prodrug to be recommended for development is MB7133, a HepDirect oncolytic for treating primary liver cancer. If all goes according to plan we will begin clinical testing of MB7133 next quarter in the United States and Asia. There are currently no approved drugs for the treatment of primary liver cancer. Our preclinical results with MB7133 combined with the early data from the Hepavir B clinical trials increases our confidence in the potential of MB7133 to successfully treat this deadly disease."

Dr. Laikind added, "We continue to execute our business model of discovering exciting new drugs to treat important, often deadly diseases and steadily advancing these products through clinical development. When MB7133 enters the clinic next quarter Metabasis will have three products at various stages of clinical development. In addition to Hepavir B and MB7133, our drug for type 2 diabetes, CS-917, a novel gluconeogenesis inhibitor, is being evaluated in phase 2 clinical trials in the United States." Metabasis' partner on that project, Sankyo Co., Ltd, has primary responsibility for developing CS-917.

    Metabasis Therapeutics, Inc. ( www.mbasis.com ) is a privately held, biopharmaceutical company that develops proprietary products for the treatment of human disease with a current focus on liver and liver-related diseases. The Company employs various resources for discovering and perfecting new products, is a leader in the field of nucleoside/nucleotide chemistry and metabolism, and has proprietary expertise in liver biology and liver-specific drug delivery. Metabasis has discovered and developed a new class of drugs for treating diabetes that act to lower liver glucose production in diabetic patients. The first drug from this program, CS-917, is being developed in collaboration with Sankyo Co., Ltd. and is currently undergoing clinical testing. The Company has also developed the HepDirect Prodrug Technology that allows liver-specific delivery of new and existing drugs. Two drugs derived from the HepDirect Technology are in development; a drug for hepatitis B called Hepavir B and a drug for primary liver cancer called MB7133. Hepavir B is the subject of a partnership with Ribapharm, Inc. and is currently being evaluated in patient trials. The drug for primary liver cancer is expected to enter the clinic during the second quarter of 2003. The Company has approximately 80 employees and occupies state-of-the-art research facilities in San Diego, California.

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Bayer HealthCare Diagnostics (BAY) Receives FDA Approval after Expedited Review for Hepatitis C Viral Load Assay, VERSANT HCV RNA 3.0 Assay (bDNA). First and Only FDA-Approved Quantitative HCV Viral Load Assay

The Diagnostics Division of Bayer HealthCare LLC, a member of the Bayer Group (NYSE: BAY), announced today that it has received premarket approval after expedited review from the U.S. Food and Drug Administration (FDA) for its VERSANT(R) HCV RNA 3.0 Assay (bDNA)*, a predictive test that directly measures hepatitis C virus RNA levels in serum or plasma. The VERSANT(R) HCV viral load assay is the first and only FDA-approved quantitative test to measure HCV viral load levels, and will aid physicians by guiding therapeutic decisions early in treatment.

Approximately 4 million people in the United States and 170 million people worldwide(2) are infected with HCV. The level of viral load, or HCV RNA, in a patient's blood can identify, early in treatment, patients who may not respond to further therapy. Utilizing an accurate HCV RNA quantitative assay such as the VERSANT(R) HCV viral load assay can help clinicians decide if therapy should be discontinued, thereby avoiding the unnecessary side effects of prolonged treatment.

"Current therapeutic recommendations rely on the accurate determination of HCV viral levels to assess a patient's potential response to treatment. This is evidenced by a 2 log(subscript 10) (100 fold or 99 percent) reduction in viral load at week twelve of therapy," said Eugene R. Schiff, MD, Director, Center for Liver Diseases, University of Miami School of Medicine. "Since this viral measurement is essential to the clinical decision to continue or discontinue therapy, a reliable result as generated by the Bayer HCV bDNA assay affords great confidence in patient care."

The VERSANT(R) HCV viral load assay is intended as an aid in the management of HCV-infected patients undergoing antiviral therapy.

NIH Recommendations
The importance of quantitative assessment of HCV RNA levels in predicting patient response to antiviral therapy is reflected in the recent (2002) National Institutes of Health (NIH) Consensus Development Conference Final Statement on Management of Hepatitis C. The NIH Statement notes that "early viral response (EVR), defined as a minimum 2 log decrease in viral load during the first 12 weeks of treatment, is predictive of sustained viral response (SVR) and should be a routine part of monitoring patients with genotype 1. Patients who fail to achieve an EVR at week 12 of treatment have only a small chance of achieving an SVR even if therapy is continued for a full year. Treatment need not be extended beyond 12 weeks in these patients."(3) Thus, the NIH recommends that testing for an EVR should be a routine part of patient monitoring.

Expedited Review
FDA granted Bayer an expedited review of its premarket approval application on July 26, 2002. The FDA grants such reviews for products that provide treatment or diagnosis of life-threatening or irretrievably debilitating diseases or conditions and for which no approved alternative exists. VERSANT(R) HCV viral load assay is cleared for marketing in most of the world, is approved in Canada and compliant with European Union requirements.

Quantitative Detection
The VERSANT(R) HCV viral load assay directly measures HCV viral levels in serum or plasma using branched DNA (bDNA) signal amplification technology with the Bayer System 340 bDNA analyzer. The test measures HCV levels over a wide quantitation range of 615 to 7.7 million HCV RNA IU/mL, and has been validated for all six HCV genotypes (1-6).

Bayer Diagnostics NAD: Infectious Disease Testing
Complimenting the new VERSANT(R) HCV viral load assay, the VERSANT(R) HCV RNA Qualitative Assay Transcription-Mediated Amplification (TMA) provides the most sensitive test for HCV RNA (less than 10 IU/mL) for the determination of active HCV infection.

"Bayer is in a unique position as we are the only molecular diagnostic company with two FDA-approved assays designed to measure HCV RNA," said Dr. Peter Knueppel, senior vice president, Nucleic Acid Diagnostics business segment. He added that the VERSANT(R) HCV genotype assay (LiPA)** determines the main types of HCV virus.

"These assays comprise the majority of our worldwide market-leading HCV product line, and are an important part of our strategy to solidify our position as a leader in infectious disease nucleic acid testing," he continued.

Bayer's nucleic acid portfolio for infectious disease also includes VERSANT(R) assays for hepatitis B virus** and human immunodeficiency virus, as well as the TRUGENE(TM) HIV-1 Genotyping Test and its GuideLines 6.0 Rules interpretive software. The Bayer System 340 bDNA Analyzer and data management software products automate measurements and analysis, reducing manual steps and human error, leading to greater confidence in results.

    Hepatitis
    Hepatitis, a general term that means inflammation of the liver, can be caused by viruses, bacteria, drugs (both prescription and abused substances), toxins, or excess alcohol intake. Only within the last decade have clinicians been able to differentiate the five major types of viral hepatitis referred to by the letters A, B, C, D and E. Hepatitis C (HCV) is a blood-borne viral infection of the liver spread primarily by direct contact with human blood. The major causes of HCV infection worldwide are use of unscreened blood transfusions, and re-use of needles and syringes that have not been adequately sterilized.

    The current standard treatment for HCV is combination therapy of pegylated interferon and ribavarin given for 48 weeks for type 1 HCV genotype or 24 weeks for other genotypes. Only a fraction of those infected are diagnosed and treated with available anti-viral medications.

    Nucleic Acid Testing (NAT)
    Nucleic acid tests use state-of-the-art technologies that enable laboratories to test for the presence of infectious agents (viruses or bacteria) by measuring the amount of the pathogen's genetic material (DNA or RNA) in a blood sample. Unlike other types of in-vitro diagnostics, which typically measure the body's response to infection or disease, nucleic acid tests are a direct measurement of the presence of the pathogen.

    About Bayer Diagnostics
    With approximately 7,000 employees worldwide and 2001 sales of $1.8 billion, Bayer Diagnostics (www.bayerdiag.com), based in Tarrytown, New York, U.S.A., is one of the largest diagnostic businesses in the world. The organization supports customers in 100 countries through an extensive portfolio of central, self-testing, nucleic acid and near patient care diagnostics systems and services for use in the assessment and management of health, including the areas of cardiovascular and kidney disease, oncology, virology, women's health and diabetes. Bayer Diagnostics' global headquarters in the United States operates as part of Bayer HealthCare LLC, a member of the worldwide Bayer HealthCare group.

    About Bayer HealthCare
    Bayer HealthCare, a subgroup of Bayer AG with annual sales amounting to some 10 billion Euro, is one of the world's leading, innovative companies in the health care and medical products industry. Bayer HealthCare combines the global activities of the Animal Health, Biological Products, Consumer Care, Diagnostics and Pharmaceuticals divisions. More than 34,000 employees work for Bayer HealthCare worldwide.

    Our work at Bayer HealthCare is to discover and manufacture innovative products for the purpose of improving human and animal health worldwide. Our products enhance well-being and quality of life by diagnosing, preventing and treating disease.
* The VERSANT HCV RNA 3.0 Assay (bDNA) is intended for use as an aid in the management of HCV-infected patients undergoing anti-viral therapy. The assay measures HCV RNA levels at baseline and during treatment and is useful in predicting non-response to HCV therapy. For information on limitations of the procedure or information that may affect the interpretation of test results contact your clinical laboratory or Bayer HealthCare LLC, Diagnostics Division.

** Available for research use only, not for use in diagnostic procedures.

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A Global Journal Report: Treating a Medical Mystery-Doctors in Hong Kong Adopt Unproven Drug, Transfusions; In U.S., Officials Are Cautious
By Matt Pottinger in Hong Kong, Betsy McKay in Atlanta and Elena Cherney in Toronto

As scientists work to pinpoint the cause of the mysterious new respiratory illness, doctors on the front lines are debating how best to treat it.

Officials at the World Health Organization and the U.S. Centers for Disease Control and Prevention say no definitive treatment for severe acute respiratory syndrome, or SARS, has yet been found. But doctors in Hong Kong are claiming success with two controversial therapies: a cocktail of a powerful antiviral drug and steroids, and for the most seriously ill patients, transfusions of blood plasma from recovered patients. In Toronto, doctors are considering a study to determine whether an oral form of the antiviral drug being used in Hong Kong is effective.

The willingness to experiment is driven mostly by desperation: SARS has spread more rapidly in densely populated Hong Kong than anywhere else in the world. It's estimated that 90 percent of those who get the disease will get better. The remaining 10 percent will get very ill, and about 4 percent will die.

Meanwhile, in Toronto the number of ill patients is still growing.

But U.S. physicians aren't leaping to adopt the aggressive tactics. The treatments being used in Hong Kong haven't been tested in clinical trials, leaving many U.S. health officials wary about drawing conclusions as to their effectiveness. What's more, the therapies can have harmful side effects.

"We have no evidence, unfortunately, right now, that any specific antiviral therapy, or steroid treatment, or other agents that are targeting this virus, are of any benefit to patients," says Julie Gerberding, director of the CDC in Atlanta.

The agency is counseling clinicians to follow standard treatment for pneumonia, including antibiotics, among other measures.

The drug cocktail that Hong Kong officials are touting is made up of ribavirin-a potent antiviral drug used to treat hepatitis C and some forms of hemorrhagic fever-and high doses of steroids. Because SARS causes inflammation in patients' lungs, breathing becomes difficult. The steroids fight the inflammation, but they also weaken the body's immune system. The ribavirin is used to slow the virus until the swelling in the lungs subsides and the patient builds up antibodies to the disease.

When taken together and administered in the disease's early stages, the drugs have beaten back SARS in many patients before it could become life-threatening, according to Hong Kong clinicians using the drugs. But doctors in the U.S., while acknowledging that they aren't the ones facing an epidemic, nonetheless express doubts. "Neither drug has been tested," says Aaron Glatt, chief of infectious diseases at St. Vincent Catholic Medical Centers in New York. "I would be very cautious in recommending it." For a seriously ill patient, however, he says, he might consider ribavirin.

