Back to News Review

The Best in the News on HCV, HBV and HIV/HCV Coinfection from December 15th, 2002 to January 15th, 2003

Alan Franciscus
Editor-in-Chief

• HIV-Positive Men With HBV At Increased Risk For Liver-Related Mortality
• Increased HCV-Specific Immune Response Linked To Hepatotoxicity In HIV Patients
• FDA Grants Nabi HCV Therapy Orphan Drug Status For Liver Transplants
• Tenofovir Potent Anti-Hepatitis Treatment For HIV/HBV Coinfected Patients
• FDA Approves GlaxoSmithkline Combination Vaccine
• Fractionated Particles Reveal Complexity Of Hepatitis C Virus Infection
• Lamivudine Too Little, Too Late For Chronic Hepatitis B Flare
• Synthetic Ribozymes A Potential Treatment For Hepatitis B Virus
• Schering-Plough Probe Deepens
• Liver Failure In The United States Often Caused By Drug Reactions
• Prevalence Of Liver Disease In Asymptomatic Persons With Hepatitis C Virus Infection
• HCV Treatment In HIV-Coinfected Patients Increases QOL And Is Cost Effective
• Live Organ Donation: One Step Forward, Two Steps Back
• New Rules Approved For Live-Donor Liver Transplants In New York
• Red Cross May Have Released Unsafe Blood
• IGF-1 Levels Predict Liver Cancer In Patients With HCV-Related Cirrhosis
• Syringe Exchange Proves Effective
• Infants Of Hepatitis B Virus Carriers Benefit From Vaccine Alone
• Lamivudine Adds Layer Of Protection To Recipients Of Core-Positive Livers
• Red Cross Did Not Probe Infections
• New Test Quickly Identifies Both Surface And E Antigen Of Hepatitis B
• Nitric Oxide Synthase A Contributor To Hepatitis Pathology
• Blood Factors For Hemophilia Don't Spread Virus-CDC
• Vertex, Lilly Restructure Drug Deal
• Label Issues Are Delaying Generic Drugs
• Update On Ribavirin Pricing
• Smoking Aggravates Liver Histology In Hepatitis C Virus Infected
• HIV Makes Hepatitis B Significantly More Lethal
• Activation Of Antigen-Presenting Cells Rebukes Viral Replication In Liver
• Progression Of Fibrosis In Chronic Hepatitis C
• Undetectable Hepatitis B Virus DNA Unlikely To Rise In Some Carriers
• Roche, ICN Pharmaceuticals And Ribapharm Resolve Ribavirin Patent Dispute
• Schering-Plough Increases Price For Rebetol (Ribavirin)
• Lamivudine Is A Stabilizer In Hepatitis B-Related Decompensated Disease
• Roche Dramatically Reduces Cost Of Combination Therapy For Millions Of Americans Chronically Infected With Hepatitis C
• Repeated Viral Load Testing Predicts Spontaneous Clearance Of Hepatitis C
• Ribapharm Down-2: Roche Worried About Generic Competition
• Synthetic Peptide A New Candidate For Supplemental Hepatitis C Screening
• Copegus: A Shake-Up Of HCV Drug Pricing?
• The Hepatitis C Caring Ambassadors Program Announces The Release Of The Second Edition Of A Comprehensive Book On Treatment Choices For People With Chronic Hepatitis C

December 15th, 2002

HIV-Positive Men with HBV at Increased Risk for Liver-Related Mortality

Men coinfected with HIV-1 and with hepatitis B virus (HBV), particularly those with low CD4 nadir counts, are at an increased risk of liver-related mortality compared with those who are not coinfected, researchers report in the December 14th issue of The Lancet (Lancet 2002;360:1921-1926).

Dr. Chloe L. Thio from Johns Hopkins University, Baltimore, and colleagues collected data on 5293 men who had sex with men. Among this cohort, the researchers determined HIV-1 status and hepatitis B surface antigen status. They also determined mortality rates for patients in the group.

Dr. Thio's team found that 326 men were positive for hepatitis B surface antigen, and 213 of them were also HIV-1-positive. Among the 4967 men who were hepatitis B surface antigen-negative, 2346 were HIV-1-positive, they add.

The overall liver-related mortality rate was 1.1 per 1000 person-years, the researchers report. Among men who were both HIV-1- and hepatitis B surface antigen-positive, the liver-related mortality rate reached 14.2 per 1000 person-years. This was much higher than in men who were only HIV-1-positive (1.7 per 1000 person-years), or men who were only hepatitis B surface antigen-positive (0.8 per 1000 person-years), Dr. Thio's team notes.

They also found that the liver-related mortality rate was highest among coinfected men with the lowest CD4 nadir cell counts and was "twice as high after 1966, when highly active antiretroviral therapy (HAART) was introduced."

Dr. Thio and colleagues suggest that "identification and comprehensive management of individuals coinfected with HIV-1 and HBV is important, especially in the era of HAART."

"Although we could only look at the end point of death, the implication is that there is serious liver disease from chronic HBV amongst the coinfected patients that goes undetected," Dr. Thio told Reuters Health. "Given these data, I think it is important for physicians to first vaccinate HIV-infected individuals against HBV, and to evaluate the stage of liver disease in HIV-infected individuals with chronic HBV."

Increased HCV-Specific Immune Response Linked to Hepatotoxicity in HIV Patients

An enhanced antibody response to hepatitis C virus (HCV) and T cell activation are associated with hepatotoxicity seen in patients coinfected with HIV and HCV who have responded to highly active antiretroviral therapy (HAART), say researchers from Australia.

As they note in a report in the November 15th issue of The Journal of Infectious Diseases (J Infect Dis 2002;186:1498-1502), HIV-HCV-coinfected patients face up to an 8-fold higher risk of severe liver damage after beginning HAART, but the mechanism behind the hepatotoxicity remains unclear.

Dr. Martyn French and colleagues from Royal Perth Hospital and the University of Western Australia in Perth, Australia, investigated the hepatotoxicity by measuring HCV core-specific antibody levels and the activity of soluble CD26 dipeptidyl peptidase—a T cell activation marker associated with inflammatory liver disease—in 16 HIV-HCV-coinfected patients.

HCV core-specific IgG antibody increased in all 7 patients whose ALT levels increased without hepatitis and in 3 of 4 patients who had elevated ALT levels and hepatitis, the authors report, but in only 1 of 5 patients with neither an ALT rise nor hepatitis after HAART.

Similarly, T cell activation doubled in the patients with an ALT increase, but did not change in patients whose ALT remained normal, the report indicates.

"Our main message," Dr. French told Reuters Health, "is that hepatotoxicity in HIV-HCV-coinfected patients who have a virological and immunological response to HAART may result from the restoration or augmentation of immune responses against HCV (immune restoration disease) rather than direct drug-related hepatotoxicity. Therefore, it may not be necessary to cease the HAART, though the long-term consequences of HCV immune restoration disease are currently unknown."

"Because HCV RNA was not measured in our study," the investigators write, "further investigation is required to determine whether increased HCV-specific antibody levels play a pathogenic (i.e., via antibody-dependent cellular toxicity) or protective role (i.e., via increased HCV RNA clearance) in the development of hepatotoxicity after HAART."

Dr. French noted that "the incidence of life-threatening clinical hepatitis associated with hepatotoxicity after HAART in HIV-HCV-coinfected patients appears to be very low, and several studies have shown that the hepatotoxicity often resolves, even if the HAART is continued."

However, he concluded, "the long-term effects of HAART-associated hepatotoxicity are unknown, and prospective long-term studies of HIV-HCV-coinfected patients commencing HAART are needed."

FDA Grants Nabi HCV Therapy Orphan Drug Status for Liver Transplants

Immune system products maker Nabi Biopharmaceuticals said that the US Food and Drug Administration (FDA) has granted its investigational hepatitis C therapy Civacir [Hepatitis C Immune Globulin (Human)] orphan drug designation for the prevention of hepatitis C infections in liver transplant recipients.

The FDA orphan drug designation entitles Nabi to tax-credits for the clinical research, seven years of marketing exclusivity upon approval and potential government grants.

Civacir is currently in its first human clinical trial. If eventually approved by the FDA, Civacir would become the first therapy specifically developed to help protect patients against HCV following liver transplant surgery, according to Nabi.

Corporate officials added that enrollment in the phase I/II trial has been completed and that the results are now anticipated in 2003.

The Civacir clinical trial is being sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), a part of the National Institutes of Health, and is being conducted by the NIAID Collaborative Anti-Viral Study Group at five study sites throughout the US.

Citing figures from the Centers for Disease Control and Prevention (CDC), Nabi said approximately 4 million people in the US and 175 million people worldwide are infected with HCV, of which approximately 5% are expected to require a liver transplant. Of the nearly 5,000 liver transplants performed in the US during 1999, about 40% were due to complications from HCV, the company added.

December 16th, 2002

Tenofovir Potent Anti-Hepatitis Treatment for HIV/HBV Coinfected Patients

In a prospective pilot study, the nucleotide analog tenofovir disoproxil fumarate exhibited potent activity against chronic hepatitis B virus (HBV) infection in patients coinfected with HIV, according to physicians at the Washington University School of Medicine.

In the Journal of Infectious Diseases for December 15 (J Infect Dis 2002;186:1844-1847), Dr. Pablo Tebas and colleagues report on results in six such patients who had failed treatment with lamivudine and interferon-alpha. Treatment with tenofovir 300 mg q.d. was added to their antiretroviral regimen, and 5 patients continued therapy with lamivudine or emtricitabine.

By week 12, HBV RNA serum levels declined from a median of 7.95 log10 copies/mL to 4.8 log10 copies/mL. Further treatment until week 24 resulted in an additional decline to 3.6 log10 copies/mL. In two patients, HBV RNA was undetectable by study end.

Furthermore, 3 subjects in whom HIV RNA was above measurable levels at baseline, the viral load decreased by 0.7 log10 copies/mL from a median of 3.1 log-10 copies/mL.

