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Alan Franciscus
Editor-in-Chief
May 15th, 2003
Combination Regimen Helps Quell Refractory Hepatitis C
Triple therapy for chronic hepatitis C using alpha interferon, ribavirin and amantadine may be effective in many patients who do not respond to alpha interferon alone, Italian researchers report in the May issue of Gut (Gut 2003;52;701-705).
Lead investigator Dr. Luigio E. Adinolfi told Reuters Health that although half of chronic hepatitis C patients do not show a response to interferon, "there are no recommended therapeutic options for these subjects, who remain at risk of progression of the disease."
Dr. Adinolfi and colleagues at the Second University of Naples studied 114 such patients, who were randomized to 3 treatment groups. All received interferon alpha 2b and ribavirin 1000 mg/day.
In the first group, the interferon dosage was 3 million units (MU) 3 times a week, the two other groups received 3 MU daily for the first 4 weeks and then 3 MU 3 times a week. The third group was also given oral amantadine hydrochloride 200 mg per day.
At the
end of the 12-month treatment period, the response was 25% in the first group, 29% in the second and 68% in the triple therapy group (p < 0.005). Follow-up, a year later, showed corresponding sustained responses to be 2%, 4% and 25% (p < 0.002).
The researchers, call for larger trials. Summing up, Dr. Adinolfi said the study demonstrates "that amantadine acts synergistically with interferon and ribavirin in chronic hepatitis C patients, who were non-responders to interferon alone, without any increase of side effects."
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MELD score predicts survival post-orthotopic liver transplantation
MELD score is a better predictor of 1-year patient survival in liver transplant recipients, than UNOS status, find researchers in the May issue of Liver Transplantation (Liver Transpl 2003; 9: 473-6).
The Model for End-Stage Liver Disease (MELD) is an important predictor in patients awaiting orthotopic liver transplantation (OLT).
However, the model's ability to predict post-transplant patient survival is unclear.
Patient survival was poorer with higher MELD scores.
In this study, researchers from Los Angeles, California, studied 1-year patient survival in 404 adults who had undergone OLT.
The team calculated survival hazard rates according to the MELD strata and United Network for Organ Sharing (UNOS) status, using Cox regression analysis.
Survival differences for MELD strata and UNOS status were also compared.
The team identified a significant difference in 1-year patient survival using different MELD strata.
They found an increased rate of death patients with higher MELD scores, and more urgent UNOS status.
Dr Sammy Saab's team concluded, "The MELD stratum is better associated with 1-year patient survival in liver transplant recipients than UNOS statuses".
"Patient survival was worse with higher MELD scores".
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May 16th, 2003
RNA Interference Inhibits HBV Replication in Vivo
By Karla Gale
Hepatitis B (HBV) viral RNA interference reduced the ability of HBV to replicate in mice, scientists in California report in the advance issue of Nature Biotechnology, published online May 12.
"We have worked for 10 years on gene therapies for hepatitis, and this is the first that I believe really looks promising," senior author Dr. Mark A. Kay of Stanford University School of Medicine, California, told Reuters Health.
RNA interference can inhibit viral replication in cell culture and target viral sequences in vivo, but thus far no one has shown the ability of this technique to prevent viral replication in vivo, Dr. Kay and associates explain.
When they transfected cultured human hepatoma cells with plasmids expressing one of seven short hairpin RNAs (shRNA) directed against sequences conserved among major HBV genotypes, all but one significantly reduced the amount of HBV surface antigen in culture. The most effective shRNA reduced antigen expression by 94.2% after 8 days.
The researchers transfected mice with the plasmid that most reduced HBV surface antigen in culture. In immunocompetent mice, treatment resulted in 77% less HBV RNA transcripts in liver compared to controls, while RNA was reduced 92% in immunocompromised mice. Treatment reduced replicated HBV DNA to undetectable levels.
The differences between immunocompetent and immunocompromised mice were "not substantial," Dr. Kay said. However, "there is the possibility of a synergistic effect between the host immune response and shRNA," he added.
In mice lacking B and T lymphocytes, plasmid treatment reduced serum levels of HBV surface antigen by 88% at day 4.
Dr. Kay said that he does not expect that an immune response would be generated to interfering RNA, and his group observed no obvious toxicity in plasmid-treated mice.
He suggested three possible scenarios for RNA silencing in hepatitis B infection. "In the best scenario, the body is purged of virus and cured." Another possibility is a significant reduction in viral load, "which may buy someone 20 or 30 more years before developing liver disease."
He also believes that combining RNA interference treatment with drug therapy would provide a synergistic effect.
"In theory, any viral disorder" could be treated in this manner, he added, noting that another research group is experimenting with RNA silencing for treatment of HIV.
He and his associates now plan to transfect small mammals using viral vectors instead of plasmids. If successful, "I think 2 to 3 years would be a reasonable time frame" for initiating phase I trials in humans.
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May 18th, 2003
Thailand's Drug War Could Mirror Iran's Failure
By Dominic Whiting
"The Thai government's drugs policy: drop dead."
Rojana, a heroin and methamphetamine addict at the age of 14 and a dealer at 15, says the slogan on her T-shirt mirrors the real fear among many Thais that a hard-line crackdown has targeted and killed the wrong people.
"People are scared. They're going after small-time dealers instead of solving the problem at the source," said Rojana, now in rehab, the bruises from injecting faded gray on her forearms.
Vowing to halt a yearly inflow of one billion methamphetamine pills from neighboring Myanmar, Prime Minister Thaksin Shinawatra, a former policeman, launched a 90-day anti-drugs crusade on Feb. 1.
The aim was to rid the country of the drug, called "ya ba" or crazy drug in Thai, on which an estimated 2.5 million Thai users spend $2 billion each year.
By the beginning of May, security forces had arrested 58,000 drugs traffickers and dealers, and the government had fired 1,300 civil servants suspected of involvement with them.
Authorities say 1,612 dealers and traffickers were killed over three months. Police say they killed only 37, in self defense, and attribute the rest to gang warfare.
Human rights groups are incensed by what they call a policy of extrajudicial killing. And groups campaigning for decriminalizing drug use say the violence is typical of anti-drugs pogroms around the world and is doomed to failure.
They advise the government to look at the case of Iran, which executed hundreds of dealers in the immediate aftermath of the 1979 Islamic revolution but later decided the policy was failing to cut drug abuse or HIV/AIDS infection among users.
Iranian security forces make about 75 percent of the world's opium seizures and have accounted for 50 percent of the heroin haul, at the cost of more than 3,300 police lives in the war against drugs since 1979.
But Iranian officials say traffickers will always find new ways to dodge crackdowns and protect a lucrative business, which supplies drugs to 1.5 million of Iran's 65 million people.
"Traffickers are up to date with government measures," Reza Sarrami, head of Iran's drug treatment policy, told Reuters at a recent conference in Chiang Mai, northern Thailand.
"If we work eight hours a day, they'll work 24 hours."
"Doing Our Job"
Destruction of opium poppy fields in Iran resulted in higher supply from Afghanistan. When transporting opium became more hazardous, use of its more lucrative and easily packaged refined form, heroin, shot up. And then came synthetic heroin. Drug purity fell as prices rose, bringing new health risks.
Thai police are spotting the same trends. They say the price of methamphetamines has quadrupled to about 300 baht ($7) a pill since February. Glue and benzene sniffing is on the rise, and more hard-core users, wanting a stronger fix to compensate for a jump in prices, are switching to heroin or injecting a mixture of heroin and much less soluble methamphetamine.
This will lead to more drug-related deaths and exacerbate the spread of viruses such as HIV/AIDS and hepatitis, groups working with drugs users say.
This realization persuaded Iran to change tack eight years ago. Now half its anti-drugs budget goes toward demand reduction.
Even the most conservative of Iran's religious leaders gave the green light to dispensing methadone, a synthetic drug less addictive than heroin, and pushing sales of sterile syringes.
Thailand, where involvement of Buddhist monasteries and community groups was held as a model for treating drugs users, is now going in the opposite direction, activists say.
"The crackdown has certainly resulted in the issue, and users, being forced underground, making it difficult to reach out to them," said Ton Smits of the Asian Harm Reduction Network, which works with drugs users.
The Thai government says it is promoting treatment alongside its get-tough policy on dealers. It says 285,000 drugs users have reported for rehabilitation since February.
But cases such as Rojana's serve to show the line between drug user and small-time dealer is blurred, critics argue.
Yet public backing has given the government confidence to brush off criticism of its heavy-handed measures.
"Human rights groups and non-government organizations are doing their own jobs and we're doing our job," government spokesman Sita Divari said.
"I think the Thai public believes in a drug-free Thailand and the government has been well supported."
One survey showed 90 percent of the population in favor of the crackdown. But many are torn. With so much pressure on security forces to produce results, seven out of 10 respondents feared arrest on trumped up charges.
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May 19th, 2003
Hepatitis C Recurrence after Liver Transplant Generally Mild, New Study Finds
By Martha Kerr
Austrian surgeons report that for patients who have undergone liver transplantation as a result of complications of hepatitis C virus (HCV) recurrence of infection is generally mild, asymptomatic, and clinically nonproblematic. The exception is with HCV recurrence of the cholestatic type.
At Digestive Disease Week 2003, Lukas Hinterhuber, MD, from the Department of Gastroenterology and Transplant Surgery at the University of Innsbruck, Austria, presented his center's findings of a group of 118 patients who underwent liver transplantation between March 1986 and March 2003. Of these, 84 patients were male, 34 were female, and mean age was 56 years. Mean donor age was 35 years.
Dr. Hinterhuber's team made a diagnosis of HCV recurrence on the basis of elevated aminotransferase levels and histological findings. HCV-RNA was detected in 114 (97%) of the 118 patients after transplantation. Histologic HCV recurrence was diagnosed in 64 patients (54%) at a mean of 22 months. HCV genotype 1 accounted for 75% of HCV recurrence, genotype 2 for 15%, genotype 3 for 8%, and genotype 4 for 3%.
Mild portal, lobular, or mixed hepatitis was most common. Cholestatic hepatitis developed in 12 patients, 9 of whom died. The incidence of cirrhosis with HCV recurrence was around 5%. Dr. Hinterhuber noted that data indicate a cirrhosis incidence closer to 30%. "We were surprised by our findings," he admitted in an interview with Medscape.
Except for the cholestatic type, HCV recurrence did not adversely influence patient and graft survival," the Austrian researchers noted in their presentation. Survival rates ranged from 83% at one year to a 10-year survival of 59%, Dr. Hinterhuber reported.
Meeting attendee Charles Kuckel, MD, commented that his experience at the University of Medicine and Dentistry of New Jersey in Newark has been much different. "We've had a lot of problems with post-liver transplant HCV recurrence. Ninety percent-plus are genotype 1. I don't know if this is a reflection of our inner city population. Also, the age of our donors was older-over 37 years of age."