Many doctors prescribing the drug cocktail acknowledge there is no way of knowing whether it works. But health officials in Hong Kong say they can't afford to wait months for clinical trials. "We're not going to stand by and say, `I'm sorry, we don't know what it is, so we're not going to treat you,'" says Yeoh Eng-kiong, the city's secretary of health, welfare and food. "Under such desperate situations, you try your best."

Many of the people world-wide who have recovered from the disease did so without the help of the drug cocktail. The majority of Hong Kong's current 708 SARS patients are taking the cocktail. The city has even begun distributing ribavirin pills as a prophylaxis, or pre-emptive medicine, to healthy people who have been exposed to SARS.

Hong Kong health officials are encouraged because while the city's total number of cases has quadrupled from two weeks ago, the number of patients requiring intensive care, such as respirators or other life support, has increased by just over two times, to 82. Dr. Yuen estimates that 95 percent of patients who get the treatment early will recover from SARS without long-term problems.

Still, ribavirin can cause arrhythmia, hemolytic anemia (a condition in which a significant portion of a patient's red blood cells begin bursting) and, if taken by pregnant women, birth defects.

"It has toxicity," says Kenneth Dardick, chief of medical staff, at Windham Community Memorial Hospital in Willimantic, Conn., who recently decided against ribavirin to treat a suspected SARS patient.

In Toronto, probable and suspected SARS cases currently are being treated with intravenous ribavirin and antibiotics. Patients who deteriorate further are being given steroids, says Donald Low, the microbiologist-in-chief at the city's Mount Sinai Hospital. Dr. Low had been treating many of the patients at Mount Sinai until Monday, when he was required to enter home isolation for 10 days.

Over the weekend, one of his colleagues came down with SARS symptoms, and Dr.Low was deemed to have had unprotected contact with her during a conversation.

Dr. Low and his colleagues are considering a study of whether patients with milder forms of SARS can be treated with oral ribavirin. The drug in oral form would be easier to administer, and patients with mild illness could be treated as outpatients. But it would require giving a placebo to some patients who have SARS symptoms, but not pneumonia, as controls, Dr. Low says, adding, "It's unethical not to do it."

When the suspected SARS patient arrived at Windham Community hospital, Dr. Dardick checked the CDC's Web site and e-mails and discovered that no specific treatment was prescribed. A CDC official told him that it couldn't recommend specific measures, but patients in Hong Kong and Toronto were receiving ribavirin.

After discussing the powerful drug's benefits and risks with the patient and his family, Dr. Dardick decided on routine therapies, including oxygen to help him breathe more easily. They also chose to use steroids.

"Although this patient was ill, he wasn't critically ill enough to make it worth embarking on this as-yet-unproven remedy," Dr. Dardick says. Two days after he was admitted, the patient was discharged.

Hong Kong physicians are treating some especially severe SARS cases with antiserum. Doctors are drawing blood from patients who have recovered from the disease; extracting the plasma, which is theoretically rich in antibodies already primed to fight the SARS infection and then transfusing it into patients for whom the drug cocktail hasn't worked.

The strategy can be dangerous. People can react badly to the introduction of another person's blood into their systems. The blood must be screened for pathogens such as hepatitis and HIV. The radical step has been taken with a dozen or more patients but with uncertain results. "Whether it is really helping them is impossible to tell," Dr. Yuen says.

In Singapore, doctors tried antiserum on a critically ill patient who showed slight improvement, says Leo Yee Sin, clinical director of Singapore's Communicable Diseases Center.

Antiserum isn't likely to be used in the U.S., says David Pegues, associate clinical professor of infectious diseases at UCLA Medical Center, Los Angeles. "Because of the issues of blood and blood-product safety, that isn't an acceptable treatment in the U.S.," he says. "I don't see it taking place here."

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April 4th, 2003

Organ Donor Deemed Hepatitis-Free Infects Recipients
By Alison McCook

An organ donor whose blood passed the standard test for hepatitis C apparently passed the virus on to eight tissue recipients, the U.S. Centers for Disease Control and Prevention (CDC) said Thursday.

Organs and tissues from the infected donor were transplanted into 40 recipients between October, 2000 and July, 2002.

Dr. Barna Tugwell of the CDC cautioned that the agency report is not meant to "raise unnecessary alarm," and that the incidence of hepatitis C infection via donated organs and tissue tested for the virus is likely extremely low.

"We are looking into evaluating whether more prevention measures are necessary," she told Reuters Health.

Tests of stored samples of the donor's blood detected genetic material from the hepatitis C virus, which matched the viral genetic material found in the newly-infected recipients of the donor's tissues and organs.

Organ transplants from an infected donor carry a high risk of transmitting the virus to the recipient, and researchers have also reported cases of hepatitis C infection from tissue transplantation.

The standard method used to screen organ donors for hepatitis C involves testing the blood for the presence of antibodies directed against the virus, indicating the body's immune system was attacking its invader.

Once infection occurs, however, the body typically takes eight to ten weeks to develop antibodies that target the virus. The donor responsible for transmitting the virus in these eight cases likely died within this window of time, Tugwell and her colleagues conclude in the April 4th issue of the CDC's Morbidity and Mortality Weekly Report.

Although tests of viral genetic material called RNA can detect the presence of hepatitis C more quickly than those that rely on antibodies, not every health center has easy access to RNA tests, and a delay in getting the results could jeopardize the success of the transplant, the CDC writes.

In addition, most tissue samples are tested for the presence of the virus after the donor has already died, and researchers aren't sure how well the RNA test works post-mortem, Tugwell said.

The number of organ donors whose infection with hepatitis C is too new to inspire an antibody response is also likely very small, she added.

"The frequency of this occurring is probably very low," Tugwell said.

"It's just in these very few cases, where you would be in a very early phase of infection, before you developed these antibodies, that you might not detect an infection," she noted.

As such, she and her colleagues recommend that researchers continue to investigate how often organ donors present with viral RNA and no antibodies against hepatitis C before changing current policies regarding how transplantable organs are screened for the virus.

About four million people in the United States and 150 million worldwide have hepatitis C, an infection of the liver that is spread by contact with blood and other body fluids.

About 20 percent of people infected with the virus will develop severe and potentially fatal liver damage, or cirrhosis, which in turn increases a person's risk of liver cancer.

The donor who infected transplant recipients with hepatitis C died in his 40s from bleeding in the head and brain. He had no symptoms of the virus at the time of his death, and his next of kin said he had no history of using intravenous drugs or receiving a blood transplant.

Health officials re-tested blood samples from the donor after a doctor reported that a transplant recipient developed symptoms of infection six weeks after the transplant operation.

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Indicators and Predictors of Response to Antiviral Therapy in Chronic Hepatitis C
Hivandhepatitis.com

There are currently about 170 million people world-wide with chronic hepatitis C virus (HCV) infection, with about three million people infected in the USA and five million in Western Europe.

Up to 20% of affected individuals will develop cirrhosis within 10-30 years, 1-4% of whom will develop hepatocellular carcinoma each year. It has been projected that from 2010 to 2019, in the USA, 165 900 individuals will die from chronic liver disease, and 27 200 from hepatocellular carcinoma.

Although the incidence of new HCV infections is falling, the enormous number of individuals with established HCV infection will generate increasing demand for health care support over the coming decades.

The accurate assessment of those patients most likely to respond to therapy will become increasingly important. Clinicians need to be able to predict treatment success and to determine the ideal duration of therapy for each patient. This article reviews the methods for the assessment of treatment response and the indicators for the prediction of therapeutic outcomes to interferon alfa (IFN-alfa)-based therapy.

The complications of chronic hepatitis C, including cirrhosis and hepatocellular carcinoma, are expected to increase dramatically worldwide over the next 10-20 years.

Immunomodulatory/anti-viral therapy, employing interferon alfa both alone and in combination with ribavirin, affords the only effective treatment for hepatitis C. Accurate early prediction of response to interferon therapy may decrease or eliminate unnecessary or ineffective treatment, permit greater flexibility in tailoring therapy on an individual basis, and enhance the cost-effectiveness of treatment.

Liver biopsy provides valuable information about the baseline severity and subsequent progression of hepatitis C.

Severe fibrosis or cirrhosis on the pre-treatment liver biopsy is associated with decreased response rates. The measurement of viral RNA levels and genotyping may be used to optimize individual patient treatment.

Genotype non-1 and a low viral load are the most significant pre-treatment indicators of sustained virological response.

The most reliable predictor of a poor virological response is continued seropositivity for viral RNA during therapy. Therefore, a decision to stop or continue treatment can be based on a positive viral RNA test at 12 weeks for interferon-naive patients receiving interferon or pegylated interferon therapy.

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Hepatitis C Virus and Arthritis
Hivandhepatitis.com

Arthritis is one of the several autoimmune disorders induced by HCV infection. There is not a specific clinical pattern of HCV-related arthritis, but two nonerosive subsets have more frequently been described: a RA-like polyarthritis and a less common mono-oligoarthritis involving medium-sized and large joints, often showing an intermittent course.

This latter form is associated with the presence of serum cryoglobulins. Because of its variable characteristics, HCV-related arthritis must be considered in the differential diagnosis of many patients having inflammatory joint involvement. Antikeratin antibodies and possibly IgA RF can be useful in distinguishing between RA and HCV-related RA-like polyarthritis. In fact, these tests are highly specific in RA patients. In any case, the search for HCV antibodies should be more widely performed in the diagnostic approach to rheumatic diseases.

An association between PsA and HCV infection has been described in the literature, but the authors were unable to confirm these data. Nonsteroidal anti-inflammatory drugs, hydroxychloroquine, and low doses of corticosteroids are the cornerstones of the treatment of HCV-related arthritis. An etiologic therapy with alpha-interferon and ribavirin is useful when required by hepatic or systemic involvement; such therapy could also be considered in selected cases of isolated arthritis that are unresponsive to other drugs.

Few case reports described the onset of polyarthritis after the administration of alpha-interferon for HCV-related chronic hepatitis. This topic should be more accurately studied in the future to exclude a spurious association between the two events.

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April 7th, 2003

Study Links Hepatitis C to Type of Lymphoma

A new study provides additional evidence that the liver infection hepatitis C may contribute to a form of the cancer lymphoma.

It is too soon to know whether the association between the hepatitis C virus (HCV) and non-Hodgkin's lymphoma will affect the treatment of the cancer, study author Dr. Eric A. Engels told Reuters Health.

"Our study was not designed to tell patients how they might be treated," said Engels, who is at the National Cancer Institute in Rockville, Maryland. "One thing I can say is that in the United States it is likely that HCV infection is responsible for only a small portion of lymphomas."

The results of at least one study suggest that treating HCV infection can improve cancer prognosis. In a study published last year, people who had HCV infection and who had a rare type of lymphoma called splenic marginal zone lymphoma went into remission after they were treated for HCV.

"For these people, treating the HCV can make a difference," Engels said. "Having said that, our study does not really provide any direct evidence regarding the role of treating HCV in lymphoma patients."

Past studies examining a possible connection between the hepatitis C virus and non-Hodgkin's lymphoma have produced "a range of results," according to Engels.

Some have found what appeared to be a strong association between the liver infection and the cancer, while others have failed to detect any connection. To some extent, the differences may be due to the design of the study or where the study was based, Engels said.

In the new study, Engels and his colleagues examined how often people with non-Hodgkin's lymphoma in four regions of the U.S. were also infected with HCV.

"We did find an association between HCV and NHL," Engels said. "It was not as strong as some of the other studies, but I think its quite representative."