Dr. Tebas and his associates note that tenofovir was well tolerated, with only a mild increase of alanine aminotransferase by 17 U/L after 12 weeks of treatment from 53 U/L at baseline.

"The anti-HIV activity of tenofovir, which adefovir lacks, and its excellent tolerability in patients with advanced HIV infection, makes it more attractive for the patient with limited therapeutic options in which the goal of antiretroviral therapy is...to try to lower as much as possible the HIV RNA load," the team writes.

They suggest that combination treatment with lamivudine and tenofovir may augment antiviral activity and increase the "genetic barrier for the development of resistance." J Infect Dis 2002;186:1844-1847.

FDA Approves GlaxoSmithKline Combination Vaccine

UK drugmaker GlaxoSmithKline said on Monday that it has received approval from the US Food and Drug Administration (FDA) to market its five-in-one combination vaccine Pediarix, which could result in 24 million fewer injections per year for US infants.

GlaxoSmithKline said the FDA approved Pediarix for protection against diphtheria, tetanus, pertussis, hepatitis B and polio in infants 2, 4 and 6 months of age, resulting in up to six fewer injections under the current recommended schedule.

At present, the company noted that children receive approximately 20 injections in the first 2 years of life, including nine injections to protect against diphtheria, tetanus, pertussis, hepatitis B, and polio alone. Pediarix was developed to protect against these diseases with only three injections in the primary series, easing the burden on parents and healthcare professionals to comply with the recommended vaccination schedule, the company said.

"The introduction of a combination vaccine like Pediarix marks a milestone for the United States immunization program," said Dr. Joel Ward, of the University of California in Los Angeles, who served as the principal clinical trial investigator. "Combination vaccines make it easier to comply with the implementation of a complicated immunization schedule and reduce the number of injections and office visits compared with separately administered vaccines."

GlaxoSmithKline said Pediarix was proven safe and effective in numerous worldwide clinical trials, involving 7028 infants who received a total of 20,739 doses.

The administration of Pediarix was associated with higher rates of fever relative to separately administered vaccines, the company added. But the most common side effects were similar to those of other vaccines, and included injection-site reactions, fever, and fussiness, the drugmaker said.

GlaxoSmithKline spokeswoman Ramona DuBose told Reuters Health the company plans to launch the vaccine in early January and would market it at a price comparable to the total cost of the individual vaccines.

GlaxoSmithKline estimates that about 3 million infants in the US would qualify for the vaccination and predicted that further development of such combination vaccines may also facilitate the addition of new vaccines into the immunization schedule.

Fractionated particles reveal complexity of hepatitis C virus infection
by Sonia Nichols, senior medical writer of NewsRx.com

Fractionated particles in the blood of people infected with hepatitis C virus (HCV) may yield pertinent information about viral persistence.

HCV RNA recovered in blood that is fractionated by ultracentrifugation could provide more information about humoral immune response and why some people experience antibody-mediated clearance while others do not, say researchers at the Medical School of Newcastle upon Tyne.

W. Pumeechockchai and colleagues recovered low-density, intermediate- density, and high-density fractions from immunocompetent and immunodeficient individuals with HCV infections.

"In patients with congenital immunodeficiencies, with no or low serum antibodies to the virus, mean HCV RNA titers were equal in each fraction, at approximately 105 IU/ml," reported Pumeechockchai and coauthors.

In contrast, viral titers could not be detected or were nearly absent in the low-density and high-density fractions of immunocompetent patients with antibodies to HCV. According to researchers, this was an indication that antibody-mediated clearance had occurred in those two fractions.

"Particles of intermediate density were approximately equal in titer in both patient groups, suggesting that these particles were neither generated by nor cleared as a result of the humoral immune response," investigators commented.

Researchers could detect immunoglobulins solely in high-density fractions. Their evaluations did not reveal any interactions between immunoglobulins or high-density fractions and intermediate-density particles. The data is published in the Journal of Medical Virology, 2002;68(3):335-342).

"Elucidation of the mechanisms by which these particles are generated and maintained in the blood may provide valuable insight into the mechanism of viral persistence," said investigators.

Key points reported in this study include:

• Hepatitis C virus (HCV) particles can be found in low-, intermediate-, and high-density fractions of blood of immunocompromised HCV-positive patients
• Among immunocompetent patients, HCV particles are primarily identified in intermediate-density fractions, suggesting antibody-mediated clearance from high- and low-density fractions
• The study of HCV particles in the different fractions of HCV-positive patients may reveal important information about viral persistence

Lamivudine too little, too late for chronic hepatitis B flare
by Sonia Nichols, senior medical writer of NewsRx.com

People with severe exacerbations of chronic hepatitis B may not respond to lamivudine, according to a Hong Kong study.

"Patients with chronic hepatitis B may develop severe disease exacerbations (flare) with jaundice, and some may progress to fulminant hepatic failure," described Henry Lik-Yuen Chan and colleagues, the Chinese University of Hong Kong.

Lamivudine cannot control such exacerbations, and patients who demonstrate such flares, particularly in the face of thrombocytopenia and high bilirubin levels, are good candidates for liver transplantation, Chan and coauthors recommended.

For their study, Chan's team compared lamivudine-treated chronic hepatitis B patients with severe flare against those who did not receive treatment. They described flare as the onset of jaundice with simultaneous fivefold elevations of alanine aminotransferase (ALT) values. Altogether, researchers evaluated 46 patients.

"Overall, nine patients died and two other received liver transplants for fulminant hepatic failure," Chan and colleagues commented.

Similar percentages of lamivudine-treated patients (21.4%) and control, untreated patients (27.8%), either died or were given liver transplantations.

Independent predictors for liver-related deaths among chronic hepatitis B patients with flare included lowered platelet levels, or thrombocytopenia, and elevated bilirubin levels. This data is published in the Journal of Viral Hepatitis, 2002;9(6):424-428).

"The mortality of patients who had thrombocytopenia and high bilirubin, thrombocytopenia, high bilirubin, and no risk factor were 69.2%, 11.1%, 12.5%, and 0%, respectively.

Patients who develop hepatitis B flare are not likely to attain extended survival with lamivudine, Chan and colleagues cautioned. "Patients with thrombocytopenia and high bilirubin should be considered for liver transplantation," they suggested.

Key points reported in this study include:

• Severe exacerbations or flares among chronic hepatitis B patients can lead to liver failure
• Similar percentages of patients with flare died or received liver transplantations regardless of whether or not they received lamivudine
• Lamivudine does not provide a survival advantage for chronic hepatitis B patients who experience severe flare

December 17th, 2002

Synthetic ribozymes a potential treatment for hepatitis B virus
by Sonia Nichols, senior medical writer for NewsRx.com

Synthetic particles that can cleave viral RNA have demonstrated effectiveness in hepatitis B virus (HBV) experiments. Researchers at Ribozyme Pharmaceuticals in Boulder, Colorado, developed the particles, which are synthetic ribozymes.

"To explore the use of ribozymes as a novel therapy for HBV infection, nuclease-resistant ribozymes that target highly conserved regions of HBV RNA were screened in cell culture," explained David D. Morrissey and coworkers. The novel constructs not only cleaved the major HBV RNA transcripts, but could cleave pregenomic RNA as well, researchers indicated.

"A number of the screened ribozymes demonstrated activity in cell culture systems, as measured by decreased levels of HBV surface antigen, HBV e antigen and HBV DNA," Morrissey and colleagues said.

One was even effective against a HBV mutant with resistance to lamivudine. The data is published in the Journal of Viral Hepatitis, 2002;9(6):411-418).

Investigators also evaluated the ribozymes in laboratory animals. "Treatment of HBV transgenic mice with lead anti-HBV ribozymes significantly reduced viremia compared with saline-treated animals and was as effective as treatment with lamivudine," they said.

The new ribozymes could be effective as monotherapy or in combination with other therapies for treating HBV, Morrissey and coauthors proposed.

Key points reported in this study include:

• Ribozyme Pharmaceuticals has developed synthetic ribozymes that can cleave pregenomic and major hepatitis B virus (HBV) RNA transcripts
• The ribozymes reduce HBV viremia in study animals and are effective against lamivudine-resistant HBV mutants in cell culture
• The synthetic ribozymes could be useful for treating HBV as monotherapy or in combination with other drugs

Schering-Plough probe deepens

Schering-Plough's marketing and accounting practices are being subject to scrutiny by the authorities in Massachusetts. There are allegations that Schering-Plough has inflated its sales figures by offering financial incentives for overstocking and using unethical incentives for doctors and pharmacists to sign contracts for the supply of several of its products including the cancer drug Intron A and hepatitis drugs Temodar and Rebetron. Other companies subject to similar scrutiny include Merck and Bristol-Myers Squibb.

Liver failure in the United States often caused by drug reactions

Researchers in the latest issue of the Annals of Internal Medicine (Ann Intern Med 2002; 137(11): 947) find that acute liver failure is most frequently caused by medication reactions.

Acute liver failure, in which the liver deteriorates over a period of days or weeks, is a relatively rare condition, with about 2000 cases in the United States each year.

Previous studies have suggested that hepatitis is the most common cause of acute liver failure. However, in this study, published in the latest issue of Annals of Internal Medicine, researchers found that failure was most frequently caused by medication reactions.

The team prospectively assessed 308 patients with acute liver failure admitted to one of 17 special liver-care centers in the United States.

They found acetaminophen overdose to be the single most common cause of acute liver failure.

Acetaminophen overdose is the single most common cause of acute liver failure.

Overall survival in this study was 67 %, with 132 patients surviving without liver transplantation.

This study shows how rapidly the disease progresses and the importance of early transfer to intensive care settings.

The research team stresses the need to better predict outcomes, so that transplantation is reserved for those who cannot survive without it.

December 18th, 2002

Prevalence of liver disease in asymptomatic persons with hepatitis C virus infection

Hepatitis C is histologically active and progressive in up to 40% of asymptomatic persons with HCV infection, find researchers in the latest issue of the Annals of Internal Medicine (Ann Intern Med 2002; 137: 961-4).