Dr. Kuckel noted the higher percentage of living donors used by the Austrian team, which Dr. Hinterhuber said was around 25% to 30%. "We use cadaveric donors almost exclusively," Dr. Kuckel told Medscape. "That makes a very big difference. You don't know the history [of the donor]. You're just handed the liver. With a living donor, you can test for everything."
On the other hand, "you take every liver you can get," Dr. Kuckel said. "You don't get too caught up in risk factors. Donor age may play a role [in HCV recurrence], but you take the liver anyway."
DDW 2003: Abstract S1167. Presented Sunday May 18, 2003.
Reviewed by Gary D. Vogin, MD
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InterMune Announces Interim Data Showing High Early Virologic Response to Infergen
in Peg-Interferon Non-Responders with Chronic Hepatitis C: 24-week Data Supports Potential Antiviral Efficacy,
Tolerability in Difficult-to-Treat
InterMune, Inc. announced today that interim 24-week data showing high early virologic response rates in a clinical
trial of daily dosing and induction dosing regimens of Infergen(R) (interferon alfacon-1) in chronic hepatitis C
patients non-responsive to pegylated interferon and ribavirin combination therapy (non-responders) were presented
at the Digestive Disease Week (DDW) 2003 conference in Orlando, Florida.
Researchers reported the interim data showed that more than half (52%) of the non-responders subsequently
responded to treatment, which included 27 micrograms daily interferon alfacon-1 monotherapy for 4 weeks,
followed by 20 weeks of daily combination therapy with lower doses of interferon alfacon-1 plus ribavirin. The
patients in the trial will continue on combination therapy for an additional 24 to 64 weeks.
"These interim data indicate the potential of interferon alfacon-1 to effectively clear the hepatitis C virus in these
difficult-to-treat non-responders, who were predominantly patients with genotype 1 HCV and high viral load," said
Dr. Stephan Kaiser of the University Hospital of Tubingen, Germany, lead principal investigator of the trial, who
presented the data at DDW. "In addition, both the daily dosing and induction dosing regimens were moderately well
tolerated. If the encouraging early antiviral response rates seen in this interim analysis translate into
correspondingly strong sustained antiviral response rates, interferon alfacon-1 may become the foundation for
optimal management of these non-responding patients."
"Over 50% of HCV patients fail standard-of-care treatment with pegylated interferons and ribavirin, and the growth of
this patient population is expected to outpace that of treatment-naive, chronic hepatitis C patients by the end of the
decade. Further, past clinical studies on the use of the combination of pegylated interferons and ribavirin for
re-treatment of non-responders to standard-of-care treatment have demonstrated only limited therapeutic efficacy,"
said James E. Pennington, M.D., InterMune's Executive Vice President of Medical and Scientific Affairs. "These
interim data, which corroborate previous studies showing interferon alfacon-1 provides a high antiviral response in
difficult-to-treat non-responders, could be very important in helping to meet this growing unmet medical need and
large market opportunity. Because the interim data show both high and early virologic response, it is our hope that
these patients will attain a sustained virologic response."
Results Review
A randomized, open-label trial was conducted in 50 chronic hepatitis C patients who were non-responders to prior
combination therapy with pegylated interferon and ribavirin. Two-thirds of the patients in the trial had failed
treatment with pegylated interferon alpha-2b, and one-third of the patients had failed therapy with pegylated
interferon alpha-2a. More than 90% of the patients in the trial were infected with HCV of genotype 1 or 4, which are
the most difficult to treat genotypes. Over 70% of the patients in the trial had high baseline levels of HCV RNA (viral
load ) 8.5 X 10(5) IU).
Patients on the daily dosing regimen received 9 micrograms interferon alfacon-1 daily for 4 weeks, followed by a
daily combination of 9 micrograms interferon alfacon-1 plus ribavirin for 20 weeks. Patients on the induction dosing
regimen received 27 micrograms interferon alfacon-1 daily for 4 weeks, then a daily combination of 18 micrograms
interferon alfacon-1 plus ribavirin for 12 weeks, followed by a daily combination of 9 micrograms interferon alfacon-1
plus ribavirin for the next 8 weeks. The patients in the trial will continue on combination therapy for an additional 24
to 64 weeks, depending on progress and whether they were assigned to the daily dosing or induction dosing
regimen.
The efficacy endpoints for this trial include: (a) the effects of initial treatment with interferon alfacon-1 on the level of
HCV RNA in serum; and (b) the ability of the combination of interferon alfacon-1 and ribavirin to render the level of
HCV RNA in serum undetectable at 24 weeks after the cessation of therapy. Antiviral efficacy was evaluated by
PCR measurement of concentrations of HCV RNA in serum. The interim analysis consisted of examination of HCV
viral load at 8 and 24 weeks and evaluation of safety data.
At week 8, an antiviral response consisting of a negative PCR result (i.e., undetectable HCV RNA) in serum was
observed in 20% (6/30) and 27% (8/30) of patients treated with the daily dosing and induction dosing regimen,
respectively. At week 24, an antiviral response consisting of HCV RNA undetectable by PCR in serum samples
was observed in 40% (10/25) and 52% (14/25) of patients treated with the daily dosing and induction dosing
regimen, respectively.
Both the daily dosing and induction dosing regimens of interferon alfacon-1 were found to be safe and moderately
well tolerated. Adverse events were consistent with past experience in clinical trials and included myalgia, fatigue
and headache. The laboratory abnormalities observed in the first 24 weeks of therapy were also consistent with
those observed in past Infergen clinical trials, with no reports of grade 4 neutropenia and grade 3/4
thrombocytopenia reported in only one patient.
About Chronic Hepatitis C
Over 4 million individuals in the United States have been exposed to the hepatitis C virus. More than 200,000
patients in the United States are treated annually for hepatitis C infection. The prevalence of chronic hepatitis C, a
serious disease, is increasing.
About Infergen
(R)
(interferon alfacon-1)
Infergen(R) is a bio-optimized type 1 interferon alpha indicated for treatment of adult patients with chronic HCV
infections. Infergen(R) 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. The most common side effects are flu-like
symptoms (i.e. headache, fatigue, fever, myalgia, and rigors). Physicians and patients can obtain additional
prescribing information regarding Infergen(R), including the product's safety profile, by visiting
http://www.infergen.com/, including the black box warning for all interferon alphas regarding psychiatric,
autoimmune, ischemic and infectious disorders.
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
http://www.intermune.com/.
Except for the historical information contained herein, this press release contains certain forward-looking
statements that involve risks and uncertainties, including without limitation the statements indicating that: (i) these
interim data indicate the potential of interferon alfacon-1 to effectively clear the hepatitis C virus in these
difficult-to-treat, non-responders, who were predominantly patients with genotype 1 HCV and high viral load; (ii) if
the encouraging early antiviral response rates seen in this interim analysis translate into correspondingly strong
sustained antiviral response rates, interferon alfacon-1 may become the foundation for optimal management of
these non-responding patients; (iii) growth in the population of patients who are non-responsive to standard-of-care
treatment is expected to outpace that of treatment-naive, chronic hepatitis C patients by the end of the decade; (iv)
these interim data, which corroborate previous studies showing interferon alfacon-1 provides a high antiviral
response in difficult-to-treat non-responders, could be very important in helping to meet this growing unmet medical
need and large market opportunity; and (v) because the interim data show both high and early virologic response, it
is hoped these patients will attain a sustained virologic response.
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Asian Americans at High Risk for Hep C Liver Cancer
By E. J. Mundell
Asian Americans infected with the hepatitis C virus have four times the risk of developing liver cancer compared
with U.S. whites at a similar stage of infection, according to a new study.
Hepatitis C, which can be passed through tainted blood transfusions, dirty needles or sexual contact, is a leading
cause of liver cancer, accounting for 50 percent of new liver cases in the U.S., according to Dr. Mindie Nguyen of
the University of California, San Francisco.
Nguyen, who presented her findings here Sunday at the Digestive Disease Week conference, said other studies
have shown especially high rates of liver cancer in minority populations, especially Asians and blacks.
Her team focused specifically on 496 San Francisco-area patients with hepatitis C whose infection had resulted in
cirrhosis, a disease characterized by scarring of the liver.
Taking ethnicity into account, the researchers looked back at each patient's medical records, comparing the race
of those who developed liver cancer with those who did not.
According to Nguyen, Asian Americans "had significantly higher risk for liver cancer as compared to the Caucasian
group."
Asian Americans infected with hepatitis C had four times the risk of developing cancer compared to white patients,
even after factoring in age, gender, and severity of liver disease, she said.
The reason for this disparity remains unclear. One reason could be overall duration of hepatitis C infection.
Hepatitis C can be a "silent killer," causing little or no symptoms for years while it begins its slow assault on the
liver.
According to Nguyen, "many Asian patients may have been infected during childhood, so at a similar age as a
Caucasian patient they may have been infected for 20 or 30 years longer."
Other factors, such as co-infection with hepatitis B (another liver cancer risk factor), drinking and smoking rates,
and access to health care, may also play a role. Nguyen said a new study, one that follows patients over time, is
already underway to investigate these factors.
Finally, genetics could be key in rendering Asian American more vulnerable to hepatitis C-linked liver cancer.
Nguyen said she believes "a comparative genetics study of liver cancer in an ethnically and racially diverse
population is also needed."
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May 20th , 2003
Study Shows Liver Complications in Chronic Hepatitis C Associated With Obesity, Especially Around the Abdomen
Patients with chronic hepatitis C who are overweight or obese-especially in the abdominal area-are at increased
risk for having fatty liver (steatosis) and a more serious condition called nonalcoholic steatohepatitis (NASH), but
the presence of steatosis does not impact the effectiveness of treatment with PEG-INTRON. (peginterferon alfa-2b)
Powder for Injection in combination with REBETOL. (ribavirin, USP) Capsules, according to findings(i) presented at
the 2003 Digestive Disease Week (DDW) conference.
"This is the first time that abdominal obesity has been shown to be associated specifically with NASH in chronic
hepatitis C, and the findings suggest body weight management can be important in reducing the risk of these
serious complications," said lead investigator Zobair Younossi, M.D., director, Center for Liver Diseases and
medical director, Liver Transplant Program, Inova Fairfax Hospital, Falls Church, Va. He noted the findings were
especially relevant, given that about two-thirds of Americans are overweight or obese(ii) and prevalence rates
continue to rise(iii). Abdominal obesity is more common in men and generally recognized as being associated with
greater health risks(iv). "Although the extent of steatosis didn't affect the efficacy of PEG-INTRON and REBETOL
combination therapy, higher grade steatosis and superimposed NASH were certainly associated with having more
advanced liver disease," Younossi said. He also noted that while the study showed that the presence of NASH had
no significant effect on efficacy, the number of patients with hepatitis C and NASH in the study was too small to
draw definitive conclusions.