In the study of about 1,500 people, people with non-Hodgkin's lymphoma were about twice as likely to be infected with HCV as healthy individuals. HCV was present in 3.9 percent of people with non-Hodgkin's lymphoma compared with 2.1 percent of healthy individuals.

Engels said he and his colleagues were unable to identify whether specific subtypes of non-Hodgkin's lymphoma were associated with HCV infection. Additional studies are needed, he added, to confirm the current findings, identify which varieties of non-Hodgkin's lymphoma are related to HCV and to uncover the mechanisms responsible for the association.

Engels was scheduled to present the findings during the American Association for Cancer Research's 94th Annual Meeting in Toronto this past Sunday, but the event was canceled due to growing concern about cases of severe acute respirator syndrome (SARS) in the city.

Non-Hodgkin's lymphoma refers to several types of cancer that start in the lymphatic system but often spread throughout the body.

Nearly 4 million Americans have hepatitis C, making it one of the most common chronic viral infections in the U.S. Chronic inflammation of the liver develops in many patients, and about 20% of people with hepatitis C will develop cirrhosis, a severe and sometimes fatal scarring of the liver. Cirrhosis increases the risk of liver cancer.

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Iron Stores are Commonly Elevated in HCV-infected African-Americans
By Brian Boyle, MD, hivandhepatitis.com

Treatment for chronic hepatitis C virus (HCV) infection-including pegylated interferon and Rebetol (ribavirin)-has improved significantly over the past several years. In addition to the dosing of pegylated interferon and Rebetol, several factors have been identified as predictors of treatment success, i.e., achieving a sustained virologic response, and these include HCV genotype, HCV viral load, black race, and increased hepatic iron stores.

In a study published in Hepatology, investigators sought to determine if 2 of the factors associated with poor response to HCV treatment are linked. They investigated whether HCV-infected African-Americans have increased iron stores relative to uninfected persons.

The investigators used the third National Health and Nutrition Examination Survey (NHANES III), to determine the risk of having increased iron stores, which were defined as an elevation of both serum ferritin and transferrin-iron saturation (TS), in 100 HCV-RNA-positive blacks and 126 non-blacks relative to 4002 HCV-RNA-negative blacks and 10,493 non-blacks.

They found that HCV-positive blacks were 5.4 times more likely to have increased iron stores than HCV-positive non-blacks. The proportion of HCV-positive blacks who had increased iron stores was 16.4% among those with abnormal liver enzymes and 2.8% among those with normal liver enzymes, compared with only 0.6% among HCV-negative blacks.

After adjustment for several other factors that may affect iron stores, HCV-positive blacks with abnormal liver enzymes had a 17.8-fold higher risk of having increased iron stores, while among persons of other races, there was a much smaller difference in the proportion of persons with increased iron stores between HCV-positive persons with (3.4%) or without (1.4%) abnormal liver enzymes and HCV-negative persons (0.9%).

Based on these data, the authors conclude, "a greater proportion of blacks than persons of other races respond to HCV infection with an increase in iron stores. This finding may partly explain the reduced response of HCV-positive African-Americans to antiviral treatment."

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Hepatitis C Vaccine, Phase-One Trials to Begin in the US
Reporter: Tanya Nolan

ELEANOR HALL: As medical experts worldwide grapple with the growing incidence of Severe Acute Respiratory Syndrome, the globe's leading virologists are meeting in Sydney this week to discuss progress on another, much more common major health problem-hepatitis.

And one of those experts is predicting a vaccine will be developed for SARS in a matter of years. Doctor Michael Houghton and his team have just developed a vaccine for Hepatitis C, the leading cause of chronic liver disease, and have received approval to begin phase-one trials in the United States.

More than half a billion people worldwide are infected with one or more of the five hepatitis viruses, with nearly 200 million suffering from Hep C.

Tanya Nolan has been speaking to Doctor Houghton, who says the Hepatitis C vaccine could be available within seven years.



MICHAEL HOUGHTON: The global burden is huge. The WHO has investigated that 170 million people are infected worldwide. What that means is over the next 10, 20 years the amount of liver disease is going to be very, very large, requiring extensive and very expensive treatment. And along with that is a necessity for preventing new infections.

TANYA NOLAN: How has your vaccine managed to overcome the ability of the virus to subvert the body's natural immune response by constantly mutating during the infectious period?

MICHAEL HOUGHTON: Yes, the vaccine that we've tested in animal models, and we're shortly going to be testing in humans, in a phase-one clinical trial in the United States, is able to prime, and I should say produce, anti-bodies to the virus, as well as prime t-helper cells that recognize the virus, and in combination the vaccine is able to prevent infection against a variety of different strains of the virus.

TANYA NOLAN: You've proved in animal trials that it could protect against heterologous viruses, not just homogenous viruses. Does that mean it could potentially provide protection against other forms or other strains of the virus?

MICHAEL HOUGHTON: Yes, absolutely, and Hepatitis C virus, like HIV, is very heterogenous, so any vaccine that you make cannot just protect against the virus from which you've made the vaccine, you have to show it can protect against other strains.

And because these are such heterogeneous viruses, it's a key point in vaccine development, and that's what we've been able to show in the last couple of years, that we can protect animals not just against homologous virus, but against different strains of that particular virus type.

TANYA NOLAN: So how likely is it that we could see new drugs to fight the virus, and a vaccine within the next decade?

MICHAEL HOUGHTON: Yes, well, we're just entering phase-one clinical trials in the United States. There are three phases to a complete clinical program. We anticipate finishing our complete program in about 5, 6 years from now. So I think by 2010, hopefully, we're optimistic that we can have a vaccine on the market to Hep C.

In terms of new drugs, there's a tremendous amount of effort going on globally at research institutes and in big Biopharma, to develop inhibitors of key enzymes involved in the viral life cycle. Rather like was done for HIV in the last 10 years, we now expect the same process to be applied to Hep C, and for new drugs to be available by the end of this decade.

TANYA NOLAN: As a virologist, how do you see the current medical ability to control the outbreak of a pandemic of the corona virus, Severe Acute Respiratory Syndrome?

MICHAEL HOUGHTON: Well, I think we need to do two things. First of all, the measure that's already being taken by many countries to quarantine infected individuals and suspected infected individuals, that's very important in order to prevent a mass epidemic; number two, with the technologies we have available now in vaccine research and development, I think we can move fast in order to develop a vaccine to this agent.

I am personally fairly optimistic that we can develop a vaccine quite quickly. But having said that, just to develop a vaccine that's safe, and has been tested, and approved by the authorities, takes time, takes several years basically, and so, in the interim, we have to be very carefully and keep up our surveillance, and take adequate quarantining procedures, I think.

ELEANOR HALL: One of the world's leading virologists, Dr Michael Houghton, speaking there to Tanya Nolan.

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April 8th, 2003

Schering-Plough Corporation (SGP) Reports FDA Grants Priority Review to REBETOL for Treating Pediatric Hepatitis C. Priority Review Designation Granted to Therapies Addressing Unmet Medical Needs

Schering-Plough Corporation today reported that the U.S. Food and Drug Administration (FDA) has granted six-month priority review status to its New Drug Application (NDA) for REBETOL(R) (ribavirin, USP) Oral Solution and Capsules. The application seeks FDA approval of REBETOL for use in combination with INTRON(R) A (interferon alfa-2b, recombinant) Injection for the treatment of chronic hepatitis C in patients 3 years of age and older with compensated liver disease previously untreated with alpha interferon. Schering-Plough submitted the NDA in January 2003.

Priority review status is granted to drugs that, if approved, would address unmet medical needs and represent significant advances over existing treatments. While it is estimated that less than 200,000 children in the United States are infected with the hepatitis C virus (HCV), new infections in children continue to occur.

"FDA approval of REBETOL for use with INTRON A would represent the first and only therapy approved in the United States for treating hepatitis C in the pediatric population," said Robert J. Spiegel, M.D., senior vice president of medical affairs and chief medical officer, Schering-Plough Research Institute. "For more than a decade, Schering-Plough has been the leader in advancing treatment of chronic hepatitis C. We are committed to developing innovative therapies to meet the needs of patients with this serious disease."

REBETOL Oral Solution represents a new formulation of ribavirin, USP. REBETOL Capsules are currently approved in the United States for use in combination therapy with INTRON A for the treatment of chronic hepatitis C in patients with compensated liver disease previously untreated with alpha interferon or who have relapsed following alpha interferon therapy. REBETOL Capsules also are indicated in combination with PEG-INTRON(R) (peginterferon alfa-2b, recombinant) Injection for the treatment of chronic hepatitis C in patients with compensated liver disease who have not been previously treated with interferon and are at least 18 years of age.

    Commitment to Hepatitis C Patients
    Schering-Plough is committed to supporting hepatitis C patients with education and service programs as well as to help locate financial assistance for patients in need. The company's programs for patients in the United States are among the most comprehensive in the industry, providing support and guidance to patients from the time of diagnosis through treatment, and ensuring that all eligible patients have access to the company's hepatitis C products.

    Since the introduction of PEG-INTRON and REBETOL combination therapy in 2001, more than 250,000 hepatitis C patients worldwide have received this treatment, including 150,000 patients in the United States. Twenty-five percent of all U.S. patients currently treated with PEG-INTRON and REBETOL are enrolled in the company's Commitment to Care program, which provides medication and/or reimbursement assistance to eligible patients. The market value of assistance and treatment provided to hepatitis C patients through this program exceeded $100 million in 2002.

    Schering-Plough's Be In Charge hepatitis C patient-support program has enrolled more than 55,000 U.S. patients to date, with more than 25,000 patients enrolling in 2002 alone. This U.S. program is designed to support patients treated with Schering-Plough hepatitis C products through the use of educational materials and telephone contact with personal nurse counselors skilled in the management of hepatitis C.

    In a 2002 survey of patients enrolled in the Be In Charge program, overall patient satisfaction was 91 percent, with 75 percent of patients saying that Be In Charge helped them manage their health condition. Of patients surveyed, 96 percent said they would recommend Be In Charge to others. A survey of physicians also reflects their satisfaction with Be In Charge: 83 percent said they would recommend the program to other physicians, 84 percent said they believe patients have a better understanding of their treatment plan because of Be In Charge, and nearly 75 percent of physicians said Be In Charge has reinforced their treatment suggestions to patients.

    REBETOL is an oral formulation of ribavirin, a synthetic nucleoside analog. Schering-Plough has worldwide rights to market oral ribavirin for hepatitis C through a licensing agreement with Ribapharm Inc. of Costa Mesa, Calif.

    PEG-INTRON is a longer-acting form of INTRON A that uses proprietary PEG technology developed by Enzon, Inc. of Bridgewater, N.J. Schering-Plough holds an exclusive worldwide license to PEG-INTRON.

    INTRON A is a recombinant version of naturally occurring alpha interferon, which has been shown to exert both antiviral and immunomodulatory effects. Schering-Plough markets INTRON A for 16 major antiviral and anticancer indications worldwide.

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Liver Fibrosis Progression in Chronic Hepatitis C

Anti-HCV patients with persistently normal alanine transaminase and an initial fibrosis of F0 or F1 are less likely to develop fibrosis progression than those with elevated alanine transaminase, find researchers in the latest issue of the Journal of Hepatology (J Hepatology 2003; 38(4): 511-7)

Detectable serum hepatitis C virus (HCV) RNA in HCV patients with persistently normal alanine transaminase (PNALT) is associated with significant liver damage.

In this study, researchers from the United States compared the histological progression of fibrosis in patients with PNALT and elevated alanine transaminase (ALT).

The research team included 40 patients with PNALT (group 1) and 41 patients with elevated ALT (group 2) in the study. Patients had fibrosis of F0 to F2.

The median time to second liver biopsies was 6.3 years.

Progression of fibrosis:

- group 1 = 23%

- group 2 = 42%

The research team found that 23% of patients in group 1 and 42% in group 2 had progression of fibrosis.