The prevalence of significant liver disease in people with asymptomatic hepatitis C virus (HCV) infection is unclear. In this study, researchers from Padova, Italy, determined the prevalence and severity of HCV infection in asymptomatic individuals. The research team performed a population-based cross-sectional study. Prevalence of HCV infection increased with age.

They assessed 4820 subjects who were undergoing screening for cardiovascular risk factors. The team performed initial screening for anti-HCV by enzyme-linked immunosorbent assay. This was followed by HCV RNA testing by polymerase chain reaction, and monitoring of alanine aminotransferase levels in viremic persons. In addition, 92% of viremic subjects had liver biopsies to assess their METAVIR scores.

The research team found that 116 subjects were positive for anti-HCV, 85 of these were also viremic. ALT levels were normal in 46% of viremic patients, but elevated in 54%.

The team detected significant hepatic histologic abnormalities in 19% of patients with persistently normal ALT levels, and in 61% with elevated ALT levels. Furthermore, they found that the prevalence of HCV infection, and number of subjects with chronic liver fibrosis increased with age.

Dr Alfredo Alberti's team concluded, "Hepatitis C is histologically active and progressive in up to 40% of asymptomatic persons with HCV infection".

"The severity of liver disease correlates with abnormal ALT levels and increases with age".

HCV Treatment in HIV-Coinfected Patients Increases QOL and Is Cost Effective

Interferon-based treatment of HIV patients with moderately severe hepatitis C (HCV) increases quality-adjusted life expectancy. Moreover, the cost-effectiveness ratio is comparable to that of other accepted clinical interventions, investigators report in the Archives of Internal Medicine for December 2002 (Arch Intern Med 2002;162:2545-2556).

Dr. Sue J. Goldie, of Harvard School of Public Health in Boston, and colleagues used a "deterministic state-transition Markov Model" to simulate a cohort of 35-year-old coinfected patients with moderate HCV and a mean CD4 cell count of 350 cells/L. They used data from more than 100 clinical studies to establish plausible ranges for multiple variables.

Treatment was defined as interferon-alfa 3 MIU 3 times/week or pegylated interferon alfa 1.5 g/kg once weekly, with ribavirin 1000-1200 mg/day or 800 mg/day for each regimen, respectively.

Their model was based on "conservative assumptions about the natural history of HCV and treatment efficacy," Dr. Goldie's team notes. They estimate the average discounted quality-adjusted life expectancy to be 83.8 months in this cohort, with average lifetime costs of $139,000.

For patients with genotype 1 HCV, the cost-effectiveness ratio of pegylated interferon alfa and ribavirin therapy was less than $40,000 per quality-adjusted life year (QALY) gained.

For patients with non-1 genotypes of HCV, the cost-effectiveness ratio of interferon alfa and ribavirin therapy was less than $50,000 per QALY. Because treatment tends to be more effective in this subgroup of patients, substituting pegylated interferon alfa caused the ratio to exceed $100,000 per QALY.

However, when ribavirin is not tolerated, pegylated interferon alfa appears to be the best option for all genotypes of HCV, the report indicates.

December 19th, 2002

Live Organ Donation: One Step Forward, Two Steps Back

The widespread adoption of live donor organ donation in kidney and liver transplantation has reaped a number of positive medical and economic benefits, including shorter hospital stays and a faster recuperation time. Nevertheless, significant educational, outreach, and ethical challenges face the organ transplant community, according to speakers at this conference on quality in organ donation and transplantation, sponsored by the National Committee for Quality Health Care, a Washington, DC health policy group.

The benefits of shorter waiting times due to the availability of live vs cadaveric donor organs do not apply to all patients equally, several speakers observed. Recent data from the United Network for Organ Sharing comparing access to live kidney donor organs highlighted the disparity between African-Americans and whites. African-Americans received 13.5% of live donor organ kidney transplants, compared with 86.5% among the non-African-American transplant patient population. These data are especially important considering the high incidence of kidney disease among African-Americans, according to Stephen T. Bartlett, MD, of the University of Maryland, Baltimore.

Speakers urged more than 150 attendees to improve the quality of live donor educational and outreach programs, develop more sophisticated risk assessment programs that factor in a donor's psychological suitability and ability to withstand financial hardship, create a national live donor registry to track donors' outcomes, and pay more attention to the ethical considerations inherent in live organ donation.

Increasing the Organ Supply with Live Donors

Despite the recent advances made in surgical techniques for kidney transplantation, balancing the escalating demand for organs against the supply remains one of the "big issues" facing the transplant community, noted Lloyd E. Ratner, MD, of Thomas Jefferson University Hospital, Philadelphia, Pennsylvania. "We are winning a lot of individual battles, but losing the war," he said.

According to November 2002 data from the United Network for Organ Sharing (UNOS), 53,270 patients are awaiting a kidney for transplantation. Kidney transplant candidates represent the largest share of the total number (80,238) of patients awaiting an organ donation.

Dr. Ratner, a renal transplant surgeon who performed the world's first laparascopic live donor nephrectomy in 1995 at Johns Hopkins, said the supply of cadaveric organs had dwindled over the past decade due to improved medical and surgical care that saves the lives of young trauma victims. Consequently, cadaver organs are more often from elderly individuals and are not as often successfully transplanted as those from younger donors. "Not all organs are created equally," he said.

Dr. Ratner outlined the medical and economic benefits of live donor vs cadaveric transplantation: shorter hospitalization, elimination of waiting time, avoidance of dialysis, improved patient graft survival, and cost-effectiveness. According to Dr. Ratner, "Live donors are a better option - period." To boost the availability of organs from live donors, he suggested that the transplant community consider loosening the criteria for donation while at the same time improving risk assessment of donor candidates. Currently, most transplant centers do not have a mechanism for long-term follow-up related to donor risks, such as developing end-stage renal disease, even though risks are small in the ideal donor.

Suitable live kidney donor candidates include:

• Older donors, even those 70 years of age or older
• Individuals with hypertension or obesity
• Individuals using nonsteroidal anti-inflammatory agents to control arthritis
• Individuals with hepatitis C virus (HCV) infection
• Individuals with a family history of diabetes mellitus
• Altruistic strangers, or those who want to donate an organ to someone they don't know.

December 20th, 2002

New Rules Approved for Live-Donor Liver Transplants in New York
By Martin F. Downs

A panel of experts has approved new rules aimed at improving safety for living donors of partial livers for transplantation performed in New York State.

The panel, convened to advise New York State Department of Health Commissioner Antonia Novello, unanimously approved the guidelines on Thursday. A spokesman for the health department, Robert Kenny, told Reuters Health that it will be "a top priority of Commissioner Novello to begin implementation."

Kenny said the regulations could be enacted as early as April 2003.

Drafting of the guidelines was prompted by the death of a Michael Hurewitz, 57, early this year at New York City's Mount Sinai Medical Center, after he donated a lobe of his liver to his brother. An investigation found that poor care following the surgery was to blame for Hurewitz's death. "The after-care was woefully inadequate," Kenny said.

One issue in Hurewitz's case was a shortage of medical staff in the ward where he had been recovering. The new rules mandate that during the first 24 hours after a transplant, one nurse must be on duty for every two patients. Later, the ratio can widen to one nurse for every four patients.

Also, doctors must be notified of any problems with a patient within 30 minutes, and doctors must be available to respond to emergencies at all times.

The guidelines also call for independent teams to act on behalf of living donors. The teams should be made up of at least a physician who specializes in internal medicine, a nurse clinician to act as transplant coordinator, and a medical social worker, who may seek advice from a psychiatrist or a medical ethicist.

This team will explain the risks of transplantation to the potential donor; and they may, if they see fit, deny the donor's intentions after evaluating the case. There will be a mandatory 2-week "reflection and reaffirmation period" before the donor can finally agree to the operation.

"They're the most comprehensive regulations in the country," said Dr. Lewis Teperman, director of transplantation at New York University Medical Center, in an interview with Reuters Health. Dr. Teperman served on the panel that drafted the rules. "I believe this will be the blueprint that the rest of the country follows," he said.

Shortly after Hurewitz died on January 13, Mount Sinai voluntarily ceased live-donor liver transplants, before the state forced them to do so. "They're working toward improving," Kenney said. Officials will visit the hospital for an unannounced inspection sometime in January 2003, and if improvements the hospital has made are deemed satisfactory, the ban may be lifted. "If there are issues, it will not be lifted," Kenny said.

"We're hopeful," said Dr. Leona Kim, director of Mount Sinai's Recanti-Miller Transplantation Institute, in an interview with Reuters Health.

She said she wholly supports the rules proposed in the Department of Health's document. "It should be put into place," she said. She was especially enthusiastic about creating teams of donor advocates. "That is one of the best things to come out of the document," she said.

Red Cross May Have Released Unsafe Blood

The American Red Cross may have released tainted blood to hospitals, the government said Friday, reporting more than 200 violations of federal blood safety rules in its battle to get the Red Cross to improve the quality of its blood operation. The Food and Drug Administration said it was investigating further to determine whether patients received bad blood.

"The blood supply is not as safe as it should be," said FDA Commissioner Mark McClellan. "I am troubled by apparent lapses in blood safety."

The Red Cross, which provides 45 percent of the nation's blood supply, said it is working hard to improve safety.

A year ago, the FDA went to court seeking contempt charges for 10 years of Red Cross safety violations. Friday's preliminary report on safety at the Red Cross biomedical headquarters suggests the problems have not been fixed, McClellan said, suggesting they point to "a culture willing to accept noncompliance."

Specifically, the FDA alleges that some Red Cross employees were instructed to skip required safety steps, and others altered records, to allow release of blood that had failed safety testing.

In addition, the Red Cross failed to screen out some people who were not supposed to give blood, the FDA said. It was unclear what happened to the units these people donated, the agency said.

More than 1,000 units of blood were unaccounted for, it said.

The FDA emphasized that anyone who needs a blood transfusion should get one, because the risk of forgoing a medical procedure is much higher than the risk of getting bad blood. The agency also noted that people who donate blood face no risk.