The study found that patients with NASH, with steatosis or with neither condition had the greatest to least degree,
respectively, of obesity, abdominal obesity, advanced fibrosis or prevalence of hepatitis C virus (HCV) genotype 3.
PEG-INTRON and REBETOL combination therapy is the market-leading HCV therapy in the United States and is
indicated for the treatment of chronic hepatitis C in patients with compensated liver disease who have not been
previously treated with interferon alpha and are at least 18 years of age. More than 250,000 hepatitis C patients
worldwide, including 150,000 U.S. patients, have received this combination therapy since its introduction in 2001.
Hepatic steatosis occurs with obesity, diabetes mellitus, poor diet, heavy alcohol use and certain illnesses, and is
diagnosed when fat makes up at least 10% of the liver. Hepatic steatosis is also more common with infection by
HCV genotype 3 than other genotypes.
NASH differs from simple steatosis in that fat accumulation is accompanied by inflammation, which damages liver
cells. Not connected with other causes of chronic liver disease (e.g., hepatitis), NASH can result in the
development of nonfunctioning scar-like tissue in the liver (fibrosis) in up to 40% of patients and cirrhosis in 5-10%
of patients(v). When NASH occurs along with hepatitis C, it is often referred to as "superimposed NASH."
Study Details
The
study examined the relationship of hepatic steatosis and superimposed NASH with patient body weight and other
clinical and demographic factors and with hepatitis C treatment outcomes. It included 119 patients who had completed
a PEG-INTRON treatment regimen (PEG-INTRON 1.5 mcg/kg/week, REBETOL and amantadine 200 mg/day
for four weeks, followed by PEG-INTRON 0.5 mcg/kg/week and the other therapies at the same dosage for another
20 weeks). Patients with undetectable HCV RNA ( < 50 IU/mL) at week 24 continued the second regimen
for another 24 weeks, and were monitored for an additional 24 weeks after treatment was complete. Patients with
undetectable HCV RNA after the 24-week follow-up period were considered to have achieved a sustained virologic
response (SVR).
Additional PEG-INTRON Studies Presented at DDW
Results of more than 20 additional PEG-INTRON clinical studies were presented at DDW involving a broad range of
HCV patient populations with disease characteristics that make them more difficult to treat successfully, including
relapsed patients or those who did not respond to previous alpha interferon therapy, cirrhotic patients, patients who
have undergone liver transplantation and patients with HCV-HIV coinfection. One study showed that psychiatric
intervention resulted in 100% adherence to PEG-INTRON and REBETOL combination therapy(vi). These findings
are encouraging because depression and other psychiatric side effects of interferon therapy are fairly common and
can result in patients discontinuing therapy.
"The numerous clinical studies with PEG-INTRON and REBETOL reported at this year's DDW conference reflect
Schering-Plough's ongoing commitment to developing improved treatments for patients with hepatitis C," said
Robert J. Spiegel, M.D., senior vice president of medical affairs and chief medical officer, Schering-Plough
Research Institute. "This research, along with the many ongoing PEG-INTRON studies in chronic hepatitis C, will
provide the medical community with a better understanding of the disease and the factors that affect patient
response to treatment."
Commitment to Hepatitis C Patients
Schering-Plough is the worldwide leader in the innovation, manufacture and sales of interferon-based therapies for
hepatitis C, and is committed to supporting hepatitis C patients in the United States with education and service
programs as well as financial assistance for patients in need. The company's U.S. patient assistance programs are
among the most comprehensive in the industry, providing support and guidance to patients during treatment, and
ensuring that all eligible patients have access to the company's HCV products.
Twenty-five percent of all hepatitis C patients in the United States currently treated with PEG-INTRON are enrolled
in the company's Commitment to Care program, which provides access to therapy and/or reimbursement
assistance for eligible patients. The market value of assistance and product 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 educate patients
about managing the side effects associated with HCV therapy
through the use of educational materials and telephone contact
with trained nurses skilled in the management of HCV.
References
i Younossi ZM, McCullough AJ, Ong JP, Barnes DS, Post A, Mullen KD, Carey W, O'Shea R, Levinthal G,
Gramlich T, Martin LM, Bringman D, Tavill AS, Ferguson R. Interaction of steatosis and non-alcoholic
steatohepatitis (NASH) with chronic hepatitis C. Poster presentation (Abstract No. M1388) at Digestive Disease
Week, Orlando, Fla., May 17-22, 2003.
ii Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999-2000.
JAMA Oct. 9, 2002; 288(14):1723-1727.
iii National
Center for Chronic Disease Prevention and Health Promotion.
U.S. Obesity Trends 1985 to 2001. (Behavioral Risk Factor
Surveillance System [BFRSS] data).
www.cdc.gov/nccdphp/dnpa/obesity/
trend/maps/index.htm
iv National Institutes of Health, National Heart, Lung and Blood Institute. Clinical guidelines on the identification,
evaluation, and treatment of overweight and obesity in adults: The evidence report. NIH publication No. 98-4083,
September 1998.
v American Liver Foundation. Liver Health Information: What is NAFLD/NASH? (Nonalcoholic Fatty Liver
Disease/Nonalcoholic Steatohepatitis). www.liverfoundation.org. Accessed May 12, 2003.
vi Moss J, Chandra A, Gaglio P, Hafliger S, Dove L, Lobritto S, Jacobson I, Brown R. Aggressive psychiatric
intervention based on clinical suspicion, not standardized depression scores, increases adherence to pegylated
interferon and ribavirin therapy for hepatitis C. Oral presentation (Abstract No. 216) at Digestive Disease Week,
Orlando, Fla., May 17-22, 2003.
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May 21, 2003
Harvard Researchers 'Building' New Livers in Lab
Martha Kerr
Past efforts to engineer new livers have received the most effort, money, and time, and achieved the least success,
a Harvard researcher told attendees of Digestive Disease Week here. But investigators in the laboratory of Joseph
P. Vacanti, MD, now appear to be making progress.
In other tissue and organ engineering projects, a biodegradable scaffold supports new cell growth until the cells are
able to divide, communicate, and form new tissue, which in turn triggers the development of a supporting
vasculature. This approach has worked in the growth of new bone, arteries, heart valves, intestines, and bladders,
said Dr. Vacanti, professor of surgery at Harvard Medical School in Boston, Massachusetts. However, in "growing"
a new liver, he has had to reverse the process.
"We are having to build the microcirculation first," Dr. Vacanti said. In collaboration with engineers at
Massachusetts Institute of Technology, Dr. Vacanti and colleagues have developed a computer model of blood flow
in the liver, based on computer microchips. The blood vessel pattern, which resembles the grid formation of a
microchip, is imprinted on a polymer. The channels are lined with endothelial cells. The polymers are then stacked
and connected together. Dr. Vacanti showed video clips in which blood cells can be seen moving through the
vasculature.
Once this technology is mastered, the investigators can move forward with growing the rest of the liver. "We've
always relied on angiogenesis in tissue engineering," Dr. Vacanti told Medscape. "This doesn't work with the liver."
Efforts to develop engineered intestines are also proceeding, Dr. Vacanti said. Engineered esophagi, jejunums, and
colons, grown on tubular degradable polymers, are showing angiogenesis and some neurogenesis. Motility is
present although dysfunctional, Dr. Vacanti reported.
Dr. Vacanti pointed to the importance of this field of research, given the acute shortage of donor organs. "Twenty
million people a year could benefit," he told meeting attendees.
DDW 2003: Society for Surgery of the Alimentary Tract, Plenary Session, Sp 632. Presented May 21, 2003.
Reviewed by Gary D. Vogin, MD
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Hopkins Researchers Find Potential New Treatment for Children with Chronic
Hepatitis C
Researchers from the Johns Hopkins Children's Center and five other institutions have found that a drug recently
approved for adults with chronic hepatitis C (CHC) also may be a safe and effective treatment for children with the
disease. The study is believed to be the first to examine how the drug, peginterferon alfa-2a, affects the young.
The hepatitis C virus (HCV), the leading cause of liver disease in the United States, is responsible for an estimated
10,000 to 12,000 deaths annually. It is spread primarily by contact with blood and blood products. Blood
transfusions and the use of shared, unsterilized, or poorly sterilized needles and syringes have been the main
causes of the spread of the virus in the U.S. among adults.
Presented today at the Digestive Disease Week conference, the findings could change the way doctors treat
children with CHC, according to the study's lead author, Kathleen B. Schwarz, M.D., director of the Division of
Gastroenterology and Nutrition at the Children's Center.
"At present, there is no FDA (news - web sites)-approved treatment for children 18 years old and younger with the
disease. Our results provide a basis for conducting a large-scale, randomized controlled trial to test this new form
of interferon alone, or in combination with ribavirin, an antiviral medication, which is the current treatment of choice
for adults with CHC," she said. "Such a study will be necessary before the Food and Drug Administration can
approve the drug for children."
Some children with CHC have been treated with three shots a week of interferon to increase the amount of the
naturally occurring infection fighter. Peginterferon alfa-2a is a new, longer acting version that, when taken weekly,
maintains interferon levels in the blood for a longer period of time. The drug also has been shown more effective in
adults with CHC than standard interferon.
In the multi-center study, 14 pediatric patients with CHC were given peginterferon alfa-2a once weekly for 48
weeks. No serious side effects were observed, and 43 percent of the children treated were free of the virus 24
weeks after the treatment ended.
"Thanks to screening programs for blood donors, transfusion-acquired HCV is now very rare. However, new
pediatric cases continue to occur through maternal-fetal acquisition," said Schwarz. "There are approximately
150,000 children in the U.S. with CHC, and this new approach to treatment offers hope to both the children
suffering from this infection and their worried families."
This study was sponsored by Hoffmann La Roche Inc., manufacturer of peginterferon alfa-2a (40KD) (Pegasys.).
The Digestive Disease Week conference was sponsored by the American Association for the Study of Liver
Diseases, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy, and the
Society for Surgery of the Alimentary Tract.
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Lamivudine and Combination Therapy for Interferon Nonresponders
Lamivudine treatment for 52 weeks is as effective in interferon nonresponders as in treatment-naive patients, finds a
research team from the United States.
Lamivudine is effective in treatment-naive patients with chronic hepatitis B. However, its role in interferon
nonresponders has not been described.
In this study, researchers assessed lamivudine, with or without interferon, in patients with hepatitis B e antigen
(HBeAg)-positive chronic hepatitis B who had failed interferon therapy.
Their findings are published in the June issue of the Journal of Hepatology (J Hepatol 2003; 38(6): 818-26).
The team randomized 238 patients to either lamivudine (100 mg), or placebo, for 52 weeks, or to a 24-week
regimen of lamivudine plus interferon.
They compared treatments at week 52, and followed-up patients over a 16-week post-treatment period.