Overall, there was a trend towards a significantly higher cumulative probability of fibrosis progression in group 2.

In patients with initial F0 to F1 fibrosis, there was a significant difference in cumulative probability of fibrosis progression between the 2 groups. Probabilities for groups 1 and 2 were 23% and 43%, respectively.

Dr Chee-Kin Hui's team concluded, "Anti-HCV patients with PNALT with an initial fibrosis of F0 or F1 were less likely to develop progression of fibrosis than those with elevated ALT".

However, "Patients with PNALT may have histologically and clinically progressive disease."

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April 9th, 2003

ZADAXIN Combination Therapy Shows 71% Sustained Response in Hepatitis B Patients

SciClone Pharmaceuticals today announced the results of a study showing a 71% long-term sustained response rate for difficult to treat hepatitis B patients. These results were achieved after only one year of combination therapy with ZADAXIN and interferon alpha. This sustained response rate compares extremely favorably to 20% of patients using interferon alpha in combination with lamivudine and 10% of patients using interferon alpha alone.

All of the patients in this study were infected with HBeAg-negative hepatitis B, commonly referred to as precore mutant hepatitis B. This strain of the virus is extremely difficult to treat and is highly prevalent in the Mediterranean region. Recommended treatment for these patients is at least one year of therapy. However, a separate study showed that even with 24 months of interferon alpha therapy only 30% of these patients achieved a sustained response.

"ZADAXIN combination therapy has shown the ability to treat successfully some of the most difficult to treat hepatitis B patients," commented Eduardo Martins, M.D., Ph.D., Vice President, Medical Affairs of SciClone Pharmaceuticals. "Achieving a sustained and durable response in the majority of patients within a reasonable treatment period is of significant benefit both for the patient and for the healthcare systems dealing with this potentially life-threatening disease."

This recent study was conducted by a team led by Dr. Murat Saruc of the University of Nebraska Medical Center in Omaha, Nebraska and Celal Bayar University in Manisa, Turkey. The study was designed to show long-term efficacy of ZADAXIN in combination with interferon alpha in the treatment of patients infected with precore mutant hepatitis B. One of the primary goals of treatment, and the measure of sustained response in the study, is sustained suppression of hepatitis B viral replication and histological improvement.

In the study, 74% (20/27) of patients receiving 26 weeks of ZADAXIN in combination with interferon followed by 26 weeks of interferon monotherapy (a total of 52 weeks of therapy) showed a sustained response at 6 months post-treatment. 71% (19/27) of these patients showed a sustained response at 18 months post-treatment.

By comparison, 53% (8/15) of patients receiving 52 weeks of interferon in combination therapy with lamivudine followed by continuous lamivudine monotherapy showed a sustained response at 6 months post-treatment but only 20% (3/15) at 18 months post-treatment. 40% (4/10) of patients receiving 52 weeks of interferon monotherapy showed a sustained response at 6 months post-treatment but only 10% (1/10) at 18 months post-treatment.

Dr. Murat Saruc concluded, "Interferon alpha and ZADAXIN combination therapy results in significant virological and biochemical improvement compared with standard therapeutic regimens and is well tolerated."

The abstract from this study was to be presented at the Annual European Association for the Study of Liver Disease (EASL) Conference to be held in Istanbul, Turkey. Unfortunately, the conference has been indefinitely postponed due to the war in Iraq.

Current Treatment Standards for Precore Mutant Hepatitis B
HBeAg-negative, or precore mutant, hepatitis B, is a mutant form of the virus which does not display on its surface the hepatitis B "e" antigen, the primary target for the immune response against the disease. In a recent consensus report, EASL states that patients with precore mutant hepatitis B require interferon alpha therapy for 12 to 24 months, which is two to three times the length of treatment for hepatitis B patients without this form of the virus. A study published this month in the medical journal Hepatology shows that even with 24 months of interferon alpha therapy, only 30% (30/101) of patients with precore mutant hepatitis B achieved a sustained response.

Importantly, interferon alpha causes severe toxicities, making patient compliance more difficult, and has an unfavorable treatment cost relative to its effectiveness. Lamivudine or adefovir, two additional hepatitis B therapies currently approved in Europe and the U.S., are recommended by EASL if interferon alpha is contraindicated, ineffective, or poorly tolerated. Long-term therapy with lamivudine or adefovir may lead to drug resistance, however, and make further therapy even more challenging.

    About Hepatitis B

    There are an estimated 350 million chronic hepatitis B carriers worldwide. The most widely used therapies for treating hepatitis B are lamivudine and interferon alpha. SciClone has recently completed a phase 3 clinical trial in Japan using ZADAXIN as a monotherapy for hepatitis B and expects to report data during the second quarter of 2003.

    About ZADAXIN

    ZADAXIN is a pure synthetic preparation of thymosin alpha 1, a substance which circulates naturally and is instrumental in the body's immune response to fight viral infections and certain cancers. ZADAXIN has been approved for sale by the ministries of health in over 30 countries and is marketed in China and selected other countries outside the U.S. ZADAXIN has been administered to more than 10,000 patients in both clinical and commercial use, alone and in combination with anti-viral and anti-cancer drugs, without producing any reported ZADAXIN related significant side effects or toxicities.

    About SciClone

    SciClone Pharmaceuticals is a biopharmaceutical company engaged in the development of therapeutics to treat life-threatening diseases. Its lead product ZADAXIN is in several late-stage clinical trials, including two phase 3 hepatitis C clinical trials in the U.S., a recently completed phase 3 hepatitis B clinical trial in Japan, a phase 2 malignant melanoma clinical trial in Europe, and two phase 2 liver cancer trials in the U.S. In addition to ZADAXIN, SciClone's drug development opportunities include SCV-07, a potentially orally available therapy to treat viral and infectious diseases, and products to address the protein-based disorder that causes cystic fibrosis.

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New Research Establishes Genetic Associations in Hepatitis C

Hepatitis C Virus (HCV), as a major agent of non-A, non-B hepatitis (NANBH), has been described as an insidious disease and a silent epidemic, mainly because the infection is often sub-clinical. Acute infection is recognized in a minority of patients and in most cases the virus results in chronic infections taking 10-20 years before the emergence of liver disease. In the US, almost four million individuals are infected and up to 170 million worldwide.

Background
An imbalance in helper T-cell type-1 (Th1) and type-2 (Th2) cytokines has been suggested as playing an important role in the cause of chronic viral infections, but this issue is not resolved in patients with hepatitis C virus (HCV) infection. Inflammation of the portal and portal areas is a common feature of chronic hepatitis C. Antigen presenting dendritic, or "tree-like," cells are located in the portal area, and infiltrating T-cells are initially exposed to infected hepatocytes in the peripheral area. Thus, these areas could be sites of the initial processes of the immune response in chronic hepatitis C.

The pathogenesis of hepatitis C virus associated liver injury involves many genes from multiple pathogenic pathways. Blockade of CC-chemokine receptor 5 (CCR5) has been proposed as therapy for HIV-1. Therefore, an examination was conducted to determine if the CCR5-delta32 homozygous genotype has phenotypic expression other than those related to HIV-1. Other genes associated with viral infection (RANTES, CD4), and in inflammation (Interleukin1B) were also reviewed for their possible association.

Hepatitis C virus (HCV) is commonly seen in the Coachella Valley of Southern California. Genetic Research institute of the Desert (GRID), a nonprofit research center was established in the Coachella valley with a goal to investigate genetic aspects of cancer, as well as infectious and some neurological diseases. This research effort focused on the genetic variants in the HCV group of patients compared to normal healthy individuals. Genetic association could determine the drug responsiveness and aid in treatment; accordingly, a research objective was to determine genetic variants associated with the disease and to find the multiple allelic associations of these genes. The associated genes can be used as prognostic markers, as well as help design drug for hepatitis.

A New Study
The authors of "Multiple Gene Associations In Hepatitis 'C' Infection, " are Radhika Gade-Andavolu, PhD from Genetic Research Institute of the Desert, Rancho Mirage, Gary Annunziata, DO, and Lawrence A. Cone, MD, DSc, are from the Eisenhower Medical Center, Rancho Mirage, CA. Their findings are being presented at Experimental Biology 2003, a meeting sponsored by the American Physiological Society, being held April 11-15, 2003, at the San Diego Convention Center, San Diego, CA.

Methodology
Patients seeking treatment at Infectious Diseases and Gastroenterology clinics at the Eisenhower Medical center participated in this research. After informed consent was obtained blood was drawn from patients; DNA was isolated from the blood and used for analysis. Genomic DNA from 26 hepatitis C patients and 318 healthy controls was subjected for PCR analysis to determine the genotypes of four genes.

Results
In this study, the frequency of the SNP's of IL1B and RANTES, a 32bp deletion in CCR5 and CD4 pentanucleotide repeat polymorphisms was evaluated. The findings were reviewed for association of various genotypes with respect to disease onset and severity scores, and a statistical analysis was done.

Out of the four genes studied in patients, only CD4 repeat (p= 0.006) was highly significant with respect to controls. With the onset of disease relative to age, CD4(p= 0.02) and IL-B (p= 0.012) were significant, while CCR5 delta 32mutation showed significance with severity score (p=0.08). IL-1B and RANTES genes showed positive correlation (p= 0.04) with pair wise bivariate analysis.

Conclusions
These preliminary findings with CD4 indicate a correlation between dominant Th1 response and disease activity and progression suggesting a possible role of intrahepatic CD4 T cells in hepatic injury of HCV infection. In addition the findings of CCR5, IL1B and its significant correlation with RANTES suggests their possible roles in the immune response to HCV infection in and around the portal area by attracting naive and active T-cells. This research will continue with the addition of more genes and the target set numbers of genes are to be pooled to ascertain the risk.

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InterMune to Announce Phase II Results Evaluating Mechanisms of Action of Actimmune In IPF. Full Results at ATS Meeting Next Month

InterMune, Inc. announced today that results of a randomized, double-blind, placebo-controlled Phase II clinical trial evaluating Actimmune's(R) (interferon gamma-1b) influence on several underlying mechanisms of action in idiopathic pulmonary fibrosis (IPF) will be presented at the 99th Annual Conference of the American Thoracic Society (ATS) next month in Seattle. The molecular measures associated with IPF, a debilitating and fatal lung disease, include measures of fibrosis, antimicrobial activity, growth factors and inhibitors of angiogenesis.

Full results of this trial, which involved 32 patients, will be presented on Sunday, May 18, at ATS in Seattle by Robert M. Strieter, M.D., Professor of Medicine and Pathology and Chief, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA in Los Angeles.

"The purpose of this trial was to understand the biological basis for interferon gamma-1b treatment in IPF and extend our knowledge of its effects in IPF at the molecular level," said Dr. Strieter. "These results help provide a plausible hypothesis for the mechanism of action of interferon gamma-1b in IPF. We are excited by these results and look forward to sharing them in more detail at the ATS meeting in May."

    About Interferon gamma-1b
    Interferon gamma is a naturally occurring protein that stimulates the immune system. InterMune markets interferon gamma-1b for the treatment of two life-threatening congenital diseases: chronic granulomatous disease and severe, malignant osteopetrosis. InterMune is also conducting a Phase III study of interferon gamma-1b in ovarian cancer and a Phase II study of interferon gamma-1b for the treatment of severe liver fibrosis, or cirrhosis, caused by hepatitis C virus (HCV). Physicians and patients can obtain additional information about interferon gamma 1-b, including the product's safety profile, by visiting http://www.actimmune.com .

    About InterMune
    InterMune is a commercially driven biopharmaceutical company focused on the marketing, development and applied research of life-saving therapies for pulmonary, infectious and hepatic diseases. For additional information about InterMune, please visit www.intermune.com.