The Red Cross acknowledged problems and promised to fix them.

"The Red Cross understands more work needs to be done to further strengthen our processes and procedures, and we are fully committed to working collaboratively with the FDA to enhance our systems," Remesh Thadani, who heads biomedical services, said a statement Friday.

More than 200 individual violations were identified, the FDA said. Among them:

• Lack of management control and quality assurance oversight. Required testing steps were not always documented, and some employees reported being told to skip required steps.
• Data integrity: Employees were alleged to have changed records to indicate that flagged blood was safe.
• Failure to correct deviations from previous inspections, including failure to follow standard operating procedures.
• Release of unsuitable products. Donors in one Red Cross region who are found unsuitable are supposed to be listed in a donor deferral registry. They were not, and some went on to donate in other regions. In some cases, the FDA does not know what happened to their donated blood.

IGF-1 Levels Predict Liver Cancer in Patients with HCV-Related Cirrhosis Reductions in serum levels of insulin-like growth factor 1 (IGF-1) correlate with the development of hepatocellular carcinoma in patients with hepatitis C (HCV)-related cirrhosis, according to results of prospective study conducted in Italy.

Measuring IGF-1 levels "may improve the effectiveness and the cost-benefit ratio of surveillance for patients with hepatocarcinoma," allowing "precocious diagnosis" of liver tumors, Dr. Carlo Carella, of Second University of Naples, and associates suggest in the December 15th issue of Cancer (Cancer 2002;95:2539-2545).

Included in their study were 104 patients with Child Grade A cirrhosis and no evidence of liver cancer. The patients, who were recruited in 1995, underwent ultrasound examinations of the liver and serum alpha-fetoprotein (AFP) testing every 6 months, and serum IGF-1 levels were assessed at least yearly.

By December of 2000, 11 patients with Child Grade A cirrhosis and 9 with cirrhosis that had progressed to Grade B had been diagnosed with liver cancer.

At baseline, IGF-1 levels averaged 70.7 g/L for patients who did not develop cancer and 72.0 g/L for those who did, not a significant difference, the authors note. However, levels dropped significantly during follow-up to 33.8 g/L (p = 0.001) among patients subsequently diagnosed, but did not change significantly among those who remained cancer-free.

Additional analysis from 17 patients who developed hepatic carcinoma showed that 21 months before their cancer diagnosis, IGF-1 levels did not differ significantly from baseline. However, 9.3 months prior to their diagnosis, mean IGF-1 levels had declined significantly (p = 0.002).

"The occurrence of a yearly reduction in serum IGF-1 levels > 9.3 g/L should induce clinicians to start more aggressive surveillance (at 3-month intervals) of patients to obtain an early diagnosis of hepatocellular carcinoma," Dr. Carella's group recommends. "Less aggressive surveillance (at 12-month intervals) could be continued in the other patients with lower decreases in serum IFG-1 levels."

The authors note that serum AFP levels were elevated in only 25% of patients who developed cancer. They conclude that serum IGF-1 levels possess greater diagnostic accuracy than do AFP determinations.

December 22nd, 2002

Syringe exchange proves effective
Source: NewRx.com

Drug users with access to controversial syringe-exchange programs are up to six times less likely to put themselves at risk of HIV infection, according to a new University of California Davis.

"While programs to control the spread of HIV by providing clean needles to drug users remain controversial in California and around the country, this study clearly shows that syringe-exchange programs save lives - and save society millions of dollars in health care costs required to treat HIV patients," said lead author David R. Gibson, associate professor of infectious and immunologic diseases at UC Davis and a senior scientist at UC San Francisco's Center for AIDS Prevention Studies.

Injection drug use is linked to about one-third of all HIV/AIDS cases, according to the U.S. Centers for Disease Control and Prevention. Drug users contract these diseases by sharing contaminated syringes. To curb this high-risk behavior, syringe exchanges operate in a variety of settings, including storefronts, vans, sidewalk tables, health clinics, and places where drug users gather.

The first organized syringe-exchange programs in the United States were established in the late 1980s, despite strong opposition from some communities on moral grounds - opposition that continues today.

"While this study should open the way to a more fact-based discussion of these controversial programs, a small, vocal minority simply refuses to look at the scientific evidence - they are essentially 'data-proof,'" Gibson said in the Journal of Acquired Immune Deficiency Syndromes. This data is published in the J Acquir Immune Defic Syndr, 2002;1;31(2):237-242).

The UC Davis study offers the most detailed examination to date of the complex factors of the role of syringe exchanges in reducing HIV risk behavior, Gibson said. The study addressed several key challenges that have tended to distort the findings of previous syringe-exchange studies, he added.

For instance, the study did a better job than previous studies in correcting for pre-existing differences between injecting drug users who seek to use a syringe-exchange program compared with those who do not. In addition, the study controlled for other sources of syringes that drug users may have and compared drug users who had other sources of syringes with those without other sources.

To adjust for these factors, the UC Davis researchers adopted more rigorous statistical controls than previous studies.

Among injecting drug users who already have some access to clean syringes, a syringe-exchange program results in a two-fold reduction in HIV risk behavior, said Gibson. For drug users with no other easy access to clean syringes, the benefits are even more significant - a six-fold reduction in risk behaviors. Syringe-exchange programs will naturally appear less effective in communities with multiple sources of clean syringes compared with programs that constitute a community's only supply.

"These findings underscore just how critical syringe exchange may be for all injecting drug users, but especially those who lack the resources or contacts to obtain syringes in other ways," said Gibson. "It also suggests syringe-exchange programs can be most effective in reducing HIV by focusing on getting sterile syringes to these most vulnerable drug users."

The findings are especially relevant in California in the wake of an intense debate over Senate Bill 1785, which would have allowed pharmacies to sell syringes to adults without a prescription. Gov. Gray Davis vetoed the bill in late September because it did not require a one-to-one needle exchange. Without this provision, Davis said, the bill could increase the number of contaminated needles and syringes in parks, beaches, and other public areas.

"Without access to clean syringes through pharmacies, injecting drug users must continue to rely on exchange programs to avoid high-risk behavior and curb the spread of HIV," said Gibson.

The study followed a group of 259 untreated injecting drug users in the San Jose area. Each of the participants was interviewed at the beginning of the study and then participated in follow-up interviews - an average of about 11 months later. Some of the participants were clients of the San Jose syringe exchange, which used a mobile van to visit five sites frequented by injecting drug users.

The new study builds on a July 2001 UC Davis study, also lead by Gibson, which reviewed 42 studies on syringe-exchange programs from the United States, Canada, the United Kingdom and the Netherlands. The study concluded that previous studies often underestimated the effectiveness of syringe-exchange programs in communities where clean needles can be easily obtained from sources other than the syringe exchange.

In addition, researchers have found that in areas where drug users have a choice between syringe exchange and legally obtaining syringes from pharmacies, the higher-risk users tend to gravitate to syringe-exchange programs. As a result, the syringe exchanges appear less effective when users of syringe exchange are compared with nonusers.

The first organized syringe-exchange programs in the United States were established in Tacoma, Washington; Portland, Oregon; San Francisco; and New York City. By 1997, there were 113 programs in more than 30 states, the District of Columbia, and Puerto Rico, which exchanged more than 17 million syringes, according to the CDC.

December 23rd, 2002

Infants of hepatitis B virus carriers benefit from vaccine alone
by Sonia Nichols, senior medical writer for NewsRx.com

Doctors in Thailand think hepatitis B virus vaccine alone is sufficient to protect against vertical transmission in most infants born to women who are hepatitis B virus carriers.

The physicians reported in the journal Vaccine that based on a study of 97 infants, routinely vaccinating every infant against HBV would be beneficial to most infants who live in areas where HBV infection rates are high and the mother's hepatitis B status may not be known.

"The primary objective of this study was to estimate the efficacy of a recombinant hepatitis B vaccine (H-B-VAXII) in preventing chronic hepatitis B infection when given alone without concomitant HBIG to healthy Thai infants born of hepatitis B e antigen (HBeAg)-positive carrier mothers," said Somsak Lolekha and coauthors, Mahidol University, Bangkok, Thailand.

Investigators gave two sets of infants the hepatitis B vaccine on two different vaccination schedules. The first group (schedule A) received their vaccinations at birth and again when they were 1 and 6 months old. The second group (schedule B) also received their first immunizations at birth, but subsequent doses were administered when the infants were 2 and 12 months old.

"At 13 months, 5 (10%) of 50 infants vaccinated on schedule A and 7 (14.9%) of 47 infants vaccinated on schedule B had experienced chronic HBV infection," Lolekha and colleagues reported.

According to the researchers, HBV infection rates of 70% or 90% are normally anticipated among infants who do not receive HBV vaccine when they are born to HBeAg-positive mothers. Therefore, the investigators predicted overall efficacy rates of 82.3% or 86.2%, respectively, for both vaccine schedules in immunized infants. They also prepared schedule-specific estimates, which showed schedule A may be more effective than schedule B. This data is published in Vaccine, 2002;20(31-32):3739-3743).

"These results suggest that in areas of high endemicity, where mothers may not always be screened for HBV infection, routine vaccination of infants at birth with a course of hepatitis B vaccine alone should be highly protective, even for very high-risk infants of HBeAg-positive mothers," Lolekha and coauthors predicted.

Key points reported in this study include:

• Infants born to mothers who are hepatitis B virus (HBV) carriers bear the risk of acquiring HBV infection through vertical transmission
• The 6-month and 12-month HBV vaccine schedules, when administered without HB immune globulin, protected most infants of HBV carriers
• Administering HBV vaccine to all infants in areas with high HBV infection rates would protect most infants against vertical transmission

Lamivudine adds layer of protection to recipients of core-positive livers
by Sonia Nichols, senior medical writer for NewsRx.com

Lamivudine can prevent de novo hepatitis B virus (HBV) infections in the recipients of hepatitis B core antibody (anti-HBc)-positive livers, doctors in Taiwan contend.