Histologic response:
- lamivudine = 52%
- combination = 32%
- placebo = 25%
The team measured histology, HBeAg response, normalization of alanine aminotransferase, reduction of hepatitis
B virus (HBV) DNA, and safety.
The researchers found that histologic response was more common in patients treated with lamivudine (52%), or the
combination regimen (32%), than the placebo (25%).
Furthermore, HBeAg loss was more common with lamivudine (33%), compared with the combination treatment
(21%) or the placebo (13%).
Virologic and alanine aminotransferase responses were also better with the lamivudine therapy.
The team found that among 28 subjects with HBeAg loss/seroconversion, 71% had durable responses 16 weeks
post-treatment.
Dr Eugene Schiff's team concluded, "Lamivudine for 52 weeks is as effective in interferon nonresponders as in
previously reported treatment-naive patients".
"However, a combination of lamivudine for 24 weeks and interferon for 16 weeks was not effective in this
population".
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Jazz Legend Drums Up Hepatitis C Awareness
By Dann Denny
When jazz legend Otis "Killer Ray" Appleton was diagnosed with hepatitis C in 1999 during a routine blood test, he
felt as if he'd been sucker-punched.
"I didn't see it coming," said the 62-year-old Appleton, who will perform Thursday at Bear's Place in Bloomington. "I
was already dealing with having my leg amputated, so it really tore me up inside. I thought, 'Here we go again.'"
Appleton, a longtime diabetic, had lost his left leg on New Year's Day, 1998. Now, he was listening to the doctor
tell him he had an advanced case of hepatitis C-a life-threatening viral infection of the liver.
A liver biopsy revealed the hepatitis C had led to cirrhosis, a permanent scarring of the liver that hinders its ability
to function.
When Appleton learned hepatitis C is a blood-borne ailment often transmitted when intravenous drug users share
needles or when cocaine users share straws, he didn't have to ponder long to realize how he'd probably contracted
the disease.
"In my younger days as a traveling musician, I partied pretty hard and used a variety of drugs," he said. "I was
running around with people much older than I was, which was a mistake. That's what led to my drug use."
Appleton, who's been drug-free for 19 years, says the reason he speaks openly about his history with drugs and
their dire consequences in his life is to persuade young people to shun them.
"They're all poison," he said. "I would beg young kids not to take drugs of any kind. Hepatitis C is just one of many
diseases you can get from using them."
But hepatitis C is among the most prevalent. The federal Centers for Disease Control and Prevention says roughly
2 percent of the American population - 4 million people are infected with the virus, making it the most common
chronic blood-borne infection in the United States.
In Indiana, 5,512 people tested positive for hepatitis C in 2001, 63 of whom lived in Monroe County. But only 1 of
the 5,512 had an acute case of hepatitis C, in which the disease has progressed to the point of causing severe liver
damage and other complications.
The rest were chronic carriers of the virus, who have no symptoms or less severe symptoms, but can transmit the
virus to others.
Blacks have the highest rate of hepatitis C in the United States. The CDC says nine of every 100 black males
between the ages of 40 and 49 are infected with the hepatitis C virus.
Hepatitis C is often referred to as the "silent epidemic," because some people are not aware of any symptoms until
10 to 20 years after being infected.
By the time symptoms such as weight loss, aching joints and fatigue first surface, victims have not only suffered
extensive liver damage but have infected countless others with the virus.
Because of this, Appleton urges people in high-risk categories intravenous drug users, hemophiliacs and those
practicing unsafe sex to get a blood test that detects the presence of antibodies to the virus.
Though there is no vaccine or cure for acute cases of hepatitis C infection, there are a variety of treatments.
"But when I was diagnosed, I refused to be treated," Appleton said. "I was still learning to walk with my prosthesis,
and that's all I could deal with at that time in my life."
Appleton refused treatment for two years. During that time, he did not play any music. He felt physically drained,
and his stomach swelled up like a beach ball.
Then, in 2001, he decided it was time to take action. He enrolled in a clinical trial at North General Hospital in New
York City.
In the trial, he was treated with a combination therapy recently approved by the U.S. Food and Drug
Administration. It involved taking Pegasys, a long-lasting form of interferon, plus an antiviral called Copegus.
"I just took one shot a week, plus three pills in the morning and three more at night," he said. "After 50 weeks, the
disease was gone."
Today, Appleton says, he feels great physically and emotionally. "I no longer have that disease hanging over my
head," he said. "To know that I've beaten it makes me feel free."
Now working with a new band and living in New York City, Appleton says he's playing the drums as well as he ever
has.
"I'm feelin' good and I want to keep playing for some time," he said. "I'm not finished yet."
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May 22nd, 2003
VA Health System Makes Headway in HCV Testing of HIV+ Patients
The U.S. Department of Veterans Affairs (VA), recently identified hepatitis C virus (HCV) as a high-priority for
improved detection and management among patients with HIV infection. According to a new study, the VA has
made considerable progress in detection, but much less so in disease management.
Dr. Shawn L. Fultz from the VA Pittsburgh Healthcare System and colleagues examined testing, referral, and
treatment patterns for HCV coinfection in a cohort of 881 veterans with HIV infection attending one of three VA
medical centers. Forty-three percent were coinfected with HCV.
"Although VA healthcare providers appear to be testing most HIV-positive patients (80%) for HCV and are making
efforts to address contraindications to antiviral treatment, very few patients are receiving antiviral therapy," they
report in the April 15th issue of Clinical Infectious Diseases.
"Further, providers are largely unaware of current illicit drug and alcohol use and depression among their
HCV-coinfected patients," they write.
Specifically, the team found that 30% of coinfected patients reported current alcohol use, which is known to
accelerate the course of HCV, increase the risk of hepatocellular carcinoma and is a contraindication to antiviral
therapy. Many physicians were unaware of their patients drinking habits and only one third of coinfected patients
were counseled to reduce or quit drinking. Similar results were found for illicit drug use.
HCV/HIV-coinfected patients with indications for HCV therapy had a high rate of contraindications for antiviral
treatment, including both medical and psychiatric comorbidities, a finding that confirms prior studies. (See Reuters
Health report January 16, 2003.)
Of the 65 patients with indications for HCV therapy and no contraindications, only 18% underwent liver biopsy and
only 3% received interferon.
The VA's emphasis on HCV infection make it a potentially "valuable laboratory in which to study current
management issues and remaining barriers to treatment of coinfected patients," Dr. Fultz and colleagues write.
Clin Infect Dis 2003;36:1039-1045.
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Roche Inks $230 Million Deal with Maxygen
By Ransdell Pierson and Jon Cox
Roche Holding said on Thursday it had struck a $230 million deal with U.S. biotech firm Maxygen Inc. to develop
hepatitis drugs, using Maxygen's technology that shreds genes and then recombines them into new genes with
altered properties.
Shares of Maxygen closed up more than 19 percent, making it one of the biggest gainers on the Nasdaq on
Thursday. Roche AG (ROCZg.VX) rose more than 3 percent after news of the Swiss drug maker's latest alliance
with a small biotech.
Under the deal, Maxygen will attempt to develop more-effective forms of alpha interferon, an immune system
protein that is the active ingredient of Roche and Schering-Plough Corp. drugs used to treat the hepatitis C and B
viruses and a variety of cancers.
The Redwood City, California-based biotech will also try to develop improved forms of beta interferon, the active
ingredient of drugs sold by Pfizer Inc. and Biogen Inc. to treat multiple sclerosis.
Maxygen has previously formed partnerships with privately held Danish drugmaker Lundbeck and Brisbane,
California-based InterMune Inc. to develop altered forms of interferon.
But its deal with Roche is far broader, giving the firms the option to also develop other alpha and beta interferons
against cancer, autoimmune diseases, inflammatory diseases and infectious diseases like HIV.
Maxygen will receive an initial payment and full research and development funding from Roche for the first two
years of the collaboration as well as option fees. It is also eligible for milestone payments and royalties based on
product sales. Total payments could exceed $230 million, plus royalties.
Hepatitis treatment is a key part of Roche's business following the launch last year of Pegasys, its new hepatitis C
drug viewed as central to reviving the company's flagging pharmaceutical sales. Roche also sells Roferon-A for
hepatitis B.
Roche has recently forged a number of deals with biotech companies, including a cancer-drug partnership late last
year with Britain's Antisoma Plc. (ASM.L) potentially worth up to $500 million.
It has also created alliances with Affymetrix Inc. and German biotech firm Epigenomics AG, and earlier this month
acquired insulin pump maker Disetronic of Switzerland for $1.2 billion.
Maxygen has patented a process by which it isolates a number of related genes, such as ones that code for
production of alpha interferon, and then uses special enzymes to randomly cut them into a large number of
fragments.
"The fragments are then put into test tubes, where they naturally recombine into full-length genes that are very
similar to the original 'parent' genes but have different characteristics," Simba Gill, Maxygen's president, said in an
interview.
Maxygen calls its technology "gene shuffling." or "molecular breeding," which is in essence an expedited form of
genetic mutation that normally takes place only with sexual reproduction among plants and animals.
"Once we produce novel interferon genes, we will get them to produce their specific proteins and test whether
these new proteins can kill hepatitis viruses," Gill said.
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Steatotic Donor Livers or Orthotopic Liver Transplantation
Steatosis has a negative impact on both recipient survival and early allograft survival, find researchers in latest
issue of Liver Transplantation (Liver Transpl 2003; 9: 500-5).
Steatosis of the donor liver impacts on both patient and allograft outcome after orthotopic liver transplantation
(OLT).
In this study, researchers from Sydney, Australia, evaluated the effect of increasing grades of cadaveric donor liver
steatosis on recipient outcome.
The team assessed 120 OLTs performed using 72 mild, 25 moderate, and 23 severely steatotic donor livers,
between 1986 and 2000.
Initial poor graft function was more common in donor livers with either moderate or severe steatosis.
The team established that donors of steatotic livers were more likely to be older, and to have died of intracerebral
hemorrhage than donors of nonsteatotic livers.
They found that initial poor graft function (IPF) was more common in donor livers with either moderate or severe
steatosis, than in livers with mild steatosis.
Primary graft nonfunction (PNF) only occurred in 1 donor liver with severe steatosis.
In addition, prostaglandin E1 (PGE1) usage was higher in recipients of donor livers with moderate or severe
steatosis, compared with donor livers with mild steatosis.
Furthermore, allograft loss was greater at 1 year both in the moderate and severe steatotic liver groups.
The researchers determined that patient survival at 3 months and overall allograft survival both were impacted
negatively by increasing grades of donor liver steatosis.
They also found that 3-month allograft survival was reduced in the steatotic donor livers if the donor was over 50
years old.
The team identified that recipient status at OLT, and donor steatosis impacted on 30 day allograft survival.
Dr Deborah Verran's team concluded, "Increasing grades of donor liver steatosis were associated with worse IPF
and increased PGE1 usage".
"There was a negative impact of steatosis on both recipient and early allograft survival".