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96-Week Data Show Hepsera Reduces Liver Damage and Improves Liver Function in More Than 70 Percent of Patients with Hepatitis B "E" Antigen-Negative Disease

Gilead Sciences today announced 96-week results from a study of its oral antiviral drug Hepsera(TM) (adefovir dipivoxil 10 mg) in patients with hepatitis B "e" antigen-negative (HBeAg-negative, or precore mutant) chronic hepatitis B virus (HBV). HBeAg-negative hepatitis B is a strain of HBV with a mutation in the viral genome that eliminates the ability of the virus to produce the envelope ("e") antigen. In this study, more than 70 percent of patients treated with Hepsera showed persistent suppression of HBV DNA viral replication, continued histological improvements and sustained improvements in liver function through 96 weeks of treatment. Study results were presented today at the 11th International Symposium on Viral Hepatitis and Liver Disease (ISVHLD) in Sydney, Australia. This presentation is one of seven Hepsera abstracts to be featured at the conference.

More than 400 million people worldwide have chronic hepatitis B, which is caused by infection with the hepatitis B virus, and between one quarter and one third of these individuals develop progressive liver disease, which can lead to cirrhosis and liver cancer. Approximately one million people die annually from complications of chronic hepatitis B, making it one of the leading causes of death worldwide. HBeAg-negative chronic hepatitis B infects up to approximately 50 percent of chronic hepatitis B carriers worldwide and is most prevalent in countries of the Mediterranean and Southeast Asia, where between 30 and 80 percent of chronic hepatitis B patients are estimated to be infected with this strain.

"Patients with HBeAg-negative chronic hepatitis B often need years of treatment to protect them against disease progression to cirrhosis and liver cancer, but high rates of viral resistance can undermine the long-term viability of other treatment options," said Professor Stephanos Hadziyannis, MD, Department of Medicine, Henry Dunant Hospital, Athens, Greece. "The lasting efficacy and tolerability and low risk of resistance we observed in this study suggest that Hepsera may offer new hope to patients with this form of hepatitis B."

Study 438 Design
Ninety-six-week efficacy and tolerability results from Study 438 were presented today by Dr. Hadziyannis (Presentation 1065). To evaluate the long-term safety and efficacy of Hepsera, patients in this study will continue to receive Hepsera for an additional three years. Study 438 is a randomized, double-blind, placebo-controlled clinical trial of 184 patients with HBeAg-negative chronic hepatitis B and compensated liver function. This study is being conducted in Australia, Canada, France, Greece, Israel, Italy and Southeast Asia. To date, this is the largest placebo-controlled clinical trial in HBeAg-negative patients.

At study entry, patients were randomized (2:1) to receive Hepsera once daily (n=123) or placebo (n=61) for 48 weeks. Results from the first 48 weeks of the study were presented at the European Association for the Study of the Liver in April 2002 and published in the February 27, 2003 issue of the New England Journal of Medicine. The 48-week results demonstrated that therapy with Hepsera was associated with significant histological, virological and biochemical improvements compared to placebo.

Following the first 48 weeks of treatment, patients who had received Hepsera for the first year of the study were re-randomized (2:1) to receive either Hepsera or placebo for a second year. Patients who received placebo for the initial 48 weeks of the study received Hepsera for the second 48 weeks of the study.

Two-year Efficacy
Among patients who received continuous Hepsera treatment over 96 weeks, 71 percent of patients achieved undetectable levels of serum HBV DNA (less than 1000 copies/mL, as assayed by PCR, n=70). The median reduction in serum HBV DNA levels among Hepsera-treated patients was 3.47 log(10) copies/mL at week 96, corresponding to approximately a 99.97 percent decrease in viral load from a median baseline level of 7.07 log(10) copies/mL. These data indicate that Hepsera provided sustained suppression of HBV viral replication - the main cause of disease progression - throughout the two year study.

Hepsera also provided sustained improvement in liver function through 96 weeks, as measured by blood levels of the liver enzyme alanine aminotransferase (ALT). The proportion of patients with abnormal baseline ALT levels whose ALT levels returned to normal at 96 weeks was 73 percent (n=64). Additionally, among patients who received an optional liver biopsy after 96 weeks of continuous Hepsera treatment (n=19), 79 percent showed improvement in liver histology.

Two-year Data Show Resistance is Slow to Develop
Data further characterizing the resistance profile of Hepsera also were presented today at ISVHLD by Stephen Locarnini, MD, Divisional Head of Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, Melbourne, Australia (Presentation 779). Through 48 weeks of treatment in previous clinical studies, including two pivotal studies of the drug, no Hepsera-related resistance mutations were identified (n=629). To assess the incidence of resistance with extended treatment, investigators monitored for viral resistance in 124 patients who completed 96 weeks of treatment in various studies (including Study 438, n=79). At 96 weeks, a novel resistance mutation (rtN236T) in the HBV polymerase was detected in two of the 124 patients (1.6 percent). The mutation reduced susceptibility to adefovir by 5- to 23-fold in vitro, but did not confer cross-resistance to lamivudine, the other oral antiviral currently approved for the treatment of chronic hepatitis B. Surveillance is ongoing for up to five years in long-term clinical efficacy and safety studies.

Safety Profile
The most common adverse reactions considered at least possibly related to Hepsera treatment through the second year of the study were headache, pharyngitis, abdominal pain and asthenia (weakness). Two patients had an increase in serum creatinine of greater than or equal to 0.5 mg/dL from baseline by week 96. Both cases resolved, one with continuation of Hepsera therapy and one with discontinuation of Hepsera therapy. No patients had a serum phosphorus level less than 1.5 mg/dL through 96 weeks.

Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of treatment with antiviral therapies for hepatitis B, including Hepsera. Special warnings and precautions for use are included in the package insert regarding monitoring of renal function and post-treatment exacerbations of hepatitis, use in patients with underlying renal impairment or patients co-infected with HIV, and occurrence of nucleoside analogue-associated lactic acidosis and severe hepatomegaly with steatosis.

    About Hepsera
    Hepsera, the first nucleotide analogue for chronic hepatitis B, is administered as a once-daily 10 mg tablet and works by blocking HBV DNA polymerase, an enzyme involved in the replication of the virus in the body. In clinical trials and expanded access programs, approximately 2,500 patients have been treated with Hepsera for periods of up to three years. Hepsera was approved in the United States in September 2002 and in the European Union in March 2003. Regulatory filings for the drug also have been completed in Australia, Switzerland, Turkey and Canada, and additional regulatory filings are planned in other countries in the coming months. In April 2002, Gilead signed a licensing agreement with GlaxoSmithKline (GSK), granting to GSK rights to commercialize Hepsera in Asia, most significantly China, South Korea, Japan and Taiwan, and in Latin America, Africa and other territories.

    In the United States, Hepsera is indicated for the treatment of chronic hepatitis B in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. Hepsera is indicated in Europe for the treatment of chronic hepatitis B in adults with compensated liver disease with evidence of active viral replication, persistently elevated serum alanine aminotranseferase (ALT) levels and histological evidence of active liver inflammation and fibrosis; or decompensated liver disease.

    About Gilead
    Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes therapeutics to advance the care of patients suffering from life-threatening diseases worldwide. The company has six marketed products and focuses its research and clinical programs on anti-infectives. Headquartered in Foster City, CA, Gilead has operations in the United States, Europe and Australia.

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Future Complications of Chronic Hepatitis C in the United States

Despite the declining incidence of acute HCV infection, chronic hepatitis C is common, find researchers in the April issue of Liver Transplantation (Liver Transpl 2003; 9: 331-8)

Chronic hepatitis C virus (HCV) infection is common and often results in slowly progressive liver disease.

Acute hepatitis C is now uncommon, however most patients with acute infection have developed chronic hepatitis. Therefore, the pool of infected patients is large.

In this study, researchers from the United States modified a previously described natural history model for HCV infection. They used this to project the number of cases of HCV infection, cirrhosis, and liver failure over the next 40 years.

The proportion of the HCV-infected individuals with cirrhosis will increase from 16% to 32% by 2020.

The model estimated that the prevalence of HCV infection in the United States was 3.07 x 106 in 1993. This compared with an adjusted National Health and Nutrition Evaluation Survey (NHANES) III estimate of between 2.8 to 3.5 x 106.

The researchers predict a gradual decline in the prevalence of infection by year 2040, due to aging and natural deaths among the infected pool.

However, the proportion with cirrhosis will increase from 16% to 32% by 2020 in an untreated population, as the duration of infection increases in the surviving cohort.

In addition, the complications of cirrhosis also will increase dramatically over the next 20 years. The team predicts that hepatic decompensation will increase by 106%, hepatocellular carcinoma by 81%, and liver-related deaths by 180%.

Furthermore, although current treatment regimens eradicate HCV in over 50% of cases, many more patients would need to be treated to significantly impact disease progression.

Identification and treatment of every case of HCV infection would reduce the number of cases of decompensated cirrhosis by almost half after 20 years.

Dr Gary Davis's team concluded, "Despite the declining incidence of acute HCV infection, chronic hepatitis C is common".

"The prevalence of cirrhosis and the incidence of its complications will increase over the next 10 to 20 years."

This is, "Because the duration of infection increases among those with chronic hepatitis C."

"These data emphasize the need for greater access to transplantation by expansion of the donor pool, increasing use of split livers and living donors, and novel options such as xenotransplantation".

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Achillion Pharmaceuticals, Inc. And EntoMed S.A. Enter Antiviral Drug Discovery Collaboration

Achillion Pharmaceuticals Inc, a leading discoverer and developer of small molecule drugs to combat resistance in infectious diseases, and Entomed SA, the world leader in the discovery and development of novel medicines derived from the biology and chemical diversity of insects, have entered into a collaboration to jointly discover and develop novel anti-viral drugs.

The partnership will focus on the discovery of new lead compounds for the treatment of a number of serious viral diseases. Under the agreement, Achillion will use its antiviral drug discovery expertise to screen Entomed's library, the Entomotheque(TM). The Entomotheque(TM) is a focused collection of insect derived molecules and analogues developed by Entomed. Achillion's drug discovery expertise includes state of the art medicinal chemistry and proprietary cell based and molecular assays. Achillion and Entomed will jointly develop any new drugs discovered.

"Entomed's library houses a novel source of chemical diversity from insects, offering great potential to identify new drug candidates to treat viral disease," said William G. Rice, Ph.D., CEO of Achillion. "This collaboration expands on our strategy to access unique and highly purified chemical libraries of natural products. From this collaboration we expect to add new candidates to our growing pipeline of drugs that combat drug resistance, the major issue in infectious disease treatment today."

Dr Jean Combalbert, CEO of Entomed commented about today's announcement, "We are delighted to join with Achillion to access their leading anti-viral drug discovery technology to find exciting new drug candidates from Entomed's unique compound collection. This collaboration, in particular, allows us to capitalize on the value of the Entomotheque(TM) in another important therapeutic field. We expect to continue to build value by developing further collaborations targeted at other significant therapeutic fields in the near future"

    About Entomed

    www.entomed.com

    ENTOMED, Strasbourg, France, is the world leader in the discovery and development of novel medicines derived from the biology and chemical diversity of insects. The Company's core technologies are built on the understanding and exploitation of the battery of molecules synthesized by the powerful defense and cellular control systems that insects have. These molecules comprise both peptides and small molecules.

    ENTOMED's strategy is to apply its core technologies and expertise to the chemical and molecular diversity of insect biology to discover and develop novel molecules as human therapeutic agents for a wide range of diseases with high medical need including infectious diseases, cancer, wound healing, ion channel effects and immunomodulation.