Physicians in many Asian countries often use portions of livers that have been exposed to HBV for transplantation.

"Exclusion of liver grafts from anti-HBc positive donors to prevent de novo HBV infection after liver transplantation is not feasible in areas highly endemic for HBV virus like Taiwan, where approximately 80% of adults are anti-HBc-positive," explained Yaw-Sen Chen and coauthors in Clinical Transplantation. Chen's team works at Kaohsiung Medical Center in Kaohsiung, Taiwan.

Lamivudine prophylaxis seems to stem de novo HBV infections after liver grafting with living liver donor anti-HBc-positive livers, according to Chen and colleagues. The team studied transplantations in 42 patients who received 42 donated liver grafts, of which 24 were anti-HBc-positive. Doctors made sure that each patient received HBV vaccines on an accelerated schedule before they underwent transplant surgeries.

"Until December 1997, 8 recipients received liver grafts from anti-HBc-positive donors without prophylaxis," Chen and colleagues said. "Since January 1998, prophylaxis with lamivudine monotherapy was given to 16 recipients receiving liver grafts from anti-HBc-positive donors."

Although de novo hepatitis developed in over a third of the 8 patients who did not receive lamivudine, no new infections developed among the 16 patients who did receive it. The data is published in Clin Transplant, December 2002;16(6):405-409).

Researchers were uncertain as to whether or not vaccination before transplantation played a role in augmenting lamivudine efficacy against de novo infection.

"Lamivudine monotherapy for recipients receiving anti-HBc-positive liver grafts is a simple, relatively inexpensive, and effective prophylactic regimen for prevention of de novo HBV Infection," Chen and coauthors recommended.

Key points reported in this study include:

• Due to high hepatitis B virus (HBV) prevalence in Asia, anti-HBc-positive liver grafts are frequently used for liver transplantation
• No de novo HBV infections developed among 16 transplanted recipients of anti-HBc-positive liver grafts who received lamivudine
• Lamivudine prophylaxis is well tolerated and may prevent de novo HBV infections when anti-HBC-positive liver grafts must be used for transplantation

December 30th, 2002

Red Cross Did Not Probe Infections
By Lauran Neergaard

The American Red Cross received reports that 134 people, including one who died, got hepatitis B after blood transfusions, but the organization did not investigate them because of internal policies that violate government safety rules, federal regulators say. In one case, an Ohio Red Cross chapter challenged the policies and eventually uncovered two additional patients who got the dangerous liver infection after transfusions that came from the same blood donor. The evidence got that donor kicked off the blood donor list, government records show. They are the latest in a series of revelations about safety violations that have plagued the Red Cross for more than 10 years. The Food and Drug Administration, which uncovered the hepatitis infections in a recent inspection of Red Cross headquarters, is pushing the organization to find out if bad blood really caused the rest of the infections.

"We will insist that they follow up," FDA spokesman Brad Stone said Monday. But the hepatitis examples show that "the blood supply is much less safe than the Red Cross, and even to some extent the FDA, has led people to believe," said Dr. Sidney Wolfe of the consumer advocacy group Public Citizen, which is urging a congressional investigation of Red Cross problems. While previous FDA inspections have uncovered procedural errors that could have harmed patients, this one may have uncovered a death, said Wolfe, who alerted lawmakers to the documents on Monday.

The Red Cross declined comment on the hepatitis cases Monday. But the charity, which provides 45 percent of the nation's blood supply, reiterated a statement it recently released saying it is working hard to improve overall safety. "The Red Cross understands more work needs to be done to further strengthen our processes and procedures, and we are fully committed to working collaboratively with the FDA to enhance our systems," that statement said.

The FDA cited the hepatitis discovery as one of more than 200 violations of federal safety rules it found during its latest inspection of Red Cross headquarters. The FDA also alleges that some Red Cross employees were instructed to skip required safety steps, and others altered records to allow release of blood that had failed safety testing.

In addition, the FDA charged the Red Cross failed to screen out some people who weren't supposed to give blood, and couldn't account for what happened to the resulting donations.

In the case of the hepatitis reports, the FDA said the failure to investigate the 134 cases resulted from Red Cross policies that limit the number of possible blood-related infections the charity investigates. It said those policies violated federal safety standards that the charity agreed to follow as part of an ongoing legal battle with the government.

Specifically, the policies called for investigating only if the donor was known to have had an abnormal hepatitis test or didn't qualify to give blood, and forbade investigation if the patient received transfusions from more than 10 donors, FDA documents say.

In January 2001, a northern Ohio Red Cross chapter got special permission to investigate one hepatitis infection linked to multiple transfusions, and discovered that one of the donors involved had been linked to an earlier, unproven hepatitis infection, the FDA inspectors found. After that discovery, the Red Cross barred the donor from giving again. The FDA called such policies a violation of a 1993 court order demanding that the Red Cross improve its safety procedures to comply with federal standards. Last year, the FDA went back to court seeking contempt charges against the Red Cross for repeated safety violations since 1993. The FDA and Red Cross have been in negotiations for several months to settle those charges.

New test quickly identifies both surface and e antigen of hepatitis B
by Sonia Nichols, senior medical writer for NewsRx.com

A new test evaluated by researchers in Ghent, Belgium can quickly and accurately identify hepatitis B virus (HBV) surface and e antigen.

The test can discriminate between active or carrier status. It should allow for rapid identification of people who would benefit from either vaccination or treatment say researchers who evaluated the test, which was developed by Binax, Inc., of Portland, Maine.

Researchers at Ghent University and Hospital in Belgium used the HBsAg/eAg test on 942 serum samples. "The clinical sensitivity of the HBsAg/eAg test was 99.75% and 96.37% for HBsAg and HBeAg, respectively," F. Clement and coworkers announced. Specificity for HBsAg and HBeAg was 99.32% and 98.99%, respectively.

Clement suggested the test could be used for population screening and that it could be read with accuracy for at least 3 hours beyond the time deemed acceptable for evaluation The data is published in the Journal of Clinical Microbiology, December 2002;40(12):4603-4606.

An added advantage of the test was that it did not cross-react with other substances, according to researchers. "In addition to the good clinical specificity and sensitivity of this test, its stability and user-friendly design mean that a correct performance, even under field conditions, is highly likely," they said.

Key points reported in this study include:

• A new test developed at Binax, Inc., can detect hepatitis B virus (HBV) surface and e antigen with a high degree of accuracy
• The test is appropriate for population screening
• The test should enable clinicians to quickly identify who needs HBV vaccine and who needs antiviral therapy

Nitric oxide synthase a contributor to hepatitis pathology
by Sonia Nichols, senior medical writer for NewsRx.com

Significant staining for inducible nitric oxide synthase in the liver tissues of chronic viral hepatitis patients suggests the enzyme may foster pathological changes, scientists in Mersin, Turkey, argue.

"Elevated nitric oxide production is assumed to be responsible for the pathological changes in many inflammatory conditions, mainly via peroxynitrite, a potential oxidant that is produced by the reduction of superoxide anion with nitric oxide," said O. Kandemir and colleagues, University of Mersin School of Medicine.

Inducible nitric oxide synthase staining analysis shows nitric oxide may play a greater role than previously believed in hepatitis pathology, according to a report issued by the researchers.

"The intensity and distribution of the immunohistochemical staining of intrahepatic inducible nitric oxide synthase were studied in the biopsy specimens obtained from 63 patients with viral hepatitis and 13 patients with elevated transaminase levels of various etiologies," described Kandemir and coauthors.

Staining for inducible nitric oxide synthase was more intense in the viral hepatitis group than in the control group, study data showed. In addition, the intensity of inducible nitric oxide synthase staining significantly associated with hepatitis severity based on Knodell scoring. This data is published in the Journal of Viral Hepatitis, 2002;9(6):419-423).

"Among the viral hepatitis group, the pathological distribution of the inducible nitric oxide synthase staining favored the periportal hepatocytes (zone 1), whereas less staining was observed in parenchymal hepatocytes (zones 2 and 3), and bile duct epithelium," researchers noted.

Based on the evaluations, Kandemir and colleagues concluded inducible nitric oxide synthase could be crucial for modulating some pathogenesis in the livers of those with chronic viral hepatitis.

Key points reported in this study include:

• Intense staining for inducible nitric oxide synthase can be detected in the liver biopsies of patients with chronic viral hepatitis
• Staining for inducible nitric oxide synthase correlates with histological activity index in livers of chronic viral hepatitis patients
• Inducible nitric oxide synthase may be responsible for some pathogenesis in the livers of patients with chronic viral hepatitis

January 2nd 2003

Blood Factors for Hemophilia Don't Spread Virus-CDC

Virally inactivated blood products used to treat patients with bleeding problems are unlikely to spread hepatitis, according to a new report from the Centers for Disease Control and Prevention.

Since 1998, the CDC and roughly 140 federally funded hemophilia treatment centers have monitored the safety of blood products through the Universal Data Collection surveillance project, the CDC's Dr. Anna Kirtava and colleagues note in January 3rd issue of the Morbidity and Mortality Weekly Report (Morbidity and Mortality Weekly Report 2003;51:1152-1154).

The blood of people with hemophilia does not clot properly, putting them at risk of uncontrolled bleeding. Hemophilia patients are treated with concentrates containing factors that help blood clot, which can contain blood donated by many different people. While there were outbreaks of hepatitis and HIV among people with hemophilia who received such products in the 1970s to early 1990s, manufacturers now use procedures to inactivate any viral material present in blood factor products.

In investigations conducted between May 1998 and June 2002, 1,149 patients with bleeding disorders seroconverted to hepatitis-positive status. This means that their blood went from being free of antibodies to the hepatitis virus to containing these antibodies, but does not necessarily signify infection with the virus. For example, vaccination for hepatitis causes seroconversion.

Importantly, the researchers say, "none of these cases was attributable to blood products received during this time period."

Most seroconversions of hepatitis A virus (HAV) and hepatitis B virus (HBV) could be attributed to vaccination, 99% and 90%, respectively, they report. The remaining seroconversions most likely represented infections from other sources, or "fluctuations in antibody levels" that can occur in people with HIV.