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Transcatheter Arterial Interferon Embolization for Patients with Hepatocellular
Carcinoma
Transcatheter arterial interferon embolization is an effective treatment for patients with inoperable hepatocellular
carcinoma, find researchers in the latest issue of Cancer (Cancer 2003; 97(11): 2776-82).
Systemic, high-dose interferon-treatment, given 3 times per week subcutaneously, causes tumor regression in
about 30% of patients with inoperable hepatocellular carcinoma (HCC).
In this study, researchers from Hong Kong, China, determined the efficacy and safety of transcatheter arterial
interferon embolization for the treatment of patients with inoperable HCC.
38% of patients had normalization of their alpha-fetoprotein level.
The research team recruited 18 patients with inoperable HCC to receive 3 different doses of interferon-alpha-2b at
intervals of 8 to 12 weeks. Doses administered were 10 megaunits (MU)/m2, 30 MU/m2, or 50 MU/m2.
The patients' tumor response, adverse events, and survival were monitored.
The team found that in 14 patients with non-diffuse HCC complete responses were observed in 29% of patients,
and partial responses in 36%. Overall, 1 of 4 patients with diffuse HCC had a partial response.
In addition, 38% of patients had normalization of their alpha-fetoprotein level.
The team also found that the median ferritin level at the last follow-up was reduced significantly (765 pmol/l),
compared with the baseline level (1980 pmol/l).
The researchers found that median survival was 15.9 months.
They determined that transient fever and rigor were the most common side effects of this treatment. In addition,
28% of patients developed hypothyroidism. However, no significant liver decompensation was observed.
Dr Man-Fung Yuen's team concluded, "This pilot study showed that transcatheter arterial interferon embolization
was an effective method for the treatment of patients with inoperable HCC without significant hepatic toxicity".
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Roche and Maxygen Establish Broad Alliance to Develop and Commercialize
Next-Generation Interferon Alpha and Beta Products. Roche Further Strengthens Its Position in Hepatitis Through
Agreement
Roche and Maxygen, Inc. announced today that they have formed a broad strategic alliance to collaborate on the
global development and commercialization of Maxygen's portfolio of next-generation interferon alpha and beta
variants for a wide range of indications.
The collaboration will initially focus on the development of lead candidates for hepatitis B virus (HBV) and hepatitis
C virus (HCV) that have been designed by Maxygen to have novel and superior efficacy compared to currently
marketed interferon alpha products. This builds on Roche's commitment to hepatitis, following Pegasys, a new
generation interferon that provides significant benefit over conventional interferon therapy in patients infected with
HCV.
Terms of the Agreement
Roche has licensed worldwide commercialization rights to specific novel interferon product candidates for HBV and
HCV. Maxygen will receive an initial payment, full research and development funding for the first two years of the
collaboration and option fees. In addition, Maxygen is eligible to receive milestone payments and royalties based
on product sales.
The agreement also provides the companies with the option to expand the collaboration to develop other novel
interferon alpha and beta products specifically tailored for indications outside of HBV and HCV, including oncology,
autoimmune diseases, inflammatory diseases, and other infectious diseases such as HIV. Maxygen retains the
right to develop such products while Roche may elect to acquire worldwide license and commercialization rights to
these product candidates.
Maxygen has the option to co-develop in the United States any product to which Roche acquires a license in
exchange for profit sharing or an increased royalty rate.
Based on the continued successful development of the novel interferon product candidates and the satisfaction of
certain contingencies, payments to Maxygen could exceed $230 million plus royalties on product sales.
"Roche has a long tradition in successfully developing and commercializing anti-viral drugs, alone or in partnership
with other companies. We believe with Pegasys and Copegus we are establishing a new standard of care.
Maxygen's portfolio of lead interferon product candidates represents an interesting and novel approach for further
improvement in treatment. We are convinced that through our collaboration we will continue to be a clear leader in
the treatment of patients suffering from this debilitating disease," said William M. Burns, Head of Roche's
Pharmaceuticals Division.
"Maxygen's strategy has always been to partner with world leaders in their respective fields, and with its track
record of excellence and an established and strong franchise, Roche is clearly a leader in the development and
commercialization of interferon therapies," said Russell Howard, Ph.D., Chief Executive Officer of Maxygen. "This
innovative collaboration is structured to maximize the commercial potential of Maxygen's novel shuffled interferons
by enabling their swift development and potential commercialization with a market leader in hepatitis. Importantly,
Maxygen retains the right to conduct further discovery and development of novel interferons for additional
indications. I am particularly excited about Maxygen's option to co-develop these products for hepatitis B and C in
the U.S., as this provides substantial potential for long-term value creation for the company."
The Interferon Alpha Market
Total global interferon alpha sales (including ribavirin) for all indications including hepatitis B, C and several cancers
were in excess of $2.9 billion in 2002.
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 HBV 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.
About Hepatitis C
Hepatitis C is a serious blood-born viral infection that attacks the liver, and in many patients it leads to liver
disease, cirrhosis and cancer. It is the leading cause of liver transplantation. Only identified in 1989, the HCV virus
has infected more than 170 million people world-wide, making it more common than the HIV virus.
Roche's Commitment to Hepatitis
Roche is committed to the viral hepatitis disease area, having introduced Roferon-A for hepatitis B and then C,
followed by Pegasys and Copegus in hepatitis C. Pegasys is a new generation hepatitis C therapy that is different
by design and 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 is approved for
monotherapy and for use in combination with Copegus, our proprietary ribavirin product 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. Pegasys is also in phase III clinical development for patients infected with the HBV virus.
Roche manufactures and sells the AMPLICOR(TM) HCV Test, v2.0 and the AMPLICOR HCV MONITOR(TM) Test,
v2.0 - two tests used to detect the presence of HCV RNA (Ribo Nucleic Acid) in a person's blood. Roche's
commitment to hepatitis has been further reinforced by the in-licensing of Levovirin, which will be studied with the
objective of demonstrating superior tolerability over the current standard, ribavirin.
About Roche
Headquartered in Basel, Switzerland, Roche is one of the world's leading innovation-driven healthcare groups. Its
core businesses are pharmaceuticals and diagnostics. Roche is number one in the global diagnostics market, the
leading supplier of pharmaceuticals for cancer and a leader in virology and transplantation. As a supplier of
products and services for the prevention, diagnosis and treatment of disease, the Group contributes on a broad
range of fronts to improving people's health and quality of life. Roche employs roughly 62,000 people in 150
countries. The Group has alliances and research and development agreements with numerous partners, including
majority ownership interests in Genentech and Chugai.
About Maxygen
Maxygen, Inc. headquartered in Redwood City, California, is focused on creating novel products using its integrated
proprietary technologies for human therapeutics and industrial applications. Maxygen's technologies bring together
advances in molecular biology and protein modification to create novel biotechnology products. Maxygen has
strategic collaborations with leading pharmaceutical companies including Roche, Aventis, InterMune, Lundbeck,
ALK-Abello, and the International AIDS Vaccine Initiative (IAVI). Additionally, Maxygen has a range of other
strategic alliances in industrial applications, as well as funding from U.S.A. government organizations including
USAID, US Army Medical Research and Materiel Command and NIST-ATP.
Conditions
The transaction is being submitted for review by the Federal Trade Commission under the Hart-Scott-Rodino
Antitrust Improvements Act of 1976.
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May 23rd, 2003
Genetic Variability of Hepatitis C Virus May Influence Treatment Outcome
Genetic variation in hepatitis C virus (HCV) may influence the outcome of alpha-interferon (IFN) treatment, including
the response to different alpha-IFN preparations, according to a report in the May Journal of Medical Virology (J
Med Virol 2003; 70:62-73).
The persistence of HCV infection has been attributed in part to its high rate of genetic variability, the authors
explain, and alpha-IFN treatment is known to influence the HCV quasispecies distribution.
Dr. Peter Karayiannis from Imperial College of Science, Technology and Medicine in London, UK and colleagues
used cloning and sequencing to investigate the pattern and significance of variability in the HVR-1 and NS5A
regions of the HCV genome during alpha-IFN treatment in 12 patients with chronic HCV infection.
Nucleotide and amino acid complexity during alpha-IFN treatment decreased markedly among responder-relapsers,
the authors report, but viral complexity increased in 3 of 4 nonresponders.
Moreover, baseline HCV diversity was significantly higher among responder-relapsers, the report indicates, and
decreased during treatment. In contrast, HCV diversity did not change or increased with treatment in
nonresponders.
The diversity of quasispecies that survived in responder-relapsers was significantly reduced, the researchers note,
whereas the pretreatment isolates in nonresponders persisted at 12 weeks and evolved to an even more diverse
population by week 24.
In baseline samples, amino acids G406 and Q409 within the HVR-1 region were highly conserved, according to the
report, and both were unchanged after alpha-IFN administration.
NS5A mutations were significantly more common among responder-relapsers than among nonresponders, the
results indicate, but mutation prevalence did not correlate with viral load.
Treatment with lymphoblastoid alpha-IFN selected for intermediate IFN sensitivity determining region sequences,
the investigators report, while recombinant-2b alpha-IFN favored maintenance or selection of conserved such
sequences.
"Our data do not allow us to speculate at present on which preparation might be more beneficial in the treatment of
chronic hepatitis C virus infection," Dr. Karayiannis told Reuters Health.
"In vitro studies have already demonstrated potent anti-viral effects by several alpha IFN subtypes, as well as beta
IFN," Dr. Karayiannis explained. "This is highly significant at present, since there exists the possibility of
chemically modifying individual alpha-IFN sub-types by pegylation. Pegylation of alpha-IFN has improved response
rates, and pegylating other subtypes could further enhance the efficacy of anti-HCV treatment."
"Failure to respond to antiviral treatment may be the result of emergence of IFN resistant virus variants," Dr.
Karayiannis concluded. "These may respond better to other IFN formulations."
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New Warning on Complications of Tongue Piercing
It dates back hundreds of years and has gained popularity with today's youth but dentists said on Friday
tongue-piercing can have serious complications.
Apart from infection, bleeding and scarring, it can also cause cracked teeth and nerve damage.
"Piercing of oral sites may lead to a number of complications, some of which are life-threatening," said Tamer
Theodossy, of University College London.
In a report in the British Dental Journal, Theodossy described how the tongue of a 28-year-old woman swelled and
totally encased a barbell pierced through it. The woman needed surgery to remove it.
"Piercing of oral sites also carries a high risk of infection with the possibility of transmission of organisms such as
HIV, hepatitis B and C, Herpes Simplex virus, Epstein-Barr virus and candida," he added.
Herpes Simplex is linked to cold sores and the Epstein-Barr virus causes glandular fever.
Dr Mervyn Druian, of the British Dental Association, also advised against tongue piercing because of the potential
complications.
"The trouble is, it has became a fashion accessory for some people," he said.