    About Achillion

    www.achillion.com

    Achillion is a privately-held pharmaceutical company focused on the discovery, development and commercialization of innovative small molecule drugs that combat drug resistance in infectious diseases. Achillion's drug development pipeline is led by the product candidate elvucitabine (Beta-L-Fd4C or ACH-126,443), which is currently in human clinical trials for the treatment of infections caused by hepatitis B virus or human immunodeficiency virus (HIV). Achillion's drug discovery pipeline embodies an innovative program-based approach to identifying new infectious disease targets and designing small molecule drugs to attack these targets, with a particular emphasis on antiviral drugs to treat diseases caused by hepatitis B and C viruses (HBV and HCV), HIV, and new antimicrobial drugs.

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PEGASYS Doubles the Efficacy in Difficult-to-Treat Hepatitis B Virus Versus Conventional Interferon

Study results presented today at the 11th International Symposium on Viral Hepatitis and Liver Disease, Sydney Australia demonstrate that PEGASYS, a new generation hepatitis C therapy, more than doubled the efficacy of conventional interferon in the treatment of chronic hepatitis B (CHB).

PEGASYS given for six months at the same 180 µg dose as in hepatitis C, showed a combined end point of HBeAg loss, HBV DNA below 500,000 copies/ml and normalisation of ALT, of 28% compared to 12% for conventional interferon (Roferona A: 4.5 MIU).

The Phase II study assessed the efficacy of PEGASYS in patients with difficult-to-treat HBeAg-positive CHB, which was defined as high pre-treatment HBV DNA (high levels of replicating virus in the patient's liver) and low pre-treatment ALT (indicating a weak natural response from the patients immune system to HBV). These factors are considered predictors of a poor response to HBV therapy. As in hepatitis C, where genotype 1 is considered difficult to treat, there is also evidence that those infected by the HBV genotype C virus respond less well to treatment.

"Until now, there was only a slim chance that these hepatitis B patients could be cured of their disease," said Professor Graham Cooksley, the lead investigator of the study and Senior Principal Research Fellow, Clinical Research Centre, Royal Brisbane Hospital, Australia. "These monotherapy results are extremely positive and demonstrate the same kind of efficacy in hepatitis B as we saw with genotype 1 patients in hepatitis C. PEGASYS works very well in those with the most treatment-resistant disease."

PEGASYS fared better than conventional interferon in every efficacy parameter measured. The efficacy parameters were:

  • HBeAg loss (loss of viral protein indicates that viral replication has stopped)
  • HBV DNA below 500, 000 copies/ml (a level that indicates the virus is being effectively controlled)
  • Normalisation of ALT (normal ALT enzyme level reflects normal function of the liver)
When all of the response criteria noted above are met, this is described as a "combined response."

Results in difficult-to-treat HBV Disease
  • In patients with low pre-treatment ALT ( 0- 2 x upper limit of normal), the combined response was achieved in 27% of patients treated with PEGASYS compared to 11% of patients treated with conventional interferon
  • In patients with high pre-treatment HBV DNA ( > log 8.5 HBV DNA), the combined response was achieved in20% of patients on Pegasys compared to 14% of patients treated with conventional interferon.
  • In patients with HBV genotype C, the combined response was achieved by 21% of PEGASYS patients compared to 6% of interferon patients.
The 194 patients in the study were treated with either conventional interferon three times weekly or PEGASYS (at 90 µg, 180 µg or 270 µg) once weekly for a 24-week-period, and were then observed with no further treatment over the subsequent 24 weeks.

In addition to this research effort, there are two phase III studies approaching completion. These studies explore the benefit of a longer duration of treatment (48 weeks) where it is postulated that even higher response rates may be achieved based on data with conventional interferon. These studies, which use the same 180 µg dose, will also explore the efficacy of combining of PEGASYS with lamivudine, a nucleoside analogue.
    New Hope for HBV Sufferers
    Currently, lamivudine, adefovir dipovoxil and conventional interferon alfa are the sole agents approved for the treatment of hepatitis B. However, these agents have clear limitations in terms of overall efficacy and about 20 per cent of patients treated with lamivudine develop resistance to the drug within one year of therapy. In addition, the majority of patients treated with lamivudine are required to continue therapy indefinitely. PEGASYS overcomes the limitations of current therapies; delivering higher efficacy within a defined treatment duration. Importantly, the hepatitis B virus is unlikely to develop resistance to PEGASYS.

    About Hepatitis B
    Hepatitis B is a blood-born virus that attacks the liver and is the most common serious liver infection in the world. The Hepatitis B virus is highly contagious and is relatively easy to transmit from one infected individual to another. It is 100 times more infectious than the HIV virus.

    Despite a highly effective vaccine, More than two billion people have been infected by HBV and 350 million people have chronic infection, which can be easily transmitted by blood-to-blood contact, during birth, sex, and by sharing needles. For those chronically infected with HBV, treatment is the only option. Hepatitis B is the ninth leading cause of death in the world; left unchecked, it can cause liver cancer and death.

    About PEGASYS
    PEGASYS, a new generation hepatitis C therapy that is different by design, provides significant benefit over conventional interferon therapy in patients infected with HCV of all genotypes. The benefits of PEGASYS are derived from its new generation large 40 kilodalton branched-chain polyethylene glycol (PEG) construction, which allows for constant viral suppression. PEGASYS also distributes more readily to the liver (the primary site of infection) than conventional interferon. PEGASYS is the only pegylated interferon available as a ready-to-administer solution. Each weekly subcutaneous injection contains 180mcg of pegylated interferon alfa-2a which is the recommended dose for all patients, regardless of body weight.

    PEGASYS has been approved for the treatment of chronic hepatitis C in more than 70 countries, including the European Union and the United States. The most recent approvals for PEGASYS have occurred in China and New Zealand.

    About Roche
    Roche is committed to the viral hepatitis disease area, having introduced Roferon-A for hepatitis B and C, followed by PEGASYS in hepatitis C and now PEGASYS is demonstrating similar superior efficacy over conventional interferon in hepatitis B. Roche has also launched its own brand of ribavirin, Copegus, to be used in conjunction with Roferon A or PEGASYS for HCV. Roche also manufactures HBV and HCV diagnostic and monitoring systems: The COBAS AMPLICORT Test, and the AMPLICORT MONITOR Test, two testing systems used to detect the presence of, and quantity of, HBV DNA or HCV RNA in a person's blood. Roche's commitment to hepatitis has been further reinforced by the in-licensing of Levovirin, an alternative antiviral. Levovirin will be studied with the objective of demonstrating superior tolerability over the current standard, ribavirin.

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Idenix Pharmaceuticals Presents Positive Hepatitis C And Hepatitis B Results-Positive data advance hepatitis C candidate into phase I/II trial and trigger start of phase III pivotal trial of telbivudine for HBV

Idenix Pharmaceuticals, Inc. today presented positive pre-clinical results of NM283, its hepatitis C virus (HCV) clinical drug candidate, at the 11th International Symposium on Viral Hepatitis & Liver Disease in Sydney, Australia. NM283, a ribonucleoside analog being developed as an oral, once-daily treatment, appeared to be well tolerated and after one week of treatment reduced mean viral load by over 90 percent (1 log10) in a primate model of human chronic HCV infection. Idenix also presented 24-week data from an ongoing phase IIb trial of telbivudine (LdT) for the treatment of hepatitis B virus (HBV) infection, further demonstrating its promising safety and antiviral efficacy. On the basis of these results, Idenix has advanced NM283 to phase I/II clinical development and initiated a phase III registration trial of telbivudine.

These data presentations follow Idenix's announcement in late March that it has entered into definitive agreements with Novartis Pharma AG, an affiliate of Novartis AG (NYSE: NVS), pursuant to which Novartis will acquire a majority equity interest in Idenix and will acquire rights to jointly develop and commercialize select Idenix drug candidates.

The NM283 preclinical study was conducted in a primate model with human-derived chronic HCV infection. NM283 was administered orally, once-daily for one week at either 8.3 or 16.6 mg/kg compared to placebo. HCV viral loads dropped rapidly in all treated animals after the first two days of dosing and fell further by day 7. Mean log10 viral load reductions at day 7 were 1.05 in the 16.6 mg/kg dose group and 0.83 in the 8.3 mg/kg dose group. In contrast, HCV titers were stable in the pre-treatment and placebo samples. NM283 appeared to be well tolerated throughout dosing. A phase I/II clinical trial of NM283 in patients with chronic hepatitis C is now underway, following the acceptance by the United States FDA of an Investigational New Drug Application.

"We believe that NM283 is the first small molecule antiviral agent shown to be effective in this primate model of chronic HCV infection", said David Standring, Ph.D., Idenix's Vice President of Biology. "These results suggest that further development of this potentially important new treatment for chronic hepatitis C is warranted."

The phase I/II clinical trial of NM283 will evaluate safety and antiviral activity in adults with genotype 1 HCV infection to determine optimal dosing levels of NM283 for future clinical trials. This short-term dose-escalation trial is being conducted at a number of sites in the United States.

    HBV Program - Telbivudine
    Data from an ongoing phase IIb clinical trial of telbivudine (LdT) for the treatment of chronic hepatitis B were also presented today by Ching-Lung Lai, M.D., Professor of Medicine at the University of Hong Kong and a principal investigator in this study. This randomized, blinded, international multicenter phase IIb clinical trial, in 104 adults with HBeAg-positive chronic hepatitis B, compares the safety and antiviral efficacy of telbivudine, and telbivudine in combination with lamivudine, to a control arm of lamivudine alone. All patients are being dosed orally, once-daily for a treatment period of 52 weeks.

    Average reductions in serum virus load were greater than 6 log10 for all trial groups receiving LdT, significantly greater than the 4.67 log10 reduction observed with lamivudine alone. Serum HBV became undetectable in twice as many patients receiving LdT monotherapy, compared with lamivudine monotherapy, as determined by a highly sensitive polymerase chain reaction (PCR) assay (32% and 16%, respectively). Within 12 weeks of treatment, 49% of patients receiving LdT monotherapy had normalized serum alanine aminotransferase (ALT), indicating reduced liver inflammation. By week 24, ALT had normalized in 75% of patients receiving LdT monotherapy. LdT treatments have been well tolerated, with no treatment-related or dose-limiting adverse events observed. Final 52-week phase IIb data are expected in the fall of this year.

    These promising data support the initiation of a large-scale international phase III clinical trial, currently underway. This pivotal registration trial, enrolling 1,200 patients worldwide, will evaluate the safety and efficacy of telbivudine compared with lamivudine, in patients with HBeAg-positive and HBeAg-negative compensated liver disease.

    Idenix recently announced that it had entered into definitive agreements with Novartis Pharma AG. Upon closing of the agreements, Novartis will acquire 51% of the issued and outstanding shares of Idenix and rights to jointly develop and commercialize Idenix's hepatitis B clinical drug candidates. Novartis will also have the option to acquire rights to Idenix's hepatitis C drug candidates.

    About hepatitis C:
    There are approximately 170 million people worldwide with chronic HCV infection, of which approximately 3 million are in the United States. HCV accounts for 30% of end-stage liver disease and liver cancer, 20% of cirrhosis cases and is the leading cause of liver transplant. Available treatment options are limited in their effectiveness and safety. Additionally, these therapies are less effective in patients infected with HCV genotype 1, a specific strain of HCV that is the most prevalent and most treatment-resistant HCV genotype found in the US, Japan and Western Europe.

    About hepatitis B:
    There are approximately 350 million people worldwide with chronic hepatitis B virus infection, of whom approximately 33% have potentially progressive and life-threatening liver disease associated with their chronic HBV infection. Chronic hepatitis B can lead to cirrhosis, liver failure and hepatocellular carcinoma (liver cancer). Globally, hepatitis B accounts for over one million deaths annually, making it the ninth leading cause of death worldwide.