Vertex, Lilly Restructure Drug Deal

Vertex Pharmaceuticals Inc. on Thursday said Eli Lilly and Co. (NYSE:LLY - news) will not participate in development of an experimental treatment for hepatitis C and said clinical trials of the drug have been delayed to later this year.

In January 2002, the two companies had announced plans to develop the antiviral drug, VX-950, a protease inhibitor, and to begin testing it in humans early this year. Under terms of the collaboration, Vertex received a $5 million milestone payment from Lilly.

Vertex said it now plans to begin clinical testing of VX-950 in the second half of 2003.

Vertex, based in Cambridge, Massachusetts, said it and Lilly mutually decided to restructure the agreement due to Lilly's reprioritization of its research portfolio and Vertex's own desire to focus on specialty pharmaceutical markets and retain greater downstream rights to its own compounds.

Vertex said it obtained worldwide rights to compounds identified during the companies' collaboration, while Indianapolis-based Lilly will receive royalties on any future net sales. Financial terms were not disclosed.

The drug VX-950 is a small molecule protease inhibitor from a new class of antiviral drugs that inhibit hepatitis C NS3-4A protease, an enzyme considered essential for hepatitis C viral replication.

Shares of Vertex, which rose 51 cents to close at $16.36 on the Nasdaq exchange, were trading lower at $16.20 after hours on Instinet. Shares of Lilly, which rose $2.74 to close at $66.24 on the New York Stock Exchange (news - web sites), were not trading after the market close.

January 3rd 2003

Label Issues Are Delaying Generic Drugs
By Melody Petersen

When the patent on Rebetol, a drug used to treat hepatitis C, expired in June, patients hoped that they would be able to buy a generic form of the medicine to help lower the $20,000 cost of treatment.

They are still waiting.

The company that wants to sell a lower-price generic version of Rebetol says that government approval is being held up by a technicality that is proving to be quicksand for many generic medicines—a dispute about the drug's label.

The manufacturer, Three Rivers Pharmaceuticals, filed an application with the Food and Drug Administration 17 months ago to make ribavirin, the generic name for Rebetol, which Schering-Plough sells for about $10 a capsule. While Three Rivers will not say how much it plans to charge, patient advocates say they expect ribavirin to sell for about half that price.

Paul F. Fagan, general counsel at Three Rivers, said that regulators have told the company that the delay stems from one sentence on the drug's label.

The label that the F.D.A. is focused on is not the one on the outside of the bottle or jar, but rather pages of information that physicians rely on. The label includes detailed instructions on how the medicine should be used, as well as information on its adverse side effects and results from clinical trials.

Under federal law, labels on generic drugs must be nearly identical to those of the brand name product they replicate. Regulators appear to fear that Schering could sue the government, Mr. Fagan said, if they let Three Rivers copy the sentence, which refers readers to the label of another Schering product, Peg-Intron, that is prescribed in combination with ribavirin.

Patient advocates say the high cost of Rebetol is causing many people with hepatitis C to go untreated. More than four million Americans are infected with hepatitis C, and many of them are H.I.V.-positive.

''Rebetol is $10 a capsule for a drug that we believe costs 10 cents to make,'' said Brian D. Klein, the co-founder of the Hepatitis C Action and Advocacy Coalition.

An F.D.A. spokeswoman said the agency did not comment on pending applications.

The government's approval of ribavirin would not immediately allow the sale of the lower-cost drug because of litigation between Three Rivers and Schering-Plough. But the lack of F.D.A. approval is slowing the litigation, Mr. Fagan said.

Experts say that the experience of Three Rivers is not unique.

Steven Lieberman, a patent lawyer at Rothwell, Figg, Ernst & Manbeck in Washington, said that drug companies are increasingly trying to block lower-cost competition by taking advantage of federal laws requiring generic and brand name drugs to have the same labeling.

The labeling issues have become a minefield for the F.D.A., said Mr. Lieberman, who represents the makers of both generic and brand name drugs. Regulators know, he said, ''whatever move they make, they are likely to be sued by one side or the other.''

In one case last year, Bristol-Myers Squibb argued that federal laws prohibited the F.D.A. from approving a generic form of its diabetes drug Glucophage because of a recent addition to the medicine's label about its use by children. The move by Bristol-Myers outraged members of Congress, who passed a law that included language aimed at closing that loophole. But drug companies continue to find other ways to use their labels to forestall competition.

William O'Donnell, a spokesman for Schering-Plough, said that the company ''rejects any implication'' that it had tried to manipulate the drug's label to keep generic companies out of the market.

''Labeling for all products is the result of extensive consultation between the F.D.A. and the sponsoring company,'' Mr. O'Donnell said. ''There is nothing in the labeling of Rebetol that the F.D.A. does not believe should be there for the safe and effective use of this product.''

Schering-Plough also defended Rebetol's price. ''Products typically are not priced at the cost to make them,'' Robert J. Consalvo, another company spokesman, said. ''They're priced at the value they bring to the patient.''

Executives of Three Rivers say the delay is especially frustrating because the F.D.A. recently approved a second brand name version of ribavirin—Copegus, sold by Roche—in just six months.

''The brands get through quickly,'' Mr. Fagan said, ''and the generics seem to languish.''

The government approves brand name drugs in about 14 months, while generic drug approvals take roughly 18 months, according to F.D.A. statistics.

Recently, the Bush administration has tried to find ways to hasten generic drug approvals.

Gary Buehler, director of the F.D.A.'s Office of Generic Drugs, said the agency approved 384 generic drug applications last year, up from 307 in 2001. ''We are getting more generic drugs into the hands of the American public,'' he said.

President Bush has also proposed a rule aimed at limiting the ability of drug companies to delay generic manufacturers by filing secondary patents on their products.

In the litigation between Schering-Plough and Three Rivers, Schering is arguing that Rebetol is still protected by one or more patents. Schering has at least eight patents protecting Rebetol—many of them added in the last two years.

When such litigation is continuing, the F.D.A. grants the generic manufacturer tentative approval until the court case is settled.

Mr. Consalvo said that Schering-Plough is only trying to protect intellectual property that it rightfully owns.

Mr. Fagan of Three Rivers contends that the absence of tentative approval of generic ribavirin is stalling the litigation. He said that when Schering has asked for more time on certain issues, its lawyers have told the judge there is no need to hurry since Three Rivers has so far failed to get F.D.A. approval.

Left untreated, hepatitis C can cause cirrhosis, liver failure and liver cancer. The virus causes an estimated 8,000 to 10,000 deaths each year in the United States.

The current recommended treatment for patients with hepatitis C is ribavirin combined with peginterferon alfa, which Schering sells as Peg-Intron.

Recently, the F.D.A. approved Pegasys, Roche's peginterferon product, as well as Copegus, its version of ribavirin.

Most patients must take the two drugs for 48 weeks. Depending on the dosage, Rebetol can cost an uninsured patient as much as $20,000. The patient would pay another $10,000 for peginterferon.

Ribavirin is relatively inexpensive to manufacture. A pharmacy in Pittsburgh is selling it to hundreds of patients for $1.50 a capsule. That pharmacy, Fisher's SPS, is owned by many of the same people backing Three Rivers, which is based in Cranberry Township, Pa.

Doctors and patient advocates say that many patients—especially the uninsured and underinsured—are going untreated because of the high cost of Rebetol and Peg-Intron.

Patricia T. Gardner, a 46-year-old mother who says she believes she contracted the virus from gall bladder surgery, said she recently lost the insurance that had paid for most of her medicine. Ms. Gardner, who lives in Louisville, Ky., said she was suffering from severe cirrhosis and was not sure how she would pay for a year's worth of treatment.

''Shame on them all,'' she said, ''for making treatment impossible for those of us who have already lost everything we have to this disease.

Update on Ribavirin Pricing
By Brian Klein, MA, LMSW

Sadly, a year after all market exclusivities on brand ribavirin have expired, generic versions of ribavirin are still being held up by all too common frivolous court battles from brand pharmaceutical manufacturers and delays at FDA.

Generic Ribavirin

While generic ribavirin will certainly be more affordable than brand drugs, these obstacles are likely to affect the final price of generic versions of ribavirin when available. Currently three know generic makers are trying to get their versions approved by the FDA: Three Rivers, Geneva and Teva.

Brand Name Products: Rebetol and Copegus

Currently, Schering-Plough's Rebetol is priced at $10.50/capsule or $1764/month for 1200mg/day dosing. That represents a $111/month increase in the last year alone and $679/month increase over the price of Rebetol in Rebetron kits 3 and a half years ago.

Hoffman-La Roche's Copegus price will not be announced until it is marketed later this month [January 2003], but recent pricing of its pegylated interferon, Pegasys, has angered community members and made them wary of just what Copegus pricing will be. Roche's recent 12-week program to provide 15,000 patients with free Pegasys has been used up quickly and did not provide access to ribavirin to use with the pegylated interferon, a situation that proved frustrating and confusing for patients.

Price increases by brand manufacturers often occur multiple times a year, usually with no announcement to patients.

Currently Schering does have a patient assistance program (Commitment to Care) to provide free Peg-Intron and Rebetol. Call 1-800-521-7157 for more information.

Roche's patient assistance program covers Pegasys and will cover Copegus in January once it is on the market. Call 1-877-Pegasys or go to www.Pegasys.com.

Both programs cover low-income patients with no access to other coverage. By law neither program will cover co-payments for insurance coverage. For both HCV and HIV/HCV patients, an excellent summary of these programs can be read at AIDS Treatment Data Network.

Compounded Ribavirin

Recently, Fisher's Specialty Pharmacy Services, one of the first and most reputable providers of high quality, low cost compound ribavirin, after 3 and a half years of no price increase, has raised its price on ribavirin from $1.25/capsule ($210/month) to $1.50/capsule ($252/month) for 1200 mg/day dose. They continue to work with patients who have limited resources when possible. This is one company that has gone out on a limb to try to meet patient needs and keep prices as affordable as possible. This current price is still 86% below Rebetol and from a small independent company that has continued to meet and exceed requirements of its quality control. Not all compounding/specialty pharmacies can do that.