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Senator Kay Bailey Hutchison and Senator Edward Kennedy Act to Protect Millions of Americans with Hepatitis C
Senators Kay Bailey Hutchison and Edward Kennedy today filed The Hepatitis C Epidemic Control and Prevention Act (S-1143), announced the National Hepatitis C Advocacy Council (NHCAC). This is the first federal
response to the hepatitis C epidemic, the most common blood-borne viral infection in the United States. An estimated four million Americans are currently infected with the hepatitis C virus (HCV). HCV yearly costs are
already at an alarming $15 billion dollars. That figure is expected to skyrocket to $26 billion by 2021.
Hepatitis C threatens the health of millions of Americans. NHCAC has worked to educate federal and state governments about the seriousness and magnitude of the hepatitis C epidemic. Approximately 85 percent of
those who contract HCV remain infected for life, and an estimated 15,000 die each year. The annual death toll is expected to triple by 2010. There is currently no vaccine to prevent HCV infection.
The Hepatitis C Epidemic Control and Prevention Act is groundbreaking legislation. It will establish a comprehensive program for HCV public awareness campaigns, screening and counseling, early detection,
professional education, and research. The program will be administered by the Department of Health and Human Services. State and local hepatitis C agencies will be supported to implement program activities.
The National Hepatitis C Advocacy Council is comprised of 22 hepatitis C groups from across the United States. NHCAC President Lorren Sandt commented: "This is a major step in achieving a key goal of NHCAC:
increasing financial and infrastructure support for the delivery of hepatitis C prevention, education, and patient care services at a level commensurate with the impact of this disease. Chronic hepatitis C is completely
preventable with sound public health policy in place."
NHCAC Government Affairs Chairperson Sharon Phillips added: "For the first time, we have a bill that will work for the millions of infected Americans. We congratulate Senators Hutchison and Kennedy for taking action
now with S-1143 and providing the resources necessary to address this previously un-funded epidemic."
Cosponsors of this bipartisan bill include Senators Daschle (D-SD), Biden (D-DE), Smith, (R-OR), Johnson, (D-SD), Bingaman (D-NM), Breaux (D-LA),Campbell (R-CO), Clinton (D-NY), Cornyn (R-TX), Dodd (D-CT),
Jeffords (I-VT), and Schumer (D-NY). A companion bill will be introduced in the House in the next few weeks.
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May 27th, 2003
Transfusion-Transmitted Virus Infection in Patients with Chronic Liver Diseases
Transfusion-transmitted virus infection is highly prevalent in patients with chronic liver disease, find researchers in the July issue of Medical Principles and Practice (Med Princ Pract 2003; 12(3)).
In this study, researchers from Turkey determined the prevalence and clinical impact of transfusion-transmitted virus (TTV) DNA in patients with chronic liver diseases.
The team evaluated this in the Southeast Anatolia region where hepatitis B and C viral infections are endemic.
Transfusion-transmitted virus DNA was found in 78% of patients with chronic liver disease.
The researchers enrolled 60 patients (19 males, 41 females), who were diagnosed with chronic liver disease by clinical, biochemical and histologic, in this study.
The chronic liver disease group included 11 patients with hepatitis B, 44 with hepatitis C, and 5 with chronic liver disease of unknown etiology.
The team collected serum samples both the patients with chronic liver diseases and 45 healthy volunteer blood donors.
They investigated the presence of TTV DNA using PCR.
In the chronic hepatitis C group, the team used a scoring system to grade inflammation and stage of fibrosis.
The researcher detected TTV DNA in 78% of patients with chronic liver disease, and 11% of volunteers in the control group.
In addition, 91% of patients with hepatitis B, 73% of those with hepatitis C, and 100% of those with cryptogenic liver disease were positive for TTV DNA.
Dr Cemil Savasa's team concluded, "TTV is highly prevalent in patients with chronic liver diseases in Southeast Anatolia, Turkey, but no pathogenic effect attributable to TTV infection was detected".
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Oregon Debates Transplant for Death Row Inmate
By Lee Douglas
Horacio Alberto Reyes-Camarena, a convicted murderer with failing kidneys, is presenting Oregon officials with a tough choice -- how best to keep him alive until they can execute him.
The cash-strapped state, struggling to provide basic education and health care to its citizens, pays $120,000 a year to clean Reyes-Camarena's blood with a dialysis machine at Umatilla State Prison. That treatment
could continue for a decade as he appeals his death sentence in the 1996 murder of an 18-year-old woman.
After Reyes-Camarena's prison doctor last month concluded he was a good candidate for a transplant, state officials may consider giving him a priceless donated kidney. The $100,000 operation could save the state
money but would deprive someone outside prison of a life-giving organ.
Reyes-Camarena says he will not ask for the operation but would accept it.
"If they offer it to me, I'll take it, but I never want to ask for a kidney," Reyes-Camarena told Reuters by telephone. "I'm on death row now. Someday, if it got allowed, I'm going to go through appeals and then the man
(executioner) has to do his job. Why take it with me?" he said.
Many people around the state agree, and news that Reyes-Camarena was a potential candidate for a transplant set off a furious debate last month.
"It's a conundrum because you clearly are required to give medical care to prisoners whether they are on death row or not," said Josh Marquis, district attorney for Clackamas County, Oregon, and a staunch death
penalty advocate.
Some hospitals have refused to put state health plan members on transplant waiting lists because the plan has cut prescription drug benefits, raising the risk that transplant patients won't be able to pay for expensive
drugs that help ensure their bodies do not reject the new organs.
A Killer
Reyes-Camarena, who stabbed Maria Zetina to death and repeatedly stabbed her sister, who survived the attack and testified against him, could be placed on those transplant waiting lists ahead of other state clients.
"The idea that he would live while someone else would die is absurd," said Marquis.
Seventeen people die each day in the United States while waiting for kidneys. The national waiting list has 57,000 names. The irony of his preferential treatment is not lost on Reyes-Camarena, who has followed the
debate about state cuts and his own care in the news.
"I know people on the outside. They need things and they don't get it. Sometimes being here is better," he said.
Patricia Backlar, who served on the National Bioethics Advisory Commission in the Clinton administration, said a death row inmate should not have greater access to medical resources than the state's other health
care clients.
But Backlar also cautioned that the state is on a slippery ethical slope if it tries to determine who deserves a transplant based on things like criminal history.
"A lot of people are convicted of crimes they didn't commit," she said. "It's very hard to put a value on someone's worth, so you would want to be cautious before you put yourself in the position of being the God squad."
Death penalty opponents and health care advocates bristle at the very thought of making such a decision. Reallocating federal funds could provide health care for everyone, said Peter Bergel, director of Oregon
PeaceWorks, an agency that opposes the death penalty.
"We need to structure our social policy in such a way as nobody has to make a decision like that," Bergel said. "When we make judgments as to the value of one person's life over the value of another person's life, we
are making judgments that the creator has reserved for him or herself. We're not gods."
A $2 billion state budget shortfall, blamed for everything from suicides by mentally ill people who could not get treatment to big cuts in education, has intensified the debate, which might have been avoided in fatter
economic years.
"If the state pays (for Reyes-Camarena's kidney) and we don't have enough money to look after our school children or our mentally ill, then that may be an unfair distribution, just because the benefits of it are limited,"
Backlar said.
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May 28th, 2003
New Occupational Hazards -Health Threats Plague Traditionally Safe and Not-So-Safe Jobs Alike
By Kirstin Downey
Working at an industrial laundry, where dirty uniforms and linens arrive by the truckload to be chemically cleaned and ironed, is hot, steamy and sometimes dangerous. Sandy Evans, 56, who earns $8.50 an hour at a
plant outside Philadelphia, has the scars to prove it.
There's a dark patch of skin on her wrist, where she burned herself one day in February while operating a 400-degree heat-seal machine that glues company emblems on customers' work uniforms. "It's easy to get
burned like this," she said.
In an era of new deadly germs such as infectious hepatitis and AIDS, laundry workers face disease risks as well, hidden among the linens sent out by blood banks and hospitals to be cleaned.
"There's so much contaminated stuff," said Victor Hidalgo, 39, a laundry worker in Connecticut who contends that he was fired from his $9-an-hour job in January after raising concerns about workers being asked to
handle blood-stained garments from a Red Cross blood bank.
Laundry workers aren't alone. Broadly speaking, the U.S. workplace has become markedly safer since 1971, when the Occupational Safety and Health Administration was created. Workplace fatalities have been cut in
half, and injury and illness have fallen 40 percent.
But while some jobs have always been pretty dismal because they are dirty, smelly, hazardous or pay poorly, the emergence of new kinds of health risks -- from terrorism to SARS -- are making some formerly good
jobs bad, and some formerly bad jobs awful.
Postal work, for example, was reliable but boring government employment, until postal workers started dying from anthrax spores. Package delivery seemed like a steady line of work, until workers had to start
screening innocent-looking parcels in an effort to determine whether they contained bombs or explosives. Nursing has always carried a certain prestige along with some risk. But now a combination of orange alerts and
a raft of infectious diseases is adding new stress to the job. Flight attendants were never highly paid, but the glamour of the job and the opportunity to travel the world made up for it, at least in the days before Sept. 11
and SARS.
"The job has become hard, really hard," said Mollie Reilley, an officer of a Teamsters union local that represents Northwest Airlines' flight attendants. "People are saying, 'Wait, this isn't what I signed up for.' "
"Some jobs have always been bad . . . and now new, bad attributes are just being loaded on," said David Weil, an associate professor of economics at Boston University's School of Management. "Some jobs were
made more attractive for a period of time but now they are drifting into the [less desirable] labor market, and they are not being compensated for the risk."
Most at-risk workers won't be paid more anytime soon, particularly in today's sluggish business climate, said W. Kip Viscusi, a professor of law and economics at Harvard Law School. If history is a guide, he said,
"people will just quit their jobs."
Studies in manufacturing plants have shown that about one-third of all job turnover occurs when newly hired workers learn about previously undisclosed job risks, Viscusi said. When new risks arise, "people tend to
overreact," and job turnover increases. Later, he said, compensation rises to make up for the real or perceived risk, unless the employer decides to accept a continued high level of turnover.
Today's new threats are "news and they're scary, but people get used to it," said John Smoyer, of Mesa, Ariz., who consults on workplace compensation and safety issues. AIDS, for example, was a frightening
disease when it appeared in the 1980s, and workplace violence was an equally novel and disturbing threat in the 1990s.
Smoyer said, "Everybody was afraid of workplace violence, but unless you are a taxi driver or work in a convenience store . . . you're probably safer at work than anyplace else."
He said that employers have to make sure they minimize hazards to workers as much as possible, but there will always be some "bad actors who will try to save money and cut costs" by discarding safety
precautions. Those are the same kinds of employers who "are hiring illegals because they won't go complain to anybody," he said.
