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

Alan Franciscus
Editor-in-Chief

1. Presence of HBV-DNA Fragment Is Pivotal Risk Factor for Hepatocellular Carcinoma
2. HCV Positive Persons with Severe Mental Illness Are Less than Half As Likely to Have Access to Care As HCV Negative Persons
3. New Glycyrrhizin Suppository Can Improve Quality of Life for Chronic Hepatitis C Patients
4. Prevalence and Etiology of Elevated Aminotransferase Levels
5. Enzon's Future May Depend on A Peg-Intron Rebound
6. Pretreatment of Chronic HCV in HIV-HCV Coinfected Patients Reduces the Severe Liver Toxicity Associated With Subsequent Anti-HIV Therapy
7. Metanalysis of Interferon Alfa in the Treatment of Children with Chronic HCV Reveals Poor Methodology of Most Published Studies
8. No Significant Difference in Rates of Sustained HBV Suppression from Therapy with Intron A Monotherapy and Intron A Plus Epivir-HBV Combination Treatment
9. Combination Treatment with Standard Interferon Alfa Plus Ribavirin Has Poor Virological Efficacy in HIV-HCV Coinfected Patients
10. Nutritional Supplementation in Advanced Cirrhosis
11. Diagnosis of Acute Hepatitis C: Test for Anti-HCV or HCV-RNA?
12. Hepatitis induced by Kava (Piper methysticum rhizoma)
13. Machine Helps Liver Failure Patients Stay Alive
14. Schering's Dr. Feelbetter? Fred Hassan Is Out To Revive The Drugmaker. It's A Big Job
15. Court: Hepatitis C Treatment Not Improperly Denied Inmate
16. IDEC To Acquire Biogen in $6.5 Billion Biotech Deal
17. Experiment: Hospitals try giving organs to people once thought doomed by AIDS and unworthy of extensive treatment.
18. Roche Says May Raise Pegasys Sales Guidance after Strong Uptake
19. Lamivudine During Pregnancy To Prevent Perinatal Transmission Of HBV
20. HCV-associated Hypobeta-lipoproteinemia Is Correlated with Plasma Viral Load, Steatosis and Liver Fibrosis
21. ICN Sues Ribapharm over Takeover Defense
22. SciClone Cites Favorable Hepatitis Drug Result
23. HBV Superinfection Has a Severe Clinical Course and Strongly Suppresses HCV in Chronic Carriers
24. HBV Genotype B Is Associated with Better Response to Interferon Therapy in HBeAg(+) Chronic Hepatitis Than Genotype C
25. Nonalcoholic Fatty Liver Disease (NAFLD) May Be a Common Underlying Liver Disease in Patients with Hepatocellular Carcinoma in the US
26. Impact of Immunosuppression in Hepatitis C Recurrence After Liver Transplantation: A Controllable Factor?
27. The Management of Ascites in Cirrhosis: Report on the Consensus Conference of the International Ascites Club
28. Can Serum HBV-DNA Levels Serve As a Primary End Point to Assess the Efficacy of New HBV Treatments?
29. Innogenetics announces additional positive liver histology results for its hepatitis C therapeutic vaccine
30. Alcohol Diminishes Therapeutic Effect of Interferon Alfa and May Be Cofactor in HCV Disease Progression
31. Treatment with Peginterferon or Interferon Alfa and Ribavirin Leads to Reduction or Disappearance of Liver Steatosis, Especially in Genotype 3 Sustained Responders
32. Moderate Alcohol Consumption Increases Oxidative Stress That May Contribute to HCV Disease Progression
33. Donor-Crisis Hospitals Gamble on Bad Organs
34. Study: 99 Percent of Pegasys Responders Virus Free Up to Four Years Later
35. Pegasys (peginterferon alfa-2a) Is More Effective Than Current Standard Therapy for Chronic Hepatitis B
36. Early Responders to PEG-Intron (peginterferon alfa-2b) Plus Ribavirin Have a Significant Reduction in HCV RNA at 48 hours That May Be Pivotal in Achieving a Sustained Viral Response
37. New Pegasys Trial to Enroll Hepatitis C Patients Not Helped by PEG-Intron
38. Hepatotoxicity Associated With Nimesulide And Other Nsaids
39. Study: Half of Cirrhosis Patients Respond to Pegasys and Ribavirin
40. Schering-Plough Sets Dimmer Earnings View
41. Schering-Plough Says 2003 Net May Sink 64 Percent Due to Competition
42. US Report Questions Early Treatment Of Hepatitis C
43. Pilot Study of Interferon Alfa and Ribavirin in Liver Transplant Recipients with Recurrent Hepatitis C
44. Researchers Rethink Options in Treating Hepatitis C
45. Serum Leptin Levels Correlate with Hepatic Steatosis in Chronic Hepatitis C
46. As Testing Campaigns Identify More People with Asymptomatic Hepatitis C Infection, Benefits, Risks and Cost-Effectiveness of Early Treatment Uncertain
47. Prison Health-Care Costs Still Going Up
48. Comparison of Assays for HCV RNA Using the International Unit Standard
49. Stigma of Hepatitis C and Lack of Awareness Stops Americans from Getting Tested and Treated
50. Roche Investigates Pegasys in Failed Pegintron Patients
51. Cost-Effectiveness of Treatment for Chronic Hepatitis C Infection
52. Roche To Release A New Drug Each Year In Japan
53. Combination Therapy with Interferon Alfa Plus Ribavirin Seems to Be an Important Advance in the Treatment of Children and Adolescents with Chronic HCV
54. Factors Associated with HCV Infection in Injection and Non injection Drug Users
55. Millions Unaware They Have Hepatitis C
56. Drug Earnings a Pill for Investors Schering-Plough Sets a Pessimistic Trend
57. Interferon May Help to Prevent and Treat Hepatocellular Carcinoma Associated with Hepatitis C Virus
58. Non Liver-related Manifestations of HCV infection
59. Does Prior Hepatitis A Virus (HAV) Infection Affect the Progression of Chronic Hepatitis C?
60. High Rate of Both Spontaneous and Treatment-induced Viral Clearance in Acute HCV Infection
61. Bleeding Complications After Percutaneous Liver Biopsy
62. County Recognized for Work on Hepatitis C
63. Vaccine Fund Gets $1 Billion to Immunize Kids
64. Adefovir Dipivoxil Improved Liver Abnormalities in Patients with Chronic Hepatitis B
65. Interferon Treatment Causes Major Depression in Many Hepatitis C Patients
66. Researchers Probe Promising Liver Cancer Treatment