    About Idenix:
    Idenix Pharmaceuticals is engaged in the discovery and development of selective and specific, small molecule drug candidates which may be administered orally, once-daily, alone or as components of combination drug therapy for infectious disease. The Company is headquartered in Cambridge, Massachusetts and has drug discovery operations in Montpellier, France and Cagliari, Italy. Idenix's current focus is on the treatment of infections caused by hepatitis B virus, hepatitis C virus and human immunodeficiency virus (HIV). For further information, please refer to http://www.idenix.com.

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April 10th, 2003

Impact of Diabetes and Obesity on Liver Histology in Hepatitis C

Body mass index is a predictor of both fibrosis and steatosis in HCV patients, find researchers in the March issue of Diabetes, Obesity and Metabolism (Diabetes Obes Metab 2003; 5(3): 150-55).

There is a recognized association between diabetes mellitus and HCV.

However, no study has examined whether there is an independent association between the degree of hepatic fibrosis and the incidence of diabetes in HCV patients.

In this study, researchers from Pennsylvania, USA, reviewed 264 consecutive patients with chronic HCV infection at a referral liver center, between 1991 and 1999.

The research team assessed patient's demographic background, medical history, and laboratory and liver biopsy results.

The researchers determined that the prevalence of diabetes was 16%.

They found that gender, intravenous drug use, steatosis scores, aminotransferase levels and iron studies were similar in patients with and without diabetes. However, mean age was higher in the diabetic group (49.8 years versus 44.3 years).

The team found that the prevalence of diabetes was substantially higher in African-Americans, and those with a BMI > 30.

The fibrosis score was higher in diabetics, however this association did not remain significant when diabetic risk factors were controlled for.

The researchers found that the degree of steatosis and fibrosis both increased with increasing BMI. Even after controlling for diabetes, age, gender, race, and current alcohol use, this association remained.

Dr Friedenberg's team concluded, "The prevalence of diabetes in our group of HCV patients was high, consistent with other studies".

"Diabetes is not an independent predictor of degree of fibrosis."

"Body mass index is an independent predictor of both fibrosis and steatosis in HCV patients."

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April 11th, 2003

Theory Links Hepatitis C to Polio Syringes in Italy
By Rossella Lorenzi

Poorly cleaned glass syringes used to administer the polio vaccine in the 1950s and 60s could have spread the hepatitis C virus from person to person in southern Italy, researches from Italy's National Cancer Institute) suggested this week.

The accidental spread of the virus might explain why southern Italy has a particularly high rate of the chronic liver disease, suggest Dr. Maurizio Montella and colleagues.

In the mid 1950s and 1960s, an injected vaccine known as the Salk vaccine was used to protect against the crippling disease polio. In southern Italy, reusable glass syringes were used to deliver the vaccine until the new oral version, known as the Sabin vaccine, was introduced in 1965. The authors' theory is that the syringes, if not properly sterilized, may have spread the hepatitis C virus.

Montella told Reuters Health Wednesday there was already some indirect evidence linking the glass syringes used for the older vaccine to high hepatitis C rates.

"The phenomenon is circumscribed to certain areas-where glass syringes were widely used, there is an increase of hepatitis C cases," he said.

To look closer at the link, he and others drew on a previous investigation that included a sample of 1,908 people aged 30 to 60 years.

The subjects were originally enrolled as healthy "controls" in another study. They were known not to have used intravenous drugs or to have had blood transfusions, both of which can spread the disease.

Tests showed that seven percent of men and five percent of women aged 40 to 49 years had antibodies to hepatitis C, suggesting infection with the virus. People born between the 1940s and early 1960s were nearly three times as likely as younger subjects to have the virus, they reported in this month's Journal of Medical Virology (Journal of Medical Virology 2003;70:49-50).

Overall, about six percent of older adults had been infected with the virus compared with about two percent of those aged 30 to 39.

The prevalence of hepatitis C is about 1.8 percent in the U.S. and ranges from 0.5 percent to nine percent in Western Europe.

"This is indisputable data, and it is linked to the years when the Salk polio vaccination was administered," Montella said. "The high rate of HCV is most likely attributable to a misuse and reuse of needles and glass syringes being inadequately sterilized."

Because chronic hepatitis C infections may not cause any symptoms, "it will be useful to inform the population of southern Italy about the implication to their future health," the authors write in the article.

About four million people in the United States and 150 million worldwide have hepatitis C, an infection of the liver that is spread by contact with blood and other body fluids.

About 20 percent of people infected with the virus will develop severe and potentially fatal liver damage, or cirrhosis, which in turn increases a person's risk of liver cancer.

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Body Piercing: Do So at Your Own Risk
By Amanda Gardner, HealthScoutNews Reporter

In the fall of 2000, seven Oregon youths were infected with a dangerous bacterium after having their upper ear cartilage pierced at a local mall. Five were hospitalized, and three others had to undergo reconstructive surgery to fix deformities in their ears.

The surprising thing was not that the youths, aged 10 to 19, became infected, but that the public even heard about the cases.

"A lot of people might encounter complications [from body piercing], but they're never counted," says Myrna Armstrong, a professor in the school of nursing at Texas Tech University in Lubbock.

Armstrong's research has revealed a 45 percent infection rate from navel piercing. And she's discovering even more problems with "high rim"-or ear cartilage-piercing.

Although it's notoriously difficult to track the complications resulting from this form of body art, interviews with experts indicate that problems are common and sometimes even life-threatening.

One person had a near-fatal hemorrhage requiring multiple transfusions as a result of a tongue piercing, says Dr. Lester B. Mayers, director of sports medicine at Pace University in Pleasantville, N.Y. Another person with a freshly pierced tongue contracted an infection that closed the airways and forced a lengthy hospital stay.

The risk of contracting hepatitis B or C is also very real, says Dr. Sandra Kemmerly, an infectious disease specialist at the Ochsner Clinic Foundation in New Orleans. Presumably, HIV transmission is a risk as well, she adds.

Despite the hazards, body piercing is increasingly popular.

An article in the February 2001 issue of the Journal of School Nursing found a 283 percent rise in the number of body art studios in Texas between 1994 and 1998.

And a survey by Mayers of 454 students found that 60 percent of female students had one or more piercings in places other than their earlobes, and 42 percent of males had piercings in their earlobes and elsewhere.

"We're talking about a very large number of people," Mayers says. "Even if it's a small percentage of complications that can be a large number because of the huge number of people who have the procedures."

Some of the most serious complications have resulted from tongue piercing.

"That's where we see the biggest problems," Kemmerly says. "I've seen cases that required antibiotics for long periods of time. The tongue was all swollen. The person couldn't eat. It was just gross."

The reason is the preponderance of bacteria that inhabit the mouth.

"We have provided a portal of entry for bacteria into the body," says Dr. Matthew Messina, a spokesman for the American Dental Association. "We've basically said, 'Come on in.' We've intentionally opened a wound and are not permitting it to heal, so find me a reason why this is good."

The American Dental Association has issued a statement opposing oral piercing. One reason: Infections can close off the airway, potentially resulting in death.

And don't forget damage to teeth, including chipping, fractures, gum abrasion and tartar and plaque build-up, the ADA says.

"In life we make decisions and balance the risks and benefits and this is a procedure with some serious and potentially life-threatening risks which I have yet to see a benefit to," Messina says.

Traveling south, the belly button is another area prone to infection. "It's close to the abdominal cavity," Kemmerly points out. "I've seen some nasty infections that required lancing-opening up the area and taking out the belly button ring."

The belly area also takes longer to heal from a piercing-some six to nine months, compared with two to three months in other areas, according to Mayers. And it's an intrinsically dirty area.

Ear lobes, of course, present fewer problems than other parts of the body. But ear cartilage is an entirely different story. Because this area doesn't have much of a blood supply, any infection that does develop will not heal as well or as quickly.

The Oregon case is instructive. Here, two things had gone wrong.

First, the cartilage had been pierced with spring-loaded "guns," which are prohibited for that use in many states, including Oregon. Second, the piercing booth, located within a mall, had inadequate sterilization procedures. One of the workers had sprayed the sterile gun with a commercial disinfectant that had the bacterium flowering in it.

Is there such a thing as safe body piercing?

"There is a way to do it right," Texas Tech's Armstrong says. "The biggest thing is to have a knowledgeable artist that is in a clean environment that is concerned about adhering to regulations."

The main rules: Don't do it yourself and don't go to the local mall.

"I would recommend the body piercing studios before I would even go to the mall," Armstrong says. "They have fewer problems because they're in the business of doing this as opposed to 14- and 16 year-old girls who are doing it in the mall with no training and no concern for what they're doing."

Which doesn't mean you're home free, even if you go the studio route.

"For a lot of people who get this now, there seems to be a sense of self-expression," Mayers says. "If you want to do it, you should do it with as little risk as possible. But there's nobody who can tell you there's no risk at all."

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Rapid Dosing Schedule of Hepatitis A/B Vaccine Effective
By Emma Patten

Immunizing against hepatitis A and B with a combined vaccine on an accelerated 21-day schedule may prove more effective than the current procedure, which takes six months, reported researchers.

Dr. Jane N. Zuckerman from the Royal Free Hospital School of Medicine, in London, UK, and collaborators presented their findings at the 10th International Symposium on Viral Hepatitis and Liver Disease (ISVHLD) in Atlanta, GA.

By performing a multi-center study, researchers investigated a total of 497 volunteers and assessed the immune response of those who had received a combined hepatitis A/B vaccine known as Twinrix(TM), given on a rapid 0,7- and 21-day schedule. They then measured the patients' immunoreactivity and compared them with a group who had received the hepatitis B vaccine Engerix(TM)-B on days zero, seven and 21 and the hepatitis A vaccine Havrix(TM) on day zero.

The researchers found that the rapid schedule yielded a strong immune response against hepatitis A and B and required fewer injections.

"Because we can administer this vaccine in only 21-days rather than six months, we can afford protection to travelers and others who may need immediate protection against hepatitis A and B." Dr. Zuckerman told Doctor's Guide.

Dr. Zuckerman hopes that this type of administration might be given as a post-exposure treatment against hepatitis A and B but cautioned that its use in this manner needs further investigation. "We have currently only examined this vaccine as a protective measure against hepatitis A and B," she explained.

"The combined antibody seems to be more effective than the administration of either antibody alone," she added. "We hope that, by the end of the year, the Twinrix(TM) vaccine will be licensed for use on the zero, seven and 21-day schedule."

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April 13th, 2003

Liver Fibrosis, a Complication of Hepatitis C Virus (HCV) Infection, Has Been Found To Progress In 33 Percent of Patients with Chronic Disease
By Emma Patten

This finding was reported researchers at the 10th International Symposium on Viral Hepatitis and Liver Disease, in Atlanta, GA, on Wednesday (April 12). Dr. Marc G. Ghany, of the National Institute for Digestive and Kidney Diseases (NIDDK), and colleagues examined 123 patients with chronic hepatitis C who had undergone at least two liver biopsies between 1981-1999.

The degree of fibrosis was categorized into four stages, ranging from no fibrosis to cirrhosis. Half of the patients with fibrosis developed a two- or three-point progression, leading to the clinically important stages of either bridging fibrosis or cirrhosis. Although fibrosis progressed in 33 percent of patients, fibrosis improved in 13 percent of the patients and showed no change in 54 percent.

Researchers used logistic regression to determine the contribution of a variety of factors that could cause the progression of fibrosis. Age at initial biopsy was the strongest predictor of progression of fibrosis. Other important factors included serum alanine aminotransferase (ALT) levels -- marker of liver inflammation -- and high level of fibrosis at beginning biopsy.

"I think that the take-home message is that the clinical parameters we used to assess patients show that there are predictors to measure when fibrosis is going to progress," Dr. Ghany told Doctor's Guide. "Patients with higher ALT and more inflammation are the ones that need therapy. One should also consider the age of the patient in question when prescribing therapy."