To reach Fischer's, call toll free (888) 347-3416, web address: www.spsdrug.com. Other local specialty or compounding pharmacies to consider are available as well.

We do encourage people who choose HCV treatment to consider all their options for ribavirin in their contacts with their healthcare providers. It's best to shop around to consider the price, quality and flexibility of brand and compound sources and to utilize insurance, government programs and pharmaceutical patient assistance programs when qualified.

Note: The Hepatitis C Action & Advocacy Coalition (HAAC) does not receive any funding from any drug company providers.

January 6th, 2003

Smoking aggravates liver histology in hepatitis C virus infected
by Sonia Nichols, senior medical writer for NewsRx.com

Smokers with hepatitis C virus (HCV) infections tend to develop more liver lesions than nonsmokers, researchers report.

Both daily tobacco consumption and total lifetime tobacco consumption increased histological activity among a group of smokers evaluated by researchers in Creteil, France. The investigators cautioned that chronic hepatitis C patients might want to stop smoking, or if failing that, at least cut back.

C. Hezode of Henri Mondor Hospital in Creteil headed the French investigation team. Team members graded the liver biopsy specimens from 244 chronic hepatitis C patients for histological activity and fibrosis.

"The proportion of patients with moderate (A2) or marked (A3) activity increased gradually from 62.0% in nonsmokers to 81.7% in patients who smoked more than 15 cigarettes per day (p<0.0009)," reported Hezode and coauthors.

Patients who smoked more than 20 packs a year also had higher grade histological activity than nonsmokers, reflecting the effects of total lifetime tobacco consumption on the liver. The data is published in Gut, January 2003;52(1):126-129.

Independent risk factors for increased histological activity included being older than age 50, drinking more than 20 grams of alcohol a day, and smoking more than 15 cigarettes per day, according to Hezode and coworkers.

Whereas there was a significant relationship between smoking and liver histology in chronic hepatitis C patients, a link between smoking and fibrosis among the patients could not be found. This was true of both daily and lifetime tobacco consumption. Age above 50 and alcohol consumption were the two independent variables for changes in fibrosis score.

"This study suggests that smoking, independent of alcohol, could aggravate the histological activity of chronic hepatitis C and that the patients with chronic hepatitis C virus infection should be advised to reduce or stop smoking," researchers said.

Key points reported in this study include:

• Daily and lifetime tobacco consumption increased histological activity in chronic hepatitis C patients
• Daily and lifetime tobacco consumption had no effects on fibrosis score in chronic hepatitis C patients
• Patients with chronic hepatitis C should reduce or stop smoking in order to alleviate the risk for liver impairment

HIV Makes Hepatitis B Significantly More Lethal
AIDS Weekly

Researchers at Johns Hopkins found that men infected with a combination of hepatitis B and HIV are 17 times more likely to die than those with hepatitis B alone. "These results underscore the importance of prevention, treatment and comprehensive management of hepatitis B in people infected with HIV," said Chloe Thio, MD, lead author of the study and assistant professor of medicine in the division of infectious diseases at Johns Hopkins.

The low rate of liver disease-related deaths in men with hepatitis B alone is consistent with the 20-30 years it typically takes for complications from hepatitis B to develop, Thio explained. The full report, "HIV-1, Hepatitis B Virus, and Risk of Liver-Related Mortality in the Multicenter Cohort Study (MACS)," was published in The Lancet (2002;360;9349). However, since HIV and hepatitis B are transmitted the same way, coinfection is common. Up to ten percent of the HIV-infected also have hepatitis B. "Our results suggest that HIV increases the severity of hepatitis B infections, and that physicians may see an increase of hepatitis B-related liver disease in the 1 million people living with HIV in the United States," said Thio.

Thio and colleagues analyzed clinical data and blood and tissue samples from 5,293 men in the Multicenter AIDS Cohort Study from 1994 to 2000. The researchers compared death rates from liver disease for four patient groups: HIV-infected men, hepatitis-B infected men, men with both viruses, and men with no viruses.

They found that 6 percent of the men (326) had hepatitis B. Of those, 213 (65 percent) also had HIV. Of the 4,987 men without hepatitis B, 2,346 (47 percent) had HIV. Liver disease-related death was highest in men with advanced HIV (measured by CD4 cell count) and was twice as high after 1996, when highly effective HIV therapies were introduced.

"Determining possible adverse effects of long-term use of HIV therapies and assessing the possible interaction with hepatitis infections are central questions that our ongoing studies will address," said Alvaro Mu, PhD, professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health.

Activation of antigen-presenting cells rebukes viral replication in liver
by Sonia Nichols, senior medical writer for NewsRx.com

Externally activated immune system cells can make a difference in the fight against chronic hepatitis B.

Medical investigators at Scripps Clinic and Research Institute of La Jolla, California say activated intrahepatic antigen-presenting cells (APCs) can stop hepatitis B virus (HBV) replication in genetically altered mice.

"Intrahepatic APCs were activated by administration of an anti-CD40 agonistic monoclonal antibody (alphaCD40)," described K. Kimura and colleagues in the Journal of Immunology.

When investigators treated transgenic mice with a single dose of activated alphaCD40, viral replication ceased. The treatment drew a variety of APCs, including T cells, dendritic cells, macrophages, and natural killer (NK) cells, to infected liver tissues.

"The antiviral effect depended on the production of IL-12 and TNF-alpha by activated APCs; however, it was mediated primarily by IFN-gamma produced by NK cells, and possibly T cells, that were activated by IL-12," said Kimura and coauthors.

Activated APCs not only stirred up a storm of antiviral cytokines themselves, but also caused other cells to do the same, study authors contended. The data is published in the Journal of Immunology, 2002;169(9):5188-5195).

"These results provide insight into a hitherto unsuspected antiviral function of intrahepatic APCs, and they suggest that therapeutic activation of APCs may represent a new strategy for the treatment of chronic HBV infection," Kimura and colleagues proposed.

Key points reported in this study include:

• Antigen-presenting cells (APCs) within the liver can be activated with agonistic monoclonal antibody
• Activated APCs reduced hepatitis B virus (HBV) replication without harming liver tissues in transgenic mice
• The deliberate activation of intrahepatic APCs could offer an important means of treating patients infected with HBV

January 7th, 2003

Progression of fibrosis in chronic hepatitis C

The best predictors of fibrosis progression in chronic hepatitis C are the extent of serum aminotransferase elevations, degree of hepatocellular necrosis, and inflammation on liver biopsy, find researchers from the United States.

Fibrosis is a hallmark of hepatic cirrhosis. The worsening of fibrosis is probably the best surrogate marker for progression of chronic liver disease.

In a study published in the January issue of Gastroenterology (Gastroenterology 2003; 124(1): 97-104), researchers evaluated 123 patients with chronic hepatitis C (CHC).

The research team used liver histology to assess the rate and predictors of progression of fibrosis.

Patients in the study had undergone 2 liver biopsies 4 to 212 months apart without intervening treatment.

The team graded the liver histology using the histology activity index.

39% of patients showed progression in fibrosis scores. They also staged the fibrosis using a scoring system of 0 (no fibrosis) to 6 (cirrhosis).

The researchers found that of the 123 patients, 39% showed progression in fibrosis scores, 37% showed no change, and 24% showed improvement. Of those with worsening fibrosis, 75% had a 1-point increase and 25% a 2-point or greater increase in scores, and 9% showed progression to cirrhosis.

The team determined that the overall rate of progression was 0.12 fibrosis units per year. The rate of fibrosis progression was variable.

Progression was higher among older patients, those with higher serum alanine and aspartate aminotransferase levels, and those with the most extensive periportal necrosis on initial liver biopsy.

Dr Marc Ghany's team concluded, "The best predictors of fibrosis progression in chronic hepatitis C are the extent of serum aminotransferase elevations and the degree of hepatocellular necrosis and inflammation on liver biopsy".

"These findings support the recommendation that patients with normal aminotransferase levels and mild liver histology can safely defer treatment".

Undetectable hepatitis B virus DNA unlikely to rise in some carriers
by Sonia Nichols, senior medical writer for NewsRx.com

Health care workers who form antibodies to hepatitis B virus (HBV) e antigen (anti-HBe) may not pose as great a risk for transmitting infection during exposure prone procedures as their HBe antigen-positive counterparts.

"Anti-HBe carriers are perceived as having low infectivity, with hepatitis B virus (HBV) DNA levels far below those seen in the HBeAg carrier," explained R.S. Tedder and colleagues at the Royal Free and University College of Medical School in London England.

In the United Kingdom, HBV carriers can perform exposure prone procedures based on their HBV DNA levels, according to Tedder and coauthors. However, it has been difficult to determine how or if DNA levels fluctuate significantly in anti-HBV carriers. Tedder's group analyzed the serum samples of almost 150 HBeAg and anti-HBe carriers for differences in HBV DNA levels over a period of time, tracking whether or not significant changes were apparent between first and subsequent samples.

Although HBV DNA remained detectable in HBeAg carriers, "there was a 5 log -10-fold reduction in DNA in 11 individuals who developed anti-HBe during follow-up evaluation."

Researchers noticed there was more HBV DNA fluctuation in serum samples collected and tested within short intervals. The data is published in the Journal of Medical Virology, December 2002;68(4):505-512).

"HBV DNA was below the detection threshold (<400 copies/ml) in 36 anti-HBe carriers at first sampling and remained so in all but five of these carriers," said Tedder and coauthors.

The investigators think that once HBV DNA levels fall to undetectable levels in HBV carriers, they are not likely to increase again. "This is an important factor when assessing health care workers for exposure-prone procedures," Tedder and colleagues said.