Workers who find themselves in possibly hazardous positions should seek training to find better positions elsewhere -- but Smoyer acknowledged that is a difficult task now because "the problem is the economy. . . .
Some highly qualified people are out of work due to downsizing or rightsizing," making the competition stiffer for other jobs, Smoyer said.
In some places, workers have become more militant. Laundry workers Evans and Hidalgo, for example, are active in a union-organizing campaign, agitating for better pay and benefits, and for hepatitis shots for workers
exposed to blood-borne pathogens.
Karen Carnahan, vice president and treasurer of Cintas Corp., the Cincinnati-based laundry and uniform rental company that employed Hidalgo and Evans, said she was "not aware" of any problems involved
blood-tainted clothing, and that if there had been, the company would have taken steps to solve the problem.
"We get high marks for our corporate culture," Carnahan said. "We would have taken care of that, there's no doubt in my mind. . . . If there was something, an exposure, our people would handle it properly." She said
Cintas has been targeted by outside union organizers involved in "a desperate effort" to gain members at a time unions are in decline.
OSHA, the government's watchdog on workplace issues, is trying to adjust to these new challenges itself, said John L. Henshaw, assistant secretary of labor for of the agency. Traditionally, he said, it focused on
internal problems at a work site. Now it must consider external events, too.
"Workers and employers are looking to OSHA for help and we need to be there," Henshaw said. But it is often difficult to determine the best course of action with these newly developing threats, he added. "We're not
the experts, the CDC [Centers for Disease Control] is. But we want to get more information to workers and employers" on issues such as which protective gear is best, and what other precautions workers and
employers should be taking.
"We will be doing more," Henshaw said. "Will we be writing regulations for these things? Probably not. . . . The important thing is not to go through a lengthy rule-making process but to get information out as quickly as
we can in easy-to-read format so people can put it out at their workplaces."
In early May, for example, the department began posting on its Web site a PowerPoint presentation for employers to use in discussing the risk of SARS with their workers, including links to other agencies tracking the
disease. In April, the agency posted information for employers to use to plan for emergency workplace evacuations.
Some workers are starting to wonder whether the paycheck is worth the risk and worry.
Even before the Sept. 11, 2001, hijackings, flight attendants had to deal with overcrowded passenger cabins and poor labor-management relations at many airlines. Now, with pilots protected by locked doors and,
soon, handguns, some flight attendants feel compelled to seek self-defense training to ward off would-be assailants. That's happening as the airline industry goes into a tailspin, with employees forced to take pay cuts
and benefits reductions in the hopes of keeping jobs at all.
In a recent memo on the SARS threat, the Flight Attendants Association, a union that represents 50,000 workers at 26 airlines, advised its members to wash their hands frequently and to seek medical attention if they
develop flu-like symptoms or a fever higher than 100.4 degrees.
In April, the group wrote to the Federal Aviation Administration, asking for emergency guidance on whether flight attendants should take any special precautions. FAA spokeswoman Rebecca Trexler said the agency is
taking the concerns seriously, but referred the issue to the CDC.
Nurses also have become more active in lobbying. Hundreds of nurses, representing a half-dozen unions, converged on Washington recently to lobby for a bill to increase staffing.
The staff shortage comes as nurses are also being expected to act as front-line shock troops against mysterious new ailments, from antibiotic-resistant infections, to smallpox, anthrax and potentially, SARS.
"The workplace and occupational hazards are a continual concern today," said Butch de Castro, occupational health and safety specialist for the American Nurses Association.
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BioCryst Announces Agreement for Testing of Its Hepatitis C Polymerase Inhibitors on SARS and West Nile Viruses
BioCryst Pharmaceuticals, Inc. (Nasdaq: BCRX) today announced an agreement with The National Institute of Allergy and Infectious Diseases (NIAID), a unit of The National Institutes of Health, and the U.S. Army
Medical Research Institute of Infectious Disease (USAMRIID), to test BioCryst's investigational hepatitis C polymerase inhibitors against Severe Acute Respiratory Syndrome (SARS) and West Nile viruses.
The compounds to be tested are novel active site-directed inhibitors of the enzyme hepatitis C polymerase, which BioCryst has designed and synthesized in collaboration with Emory University and the French National
Center for Scientific Research (CNRS). BioCryst has an exclusive license to compounds resulting from this collaboration. BioCryst's hepatitis C polymerase inhibitors are already being tested on the Ebola virus,
pursuant to a Cooperative Research and Development Agreement for Material Transfer entered into with USAMRIID on January 11, 2002.
"We are pleased to be able to offer our hepatitis C polymerase inhibitor candidates for testing against these serious diseases," said Charles E. Bugg, Chairman and Chief Executive Officer of BioCryst. "The hepatitis C
virus requires an RNA polymerase, which appears to have an active site three- dimensional structure that is similar to that found in the polymerases of other RNA viruses. Therefore, compounds such as those
developed at BioCryst that are designed to attack hepatitis C virus by binding directly to the active site of the polymerase may also inhibit the polymerases of other RNA viruses, such as SARS, West Nile and Ebola."
Testing of BioCryst's compounds against SARS and West Nile viruses will be coordinated through Southern Research Institute (SRI) in Birmingham, Alabama, under a contract from NIAID and USAMRIID. According to
Dr. John A. Secrist, III, Vice President of the Drug Discovery Division of SRI, "We are especially eager to test inhibitors of key RNA viral enzymes, including the polymerases and proteases, as potential anti-virals
against the SARS and West Nile viruses, and we are delighted that BioCryst has arranged to provide their compounds for our testing program."
BioCryst Pharmaceuticals, Inc. designs, optimizes and develops novel drugs that block key enzymes essential for cancer, cardiovascular diseases and viral infections. BioCryst integrates the necessary disciplines of
biology, crystallography, medicinal chemistry and computer modeling to effectively use structure-based drug design to discover and develop small molecule pharmaceuticals. In addition to its hepatitis C polymerase
inhibitor program, enrollment in four Phase I trials for one of BioCryst's product candidates, BCX-1777, is underway at several cancer centers for patients with T-cell malignancies, hematologic malignancies, and other
refractory cancers. BioCryst also has several new enzyme targets in drug discovery including tissue factor/factor VIIa and complement component C1s. For more information about BioCryst, please visit the company's
web site at www.biocryst.com .
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May 29, 2003
Viral Genotypes, Rejection, and Hepatitis C Recurrence after Liver Transplant
Hepatitis C genotype 1b results in a higher rate of recurrence after orthotopic liver transplantation, find researchers in the latest issue of Surgery Today (Surg Today 2003; 33(6): 421-5).
In this study, researchers from Australia and Japan evaluated the influence of hepatitis C virus (HCV) genotype and rejection episodes on orthotopic liver transplantation (OLT). They also determined the influence of
these factors on hepatitis recurrence, and progression to graft cirrhosis after OLT.
The research team included 53 patients who had undergone OLT for end-stage liver cirrhosis. They determined the hepatitis C genotype for each patient.
They diagnosed recurrent hepatitis and rejection using liver function tests and a liver biopsy.
- 32% of patients were infected with HCV genotype 1b.
- The patients were followed up for a mean of 51.9 months.
The researchers found that the cumulative survival rate in patients with OLT for hepatitis C was no different to that for all other liver diseases.
The team detected serum HCV RNA in 93% of patients after OLT, and histological recurrence in 85%.
They found that 1-, 3-, and 5-year recurrence rates were 48%, 77%, and 85%, respectively.
Of the 41 patients with recurrent hepatitis C, the researchers found that 10% had cirrhosis, 44% hepatitis with fibrosis, and 46% hepatitis without fibrosis. In addition, the team found that 32% of patients were infected
with HCV genotype 1b, and 68% with other HCV genotypes.
The team determined that recurrence rates were significantly higher in patients infected with genotype 1b than in those with other genotypes.
Overall, 42% patients experienced acute rejection. The researchers identified a strong association between the number of rejection episodes and incidence of HCV-related cirrhosis.
Dr Hiroyuki Sugo's team concluded, "Our findings showed the genotype 1b to result in a higher recurrence rate after OLT".
"On the other hand, rejection episodes were associated with a more rapid progression to graft cirrhosis".
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Schering Canada Inc. - Ontario Approves Pegetron for Hepatitis C - Patients Will Gain Access to Treatment for Chronic and Debilitating Disease
Schering Canada is pleased to announce the approval of PEGETRON(TM) (peginterferon alfa-2b powder for solution plus ribavirin 200 mg capsules), a pegylated interferon combination therapy for the treatment of
chronic hepatitis C, by the Ministry of Health and Long Term Care in Ontario.
PEGETRON is being reimbursed under the Individual Clinical Review mechanism (Section 8) for the treatment of chronic hepatitis C in previously untreated (naive) patients and for patients who have relapsed after initial
treatment for 6-12 months with interferon monotherapy or failed initial treatment with interferon.
"Pegylated interferon therapy represents the latest advance in treatment for hepatitis C," said Dr. Paul Marotta, Assistant Professor at the University of Western Ontario and Medical Director of Transplants at the
London Health Sciences Centre. "I am pleased that patients in Ontario who are infected with HCV now have access to this agent."
PEGETRON is the only pegylated interferon combination treatment approved and available in Canada for the treatment of chronic hepatitis C, which is estimated to affect up to 240,000 Canadians. Hepatitis C is one of
the most common reasons why people need to have liver transplants.
Quebec, Alberta, Saskatchewan and Manitoba also include PEGETRON on their lists of provincially approved drugs. PEGETRON is also being covered by a growing number of private medical insurance plans.
Schering Canada's commitment to the treatment of hepatitis C is grounded in more than 12 years of research, daily contact with the medical community and patient support programs.
Schering Canada is a wholly owned subsidiary of Schering-Plough Corporation, a research-based company engaged in the discovery, development, manufacturing and marketing of pharmaceutical products worldwide.
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May 30, 2003
Schering-Plough Targeted for Federal Criminal Indictment
Drugmaker Schering-Plough said Friday it is the target of a federal grand jury investigation into its marketing practices, whether it overcharged the government for medicines and possible obstruction of justice.
Schering-Plough received a letter Wednesday from the U.S. Attorney's Office for the District of Massachusetts informing it of the investigation, which focuses on the subsidiary running U.S. operations, Schering, said
spokeswoman Denise Foy.
The company said it believes the letter shows that the government plans to pursue a criminal indictment and likely has substantial evidence supporting an indictment. "The company is continuing to cooperate with the
U.S. Attorney's Office on this matter," Foy said.
Samantha Martin, spokeswoman for the U.S. Attorney's Office in Boston, said the office would neither confirm nor deny the investigation.
Schering-Plough had previously disclosed that federal prosecutors in Boston were probing its practices regarding sales, marketing and funding for testing of its medicines on people. The new letter from the U.S.
Attorney's Office there states that Schering-Plough is a target of a criminal investigation on four fronts.