June 16th, 2003

Presence of HBV-DNA Fragment Is Pivotal Risk Factor for Hepatocellular Carcinoma
By hivandhepatitis.com

The objective of the current study was to clarify risk factors for hepatocellular carcinoma (HCC) other than hepatitis B surface antigen (HBsAg).

Japanese researchers at the University Aoto Hospital in Tokyo investigated serum HBV-DNA and other factors in 146 patients with liver cirrhosis (LC) or HCC who were HBsAg negative. The investigators analyzed the clinical background of the patients, status of hepatitis B (HBV) viral markers and platelet count as well as the presence of an HBV-DNA fragment by PCR and elucidated risk factors for HCC generation using a logistic regression model.

Among ten factors, they determined that four represented a significant risk for HBsAg negative HCC:
male gender
total alcohol consumption
total cigarettes smoked; and
presence of an HBV-DNA fragment.

Multivariate analysis showed that among the four factors, the HBV-DNA fragment was an independent factor associated with HCC.

The authors conclude, "The presence of an HBV-DNA fragment irrespective of the status of antibodies to either HBsAg (anti-HBs) or hepatitis B core antigen (anti-HBc) is a pivotal factor associated with the development of HCC."

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University Aoto Hospital, Tokyo. 06/16/03

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HCV Positive Persons with Severe Mental Illness Are Less than Half As Likely to Have Access to Care As HCV Negative Persons
By hivandhepatitis.com

An estimated 19.6 percent of persons with severe mental illness are infected with the hepatitis C virus.

Given the pressing need to identify and treat persons with severe mental illness who are at risk of hepatitis C infection and transmission, the authors of the current study sought to estimate the proportion of hepatitis C-positive and -negative persons with severe mental illness who have a regular source of medical care.

Data for this study were obtained from 777 adults with severe mental illness at four diverse geographic sites at which respondents with severe mental illness participated in a structured interview and laboratory testing for HIV infection, AIDS, hepatitis B infection, and hepatitis C infection.

In bivariate analyses, 54.2 percent of hepatitis C-positive and 62.5 percent of hepatitis C-negative study participants with severe mental illness had a regular source of medical care.

In multivariate analyses in which potential confounders were statistically controlled for, hepatitis C-positive persons with severe mental illness were less than half as likely as hepatitis C-negative persons to have a regular source of care.

Being older, married, insured, or employed or having self-reported health problems increased the likelihood of receiving care. Being black or male or living in a community with high exposure to community violence lowered those odds.

Conclusion: There is an urgent need to improve access to medical care for persons with severe mental illness, especially those who may be at high risk of or are already infected with the hepatitis C virus.

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New Glycyrrhizin Suppository Can Improve Quality of Life for Chronic Hepatitis C Patients
By hivandhepatitis.com

Intravenous administration of glycyrrhizin has potential efficacy in decreasing serum aminotransferase levels in patients with chronic hepatitis. However, patients are currently advised to receive this treatment only in a hospital or clinic.

Japanese researchers developed a glycyrrhizin suppository as a means of improving the quality of life for these patients. In this pilot study, they studied the contents of the suppository and evaluated its clinical efficacy for patients with biopsy-proven chronic hepatitis C by comparing intravenous administration of glycyrrhizin with use of the suppository.

The contents of the suppository are a mixture of glycyrrhizinic ammonium salt and sodium capric acid, with pH neutralization. This combination was confirmed to have most effective and safe content, based on analysis of serum glycyrrhizin levels and the grade of rectal irritations in tested patients.