Dr. Ghany theorizes that increased fibrosis in older patients probably is due to increased stellate cell activity, a more vigorous response to infection, and an inability to turn the response off.

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April 14th, 2003

Schering-Plough Still Mum about Possible Role for Hassan
By Hollister H. Hovey

As expected, Fred Hassan, the Chief Executive of Pharmacia Corp., won't be playing second fiddle to Hank McKinnell, Pfizer Inc.'s Chairman and CEO who will keep his titles at the combined company.

After months of anticipation and regulatory delays, the Federal Trade Commission approved Monday the $57 billion merger of the two drug giants.

Wall Street never really expected Hassan to take the vice chairman position he was offered at the combined company. Instead, analysts have predicted, he would jump into the top spot at the beleaguered Schering-Plough Corp.

But Schering-Plough still remains mum about who will fill the chairman and CEO positions.

Hassan made his name by turning Pharmacia around, but he would have a steep uphill battle at Schering-Plough.

The Kenilworth, N.J. company is struggling to overcome the vast revenue falloff it has seen since it lost its patent protection on blockbuster allergy drug Claritin. The company now sells the pills over-the-counter, but that can't make up for its previous hold on the prescription market.

And exiting CEO Richard Jay Kogan, the man who basically triggered the direct-to-consumer marketing craze in the drug industry, has left the company under the very watchful eye of federal authorities.

In mid-March, the Securities and Exchange Commission notified the company it would recommend a civil action against the company and Kogan for allegedly leaking bad news to a small number of shareholders as much as three days before releasing it to the wider public.

The SEC has been investigating the matter since early October, when Schering-Plough stock plummeted 17% over three trading sessions with no public explanation from the company. At the end of the third day, the company issued a profit warning.

Kogan stepped down as chairman the next month, saying he would relinquish his position as CEO by the company's annual meeting scheduled for April 22.

That's not the end of the company's legal problems, though.

In late February, the company had to restate its fourth-quarter and 2002 earnings after boosting its litigation reserves by $150 million. The decision came as a result of "additional information" and a continuing review of the litigation.

The company said it was served with two additional grand jury subpoenas by the U.S. attorney for Massachusetts in November. The office has been investigating the company's sales, marketing and clinical-trial practices for its hepatitis C treatments Intron A and Rebetron, and brain-tumor treatment Temodar.

Schering-Plough is also one of several companies under investigation since 1999 by the U.S. attorney's office for the Eastern District of Pennsylvania. The government is investigating if drug makers provided pharmaceuticals at a deep discount or free to managed-care plans to ensure their drugs were on the health-management organizations' formulary, a list of drugs for which HMOs will reimburse.

Schering-Plough spokeswoman Denise Foy pointed to the company's annual report when asked about the company's plans to fill the positions.

"The search for a new chairman and CEO has progressed well and the Board of Directors hopes to be in a position to announce its outcome in the near future," acting Chairman Richard Osborne wrote in the letter to shareholders attached to the company's 2002 annual report filed with the SEC in March.

As early as December, McKinnell acknowledged that there was a good chance Hassan would depart. "He's one of the most attractive CEO candidates in the industry," McKinnell said at Pfizer's merger shareholder vote on Dec. 6. "We work extremely well together" and if he decided to take a position at another company, "we would wish him well and miss him."

Hassan didn't immediately return a phone call seeking comment.

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Simple Scoring System Can Help Identify Patients with Cirrhosis at Low or High Risk for Hepatocellular Carcinoma
hivandhepatitis.com

Increased knowledge of the risk factors associated with the appearance of hepatocellular carcinoma (HCC) could improve the efficacy of surveillance programs. In the March issue of Hepatology, R F Velįzquez and colleagues describe the development of a simple scoring system that can help detect early signs of HCC.

A total of 463 patients aged 40 to 65 years with liver cirrhosis in Child-Pugh class A or B were included in a program of early diagnosis. The predictive value of different risk factors was evaluated using the Kaplan-Meier method and Cox regression model.

Thirty-eight patients developed HCC. In the multivariate analysis, 4 variables showed an independent predictive value for the development of HCC: age 55 years or older, antibody to hepatitis C virus (anti-HCV) positivity, prothrombin activity 75% or less, and platelet count less than 75 × 103/mm3.

According to the contribution of each of these factors to the final model, a score ranging between 0 and 4.71 points was constructed to allow the division of patients into 2 different risk groups.

The low-risk group included those with a score of 2.33 points or less (n = 270; 4 with HCC; cumulative incidence of HCC at 4 years, 2.3%), and the high-risk group included those with a score greater than 2.33 (n = 193; 34 with HCC; cumulative incidence of HCC at 4 years, 30.1%).

In conclusion, a simple score made up of 4 clinical and biological variables allowed the investigators to distinguish 2 groups of cirrhotic patients at high and low risk for the development of HCC. They believe this score can be useful in establishing a subset of cirrhotic patients in whom a surveillance program for early detection of HCC could be unjustified.

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Hepatitis C Infection Linked to Type 2 Diabetes
By Emma Patten

Type 2 diabetes (diabetes mellitus) may be associated with hepatitis C virus (HCV) infection, according to researchers at the 10th International Symposium on Viral Hepatitis and Liver Disease (ISVHDL).

Shruti Mehta, a doctoral student at the School of Hygiene & Public Health, Johns Hopkins University, Baltimore, MD., and colleagues from the Johns Hopkins University, examined data from the third National Health and Nutrition Examination Survey (NHANES III), conducted between 1988-1994 in the US. Of the 9,841 subjects over the age of 20 who were assessed for diabetes and HCV infection, 1,242 (8.4 percent) had diabetes (type 1 and type 2) and 230 (2.1 percent) were anti-HCV positive.

After adjusting for factors such as age, race, and socioeconomic status, the researchers found that HCV-infected subjects were four times more likely to have type 2 diabetes than those without HCV infection (adjusted odds ratio 3.77; 95 percent confidence interval, 1.80-7.87).

They found no association, however, between HCV infection and type 1 diabetes. Similarly, they found no association between hepatitis B virus (HBV) infection and diabetes type 1 or 2.

Suggesting a cause for the association, Mehta told Doctor's Guide that "it might be a combination of factors that produce this association. Hepatitis C virus has been shown to replicate outside the liver and in the pancreas so it could be that HCV may be causing some concomitant beta cell dysfunction."

Mehta could not confirm whether the fact that diabetics have to inject themselves could cause HCV transmission or if HCV transmission caused beta cell dysfunction and, consequently, diabetes. "We're not sure what the mechanisms are or which condition causes which," she said.

"Providers should consider screening persons with one condition for the other since the adverse outcomes of each can be medically prevented," she added.

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April 15th, 2003

Intense Hunt Is On to Find Existing Drug That Works
By Andrew Pollack

With scientists almost certain they have found the virus that causes the respiratory infection known as SARS, a breakneck effort has begun to develop a vaccine and drugs to prevent and treat the disease.

Scientists at the United States Army's biodefense laboratory in Fort Detrick, Md., in cooperation with other federal agencies, are screening up to 2,000 approved and experimental drugs, including some cleared for use against other viral diseases, in hopes of finding medicines that will inhibit the growth of the virus in laboratory cultures.

If scientists can find a drug that has proved safe for humans, or at least one that has gone through animal toxicity testing, it would accelerate development of a drug to treat SARS, which stands for severe acute respiratory syndrome. Developing a drug from scratch would take years, experts said.

The genetic sequencing of the virus, which was completed over the weekend by Canadian scientists and yesterday by Americans, is also expected to provide many clues about how the armor of the virus can be pierced.

Scientists at the National Institute of Allergy and Infectious Diseases, meanwhile, are growing the virus in cultures with the aim of killing it to use in a first attempt at a vaccine. Killed viruses have long been used for vaccines because they prepare the body's immune system to be ready in case of an infection by the live virus.

''The quick and easiest one is the killed vaccine,'' said Dr. Anthony S. Fauci, the director of the institute. He said that while developing and testing a vaccine would take several more years, scientists should have an idea in about a year whether a vaccine might be feasible.

But scientists warn that many obstacles loom. The type of virus thought to cause SARS, a coronavirus, has never received serious attention from drug makers. ''I don't know anything that works for coronavirus right now,'' said Dr. Susan R. Weiss, a professor of microbiology at the University of Pennsylvania.

That is because the two human coronaviruses known until now cause only the common cold, and they are not even the main cause of that. ''People never got to corona because it's a minor player in causing colds,'' said Mark A. McKinlay, vice president for research and development at ViroPharma of Exton, Pa., which worked on a cold treatment aimed at a different virus.

Coronaviruses, named for their crown-like shape, cause serious diseases in many animals, and vaccines have been developed for some animal coronaviruses, but not without great difficulty.

''All of them don't work very well,'' said Dr. Niels Pedersen, professor of veterinary medicine at the University of California at Davis. The animal vaccines often do not provide strong immunity, and the virus can mutate so that some vaccines will not affect it, he said. Some vaccines developed for cat coronavirus actually made the disease worse, he said.

Nevertheless, Dr. Pedersen said, SARS might provoke stronger immunity in humans because it appears to invade the body more deeply than some of the animal viruses do, leading to a more powerful immune response. That would raise the prospects for a SARS vaccine.

One bright spot of the research so far is that the SARS virus grows well in cultures of cells derived from monkey kidneys. That makes studying the virus easier. Having an animal that becomes infected by the virus would also be useful for testing drugs and vaccines, so federal researchers are trying to determine whether they can infect animals like mice or monkeys.

Some experts say that is not likely because coronaviruses tend to infect only one species. The rat coronavirus does not even infect mice, said Dr. Kathryn V. Holmes of the University of Colorado, an authority on the viruses. Moreover, the freshly deciphered genetic sequence of the SARS virus shows that it is not very similar to other known coronaviruses.

As for treatments, doctors in Hong Kong, a center of the outbreak, reported last week in the The Lancet that the combination of steroids and the antiviral drug ribavirin appeared to help. But the Army biodefense lab found in its tests that ribavirin did not inhibit the replication of the SARS virus grown in the laboratory. And a spate of new deaths over the weekend in Hong Kong has dimmed enthusiasm for the treatment even there.

Alpha interferon, a drug used to treat hepatitis C, will be a ''prime candidate'' for clinical trials for a SARS treatment, Dr. Fauci said. In the mid-1980's, Dr. Ronald Turner, then of the University of Utah and now at the University of Virginia, found that alpha interferon, sprayed into the noses of volunteers, reduced symptoms when the volunteers were then exposed to a coronavirus that causes the common cold.

The interferon caused nasal irritation severe enough to make it unacceptable as a treatment for colds. But the side effects might be acceptable for a more serious disease like SARS, Dr. Turner said. However, it is ''pretty iffy'' that the approach would work against SARS, he said.

The government is also looking at other immune therapies, like extracting antibodies to the SARS virus from the blood of people who have recovered from the disease.

Scientists will also look for drugs that block crucial enzymes the virus uses for replication, like proteases. This approach has been successful in treating diseases like AIDS. The drugs used to treat those diseases are not expected to work on SARS because the enzymes are different, but the approach might be used.

In laboratory tests, cystatin C, a protease inhibitor found in human blood, blocks replication of the coronaviruses that cause colds, said Dr. Arlene Collins, associate professor of microbiology at the State University of New York at Buffalo. But it is unclear if it would inhibit the SARS virus, she said. Nor has cystatin C ever been tested for safety and efficacy as a drug.

AVI BioPharma of Portland, Ore., said its technology for turning off particular viral genes has been used to treat animals with other viral infections. Advanced Viral Research of Yonkers, said a drug it was testing for use against AIDS and other diseases should be tried for SARS.

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