Key points reported in this study include:

• Few studies have looked at the movement of hepatitis B virus (HBV) DNA levels over a period of time in HB e antigen (HBeAg) or anti-HBe carriers
• HBV DNA levels often fell to below detectable levels in anti-HBe carriers
• Once HBV DNA levels fell in anti-HBe carriers, they were not likely to rise again

January 8th, 2003

Roche, ICN Pharmaceuticals and Ribapharm resolve ribavirin patent dispute

Roche, ICN Pharmaceuticals and Ribapharm announced today that they have agreed on a settlement regarding the pending patent disputes over ribavirin. The companies will stop all legal actions regarding ribavirin, including the lawsuits filed in the US. Roche will continue to register and commercialise its own version of ribavirin, Copegus, globally. The financial terms of this settlement agreement, which includes a license by Ribapharm of ribavirin to Roche, are not disclosed.

“This settlement is in the interest of all parties and we can now fully concentrate on the marketing of our respective products,” said William Burns, Head of Pharmaceutical Division at Roche. Roche, ICN and Ribapharm, ICN’s 80-percent owned subsidiary, co-operate on several other projects, including Roche’s exclusive license to Ribapharm’s Levovirin, an antiviral currently in clinical development for patients infected with HCV.

Robert W. O’Leary, chairman and chief executive officer of ICN, commented, “We are pleased to have played a significant role in resolving the legal issues surrounding ribavirin.” Dr. Johnson Y.N. Lau M.D., chairman, chief executive officer and president of Ribapharm, stated, “We are very pleased that this agreement will add to Ribapharm’s revenues and further our ongoing business relationship with Roche.”

About Copegus

Copegus was approved in the European Union in September 2002. Copegus is indicated for the treatment of adult patients with chronic hepatitis C who have not previously been treated, including patients with fibrosis or compensated cirrhosis. It is also indicated for the treatment of adult patients who have responded to interferon alpha monotherapy but have since relapsed. Copegus is prescribed as a combination regimen with Pegasys (peginterferon alfa-2a [40 KD]).

In the United States, Copegus was approved in combination with Roche’s Pegasys, on December 3rd 2002. Copegus is supplied as a light pink, oval shaped, film-coated tablet containing 200 mg of ribavirin.

About Roche

Headquartered in Basel, Switzerland, Roche is one of the world’s leading research-orientated healthcare groups. The company's two core businesses in pharmaceuticals and diagnostics provide innovative products and services, that address prevention, diagnosis, and treatment of diseases, thus enhancing people’s health and quality of life. The two core businesses achieved a turnover of 19.3 billion Swiss Francs in the first three quarters of 2002 and employed about 57'000 people worldwide.

Roche is committed to the viral hepatitis disease area, having introduced Roferon-A for hepatitis B and then C, followed by Pegasys in hepatitis C. Pegasys is also in phase III clinical development for patients infected with the HBV virus. Roche manufactures and sells the Amplicor HCV Test (v2.0) and the Amplicor HCV Monitor Test (v2.0) - two tests used to detect the presence of HCV RNA (Ribo Nucleid Acid) in a person’s blood. Roche's commitment to hepatitis has been further reinforced by the in-licensing of Levovirin, an alternative antiviral in commercial development.

About ICN

ICN is an innovative, research-based global pharmaceutical company that manufactures, markets and distributes a broad range of prescription and non-prescription pharmaceuticals under the ICN brand name. Its research and new product development focuses on innovative treatments for dermatology and infectious diseases.

About Ribapharm

Ribapharm is a biopharmaceutical company that seeks to discover, develop, acquire and commercialise innovative products for the treatment of significant unmet medical needs, principally in the antiviral and anticancer areas.

Schering-Plough Increases Price for Rebetol (Ribavirin)
By HIVandHepatitis.com

The average wholesale price (AWP) for Schering-Plough's Rebetol (ribavirin) has increased, effective 12/15/02, according to sources at the Hepatitis C Action & Advocacy Coalition in San Francisco, a hepatitis C patient advocacy group. The new AWP is $11.04 per 200 mg capsule, up from $10.50. Therefore, the monthly (28-day) cost (AWP) of a daily dose of Schering-Plough's Rebetol is now $1,236.48 for the 800 mg/day dose and $1,854.72 for the 1,200 mg/day dose.

The cost of compounded ribavirin (SPS compound ribavirin) from Fisher's Pharmacy in Pittsburgh, PA is $1.50 per capsule OR $168 for the 800 mg dose and $252 for the 1,200 mg/day dose. For more information, call Fisher's Pharmacy toll free 1-888-347-3416, web address: www.spsdrug.com. As of this writing, there is no announcement of the price for Copegus, Roche Laboratories' brand of ribavirin, which the FDA approved recently for use in combination with Roche's Pegasys (pegylated interferon alfa-2a). An announcement is expected soon.

January 13th, 2003

Lamivudine is a stabilizer in hepatitis B-related decompensated disease
by Sonia Nichols, senior medical writer for NewsRx.com

When treatment options are limited, patients with hepatitis B virus (HBV)-related decompensated liver cirrhosis can benefit from long-term lamivudine therapy, according to a team of doctors in the United States.

Researchers from medical institutes who participated in the United States Lamivudine Compassionate Use Study Group recently announced that finding in the January 2003 edition of Liver Transplantation.

In that trial, 75 patients who were being treated at centers across the U.S. and who were not in line for liver transplantations received lamivudine for a median of 12 months. Each tested positive for hepatitis B surface antigen (HBsAg) before beginning therapy, while many were also positive on assays for hepatitis B e antigen (HBeAg) and HBV DNA.

"In patients with detectable HBV DNA pretreatment, the virus became undetectable by the bDNA assay in 69% of patients with S6 months treatment and in 64% overall," reported study coauthor Hie-Won L. Hann of Jefferson Medical College in Philadelphia, Pennsylvania.

Levels of the liver enzyme alanine aminotransferase (ALT) improved in nearly all the patients and normalized in approximately half. Bilirubin levels also improved. Median Child-Pugh scores, using for classifying a patient's extent of cirrhosis, improved in nearly a third of the patients, but remained unchanged or worsened in others. A few patients developed mutated virus after being on the therapy for some time. The data is published in Liver Transplant, January 2003;9(1):49-56.

According to the researchers, 8 of 41 patients with undetectable viral DNA after 6 months or more of lamivudine therapy eventually exhibited virological breakthrough. "Nevertheless, at last visit, ALT, albumin, and bilirubin levels were similar for patients with and without breakthrough," they indicated.

Lamivudine monotherapy can be advantageous for treating patients with severe HBV-related liver disease who are not transplant candidates, Hann and colleagues advised.

Key points reported in this study include:

• There are few treatment options for patients with hepatitis B virus (HBV)-related decompensated liver cirrhosis
• Lamivudine reduced viral DNA and improved liver disease markers in many patients with severe HBV-related liver disease who were not candidates for liver transplantation
• Where liver transplantation is not accessible or not an option, lamivudine can help to improve the severity of HBV-related liver disease

Roche Dramatically Reduces Cost of Combination Therapy For Millions Of Americans Chronically Infected With Hepatitis C

Copegus, used in combination with Pegasys, rolls ribavirin cost per milligram back 43 percent to 1998 price.

Roche today announced that Copegus (ribavirin, USP), the medication used in combination with Pegasys (peginterferon alfa-2a) for the treatment of chronic hepatitis C, is being introduced with a list price or wholesale acquisition cost that is 43 percent less per milligram than the other available brand of ribavirin, Rebetol (Schering Plough).

Copegus will be available in U.S. pharmacies beginning the week of January 13. The list price or wholesale acquisition cost for Copegus is $5.06 per 200mg tablet.

Pegasys and Copegus combination therapy was approved by the U.S. Food and Drug Administration (F.D.A.) on December 3, 2002, for adults who have compensated liver disease and have not previously been treated with interferon alpha. An estimated 2.7 million Americans are chronically infected with hepatitis C.

"Roche is very proud of the steps the company has taken to drastically reduce the cost of combination therapy for the millions of Americans chronically infected with hepatitis C," said George B. Abercrombie, Roche President and Chief Executive Officer. "With Pegasys and Copegus, physicians and patients can have confidence knowing that this therapy is backed by an unprecedented development program--the most extensive ever conducted in hepatitis C."

A Visible Difference in Price

Roche has rolled back the list price or wholesale acquisition cost of Copegus to that of branded ribavirin in August 1998.* For patients prescribed 1200mg of ribavirin per day, there is a list price or wholesale acquisition cost savings with Copegus of approximately $7,600 for 48 weeks of therapy.

Backed By Most Extensive Development Program

Pegasys is backed by the most extensive development program ever undertaken in hepatitis C. As part of its clinical development program, Roche conducted five pivotal studies (three for the Pegasys monotherapy indication and two for the Pegasys and Copegus combination therapy indication). Included was a study to evaluate Pegasys monotherapy in patients with cirrhosis and a study to evaluate shorter durations of therapy and lower doses of Copegus for patients with certain genotypes (strains) of the hepatitis C virus.

As a result of the combination therapy study, the following dosing regimens are recommended for Pegasys and Copegus combination therapy:

• Genotype 1 and 4: 48 week duration with 180mcg Pegasys weekly and 1000 – 1200mg of Copegus daily
• Genotype 2 and 3: 24 week duration with 180mcg Pegasys weekly and 800mg Copegus daily

About Roche

Hoffmann-La Roche Inc. (Roche), based in Nutley, N.J., is the U.S. prescription drug unit of the Roche Group, a leading research-based health care enterprise that ranks among the world’s leaders in pharmaceuticals and diagnostics.

Roche discovers, develops, manufactures and markets numerous important prescription drugs that enhance people's health, well-being and quality of life. Among the company’s areas of therapeutic interest are: dermatology; genitourinary disease; infectious diseases, including influenza; inflammation, including arthritis and osteoporosis; metabolic diseases, including obesity and diabetes; neurology; oncology; transplantation; vascular diseases; and virology, including HIV/AIDS and hepatitis C.

For more information on the Roche pharmaceuticals business in the United States, visit the company’s website at: http://www.rocheusa.com.