The company said those allegations are:
- Providing remuneration to physicians, managed care organizations and others to induce purchase of its pharmaceutical products under federal health care programs. The remuneration being investigated includes
providing drug samples, grants for patient testing of drugs, known as clinical trials, and other items or services.
- Selling drugs for conditions for which the Food and Drug Administration has not specifically approved their use.
- Giving the government false or incomplete wholesale pricing information on its drugs, inflating prices paid for those drugs by the Medicaid program.
- Destruction of documents and obstruction of justice relating to this investigation.
Schering-Plough said it has implemented "certain changes to its sales, marketing and clinical trial practices and is continuing to review those practices to ensure compliance with relevant laws and regulations."
It also said the U.S. Attorney's Office has advised the company that it will have an opportunity to submit evidence and legal arguments responding to the allegations.
Foy said the company would not discuss when it will submit those documents.
Only last month, former Pharmacia chief Fred Hassan took over as Schering-Plough's chief executive amid hopes that he could breath new life into the floundering drug company as he had with Pharmacia.
The laundry list of problems besetting the company-among them tumbling revenue following the patent expiration of its former top-selling Claritin, quality control issues at its plants that have held up approval of
important drugs and the allegations of overly aggressive sales practices were well known when Hassan took over as CEO.
It was not immediately known whether Hassan was made aware of just how serious and wide ranging the government's list of allegations against the company might become, or that a criminal indictment might be
imminent, when he accepted his latest challenge.
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May 31, 2003
Indictment Seen By Drug Maker over Marketing
Melody Petersen
The Schering-Plough Corporation said yesterday that it could soon be indicted in a federal investigation into its prescription drug marketing practices, and face charges that employees destroyed documents related to
the case.
According to the company, prosecutors are examining whether Schering-Plough illegally gave financial grants and other items of value to doctors and other customers, whether it marketed drugs for unapproved uses
and whether it submitted false pricing information to the government so that Medicaid paid too much for its products.
Most significant, lawyers said, was Schering-Plough's disclosure that a grand jury was weighing obstruction of justice charges. Evidence that the company sought to impede a government investigation could prompt
prosecutors to take a tougher line against Schering in resolving any charges.
The allegations against Schering-Plough are the latest in a spate of investigations and lawsuits by private parties, state governments and the federal government focused on the pharmaceutical industry's marketing
practices. The cases have been spurred by rapidly rising increases in the costs of prescription drugs and the burden those costs place on governments, employers and patients.
Schering-Plough, which is based in Kenilworth, N.J., said it received a letter Wednesday from the United States attorney's office in Boston saying it was a target of a criminal investigation of these matters. By law,
publicly traded companies must quickly disclose significant information to their shareholders.
Schering reiterated yesterday that it had made changes in its sales and marketing practices, and that it was cooperating with the United States attorney's office.
The investigation began more than two years ago, and the company has acknowledged aspects of it. But legal experts said the company's receipt of what it called ''a target letter'' diminished its chances of being able
to settle the matter soon.
In February, the company said it had set aside $150 million to help cover a settlement with federal prosecutors in Boston and Philadelphia. Analysts said they thought that the company, which is struggling with
declining sales and a host of other legal matters, would now be forced to pay far more to resolve the case. The company did not disclose any new information about the investigation by the Philadelphia office.
A spokeswoman in the United States attorney's office in Boston declined to comment yesterday.
It was not clear what documents the government thinks were destroyed, who it thinks destroyed them or when the events took place. The company declined to comment further, other than to say that prosecutors had
given it the chance to submit evidence to defend itself.
If Schering-Plough is ultimately convicted of a felony involving health care fraud, the government could seek to bar its prescription drugs from the federal Medicare and Medicaid programs. Health care companies and
their lawyers call such a step ''the death penalty,'' because of the devastating effect it would have on a company's business.
To date, no large pharmaceutical company has been excluded from the Medicare and Medicaid programs, even after pleading guilty to felony violations.
Last year, TAP Pharmaceutical Products paid $875 million to settle criminal and civil charges that it had illegally manipulated the Medicare and Medicaid programs. The company was not excluded from the programs,
but was forced to enter into a ''corporate integrity agreement'' in which it agreed to widespread changes in its marketing practices under monitoring by the government.
Some of the charges being leveled against Schering are similar to those in the TAP case. Prosecutors contended that TAP sales representatives gave free samples of Lupron, a drug for prostate cancer, to urologists
and then helped the doctors get government reimbursements of hundreds of dollars for each dose.
Other claims against Schering are similar to prosecutors' findings earlier this year in a case against Bayer. The company, based in Germany, agreed to pay $257 million in April to settle allegations that it had engaged
in a scheme with Kaiser Permanente, a large health care provider, to relabel bottles of Cipro, an antibiotic, to hide the low prices it was charging Kaiser. Under federal law, drug companies must sell drugs to Medicaid
programs at their lowest price.
The charge that Schering may have been promoting its medicines for uses that the government has not approved is similar to charges raised against Warner-Lambert in a continuing investigation. In that case, the
government is looking at whether Warner-Lambert illegally promoted an epilepsy drug called Neurontin for more than a dozen unapproved uses.
Like the Schering-Plough case, the TAP, Bayer and Warner-Lambert investigations all have been conducted by the United States attorney's office in Boston, which has become known for its aggressive and successful
prosecutions of pharmaceutical companies, nearly all of which have drug sales in Massachusetts.
John T. Bentivoglio, a lawyer at Arnold & Porter and a former special counsel for health care fraud at the Justice Department, said he could not comment on the Schering case specifically. But in general, he said,
federal prosecutors have become much tougher with companies that seek to obstruct justice since document destruction became an issue in the investigation of Enron's collapse. Obstruction of justice charges against
Enron's accounting firm, Arthur Andersen, led to the firm's demise.
''The government is taking this much more seriously,'' Mr. Bentivoglio said.
It is not clear what Schering medicines may be involved in the government's investigation. The company said in November that it had received two grand jury subpoenas from prosecutors in Boston seeking a broad
range of information about how the company had marketed Temodar, a brain cancer drug, and Intron A and Rebetron, two medicines that treat hepatitis C.
Neil B. Sweig, a pharmaceutical industry analyst with Fulcrum Global Partners, a New York brokerage firm for institutional investors, said that the investigation could involve all the company's major lines of medicines,
including those for allergies and asthma.
''The fines could be very heavy,'' Mr. Sweig said. ''There is no way to quantify it.'' He said he thought the government would seek a financial penalty substantially higher than the $150 million that Schering had set aside
in February.
Shares of Schering-Plough fell 45 cents, or 2.4 percent, yesterday, to $18.45. Its shares are down 17 percent this year.
Schering had sales of $2.7 billion from Intron A, Rebetron and its other medicines for hepatitis C last year, Mr. Sweig said. Its sales of Temodar totaled $278 million, he said.
Mr. Sweig and other analysts said the letter from the prosecutors in Boston was a significant blow to a company that is already reeling from the loss of the patent protecting its top-selling allergy medicine, Claritin, and
a host of legal troubles.
A year ago, Schering-Plough agreed to pay $500 million to the government because of its repeated failure over the years to fix problems in its factories and in the manufacturing of dozens of drugs. The company also
disclosed that the Food and Drug Administration's Office of Criminal Investigation was investigating its manufacturing operations in Puerto Rico, where it has two large factories.
In March, the company said that the Securities and Exchange Commission intended to recommend charging the company and its chief executive at the time, Richard Jay Kogan, with violations of financial rules on
disclosing information to shareholders.
In April, the company named Fred Hassan, the former head of Pharmacia, to succeed Mr. Kogan. Mr. Kogan said late last year that he planned to retire. Schering-Plough says that the company may be indicted soon
in a number of federal crimes.
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June 02, 2003
Hepatitis C Acquired Through Tattooing Often Asymptomatic
People who become infected with the hepatitis C virus when getting a tattoo may be less likely to develop symptoms than people who become infected in other ways, according to Texas researchers.
In a small study, both people with tattoos and those with a history of injection-drug use were more likely than others to be infected with hepatitis C. But unlike subjects who had injected drugs, individuals who had a
tattoo were less likely to develop acute hepatitis symptoms, such as jaundice, vomiting and fatigue.
According to Dr. Robert W. Haley, lead author of the study, a tattoo needle carries a smaller viral load than a standard hypodermic needle and it does not inject the virus directly into the bloodstream.
As a consequence, it takes longer for the virus to enter the bloodstream and make its way to the liver and cause symptoms, Dr. Haley, from the University of Texas Southwestern Medical Center in Dallas, told Reuters
Health.
In the study, Dr. Haley and Dr. R. Paul Fischer, from Presbyterian Hospitals of Dallas, re-analyzed data collected in the early 1990s on 626 patients seeing a physician for back problems. Patients were asked about
risk factors for hepatitis C, and were screened for the virus after the interview.
The findings are published in the May 12th issue of the Archives of Internal Medicine (.Arch Intern Med 2003;163:1095-1098).
Researchers found that those who had a tattoo had a 6.5-fold higher risk of testing positive for hepatitis C than other subjects. However, infected subjects with tattoos were not at increased risk for acute hepatitis
symptoms compared with their peers without tattoos.
In contrast, people with a history of IV drug use were 7.2-times more likely to be infected with the hepatitis C virus than other subjects and 5.9-times more likely to have experienced acute hepatitis symptoms.
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Transplant Patients Vulnerable to West Nile Virus
People who have received organ transplants may be especially vulnerable to the West Nile virus, doctors reported here Monday.
The University of Cincinnati treated two transplant patients for the virus last summer, but detected the virus too late in one patient to help him, said Debby DeSalvo, lead author of the study.
She presented her data at the American Transplant Congress, the largest annual gathering of transplant surgeons and researchers in the U.S.
Both patients were white men in their 40s, and both had received a kidney from a living donor. Neither appears to have been infected by the transplanted organ.
The first patient came to the university with what appeared to be a viral gastrointestinal infection and fever. Within days, the man had symptoms of brain swelling, but an initial CT scan showed nothing abnormal, said
DeSalvo.
He quickly began showing signs of severe neurological problems, and was treated for bacterial and viral meningitis, and his anti-rejection drugs were reduced, but he still did not respond. An MRI showed that he had
massive swelling in his brain, which the Cincinnati doctors realized was characteristic of West Nile virus, even though blood tests they had conducted before were negative for the mosquito-borne illness.
Before they could treat him any further, the man died, two weeks after being admitted.
A month later, another man came in, seeming to have a gastrointestinal infection. Because of the earlier case, the physicians tested for West Nile, but results were negative. An MRI, however, showed the brain
swelling associated with the illness.
Doctors stopped his immune-suppressing drugs completely, and enrolled the man in a trial of alpha interferon, a drug being tested for West Nile.
Within days, he recovered, and was continued on the drug for two weeks, said DeSalvo. Ten months later, he's doing well, |