The efficacy of the suppository in decreasing serum alanine aminotransferase levels following 12-week administration of the suppository in 13 patients with chronic hepatitis C was similar to that in another 13 patients receiving intravenously administered glycyrrhizin. In addition, no serious side effects were observed.

The authors conclude, "Usage of the newly developed suppository of glycyrrhizin can improve the quality of life for chronic hepatitis C patients, especially those who do not respond with viral clearance to interferon therapy."

They also note that larger and longer-term studies are needed to confirm the effectiveness of the glycyrrhizin suppository.

Department of Internal Medicine, Self-Defense Forces Central Hospital, 1-2-24 Ikejiri, Setagaya-ku, Tokyo, Japan

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Prevalence and Etiology of Elevated Aminotransferase Levels

Elevated aminotransferase is common in the United States, the majority of cases can not be unexplained by alcohol consumption, viral hepatitis or hemochromatosis, find researchers in the May issue of the American Journal of Gastroenterology (Am J Gastroenterol 2003; 98(5): 960-7)

Chronic liver disease is a major cause of morbidity and mortality in the United States.

Elevated aminotransferases are often used to detect liver disease, however, their prevalence and etiology are unknown.

In this study, researchers from Baltimore, Maryland, evaluated 15,676 adults(>17 years) from the Third National Health and Nutrition Examination Survey.

The team considered participants to have elevated aminotransferase levels if either aspartate aminotransferase or alanine aminotransferase was above normal.

The researchers "explained" aminotransferase elevation if they found laboratory evidence of hepatitis B or C infection, iron overload, or if patients had a history of alcohol consumption.

They weighted analyses to provide national estimates.

Aminotransferase elevation was unexplained in the 69%.American Journal of Gastroenterology

The team found that the prevalence of aminotransferase elevation in the United States was 8%.

Aminotransferase elevation was more common in men (9%), compared to women (7%). It was also more common in Mexican Americans (15%) and non-Hispanic blacks (8%), compared to non-Hispanic whites (7%).

The team were able to identify high alcohol consumption, hepatitis B or C infection, and high transferrin saturation in 31% of cases.

However, aminotransferase elevation was unexplained in the 69%.

The researchers found that in both sexes, unexplained aminotransferase elevation was associated with higher BMI, waist circumference, triglycerides, fasting insulin, and lower HDL. It was also associated with type 2 diabetes and hypertension in women.

Dr Jeanne Clark's team concluded, "Aminotransferase elevation was common in the United States, and the majority could not be unexplained by alcohol consumption, viral hepatitis or hemochromatosis".

"Unexplained aminotransferase elevation was strongly associated with adiposity and other features of the metabolic syndrome, and thus may represent nonalcoholic fatty liver disease".

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June 17th 2003

Enzon's Future May Depend on A Peg-Intron Rebound
Susan Todd

Enzon is not looking over its shoulder. After the collapse of its proposed marriage to NPS Pharmaceuticals, Louis Webb of W.R. Hambrecht & Co. is describing Enzon as a "timely purchase." He anticipates a rebound in sales of hepatitis drug Peg-Intron in the fourth quarter once a surplus has been exhausted. The breakup with NPS also left Enzon $135 million richer, funds that can be used to strengthen Enzon's pipeline.

In February, NPS, struggling to finance its drug development work, announced plans to merge with Enzon. The merger was seen as a way of melding the strengths of two promising biotech companies. But investors never warmed up to the match. Analyst Bert Hazlett at SunTrust Robinson Humphrey continues to see a rocky road ahead for Enzon. Hazlett downgraded the Bridgewater-based company when the deal was called off. The downgrade was largely a result of risks Hazlett saw to the current revenue stream for Peg-Intron, which is facing stiff competition.

In Webb's eyes though, the possibility of a rebound in Peg-Intron sales made Enzon appear capable of carrying on as a stand-alone profitable company. "We view Enzon's deeply depressed valuation as an excellent buying opportunity," he said. Webb predicted its earnings per share would be $1.22 for the fourth quarter.

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June 18th 2003

Pretreatment of Chronic HCV in HIV-HCV Coinfected Patients Reduces the Severe Liver Toxicity Associated With Subsequent Anti-HIV Therapy
HIVandHepatitis.com

Chronic hepatitis C virus (HCV) is an independent risk factor for antiretroviral-related hepatotoxicity, but little is known about the frequency of severe liver toxicity in patients with HIV-HCV coinfection first treated for HCV (pretreated).

The aim of this prospective study of 105 patients was to compare the incidence of progression to severe antiretroviral-related liver toxicity in 66 patients pretreated (36 with interferon-alpha [IFN alfa], 30 with IFN alfa plus ribavirin), and 39 patients not pretreated.

The subjects could choose whether to receive anti-HCV therapy. Severe liver toxicity was defined as alanine aminotransferase (ALT) level >/=5-times the upper limit of normal in patients with normal baseline levels and >/=3.5-times in those with increased baseline levels.

The authors also estimated the hepatotoxicity-related risk of discontinuing antiretroviral therapy. During antiretroviral therapy, 10 subjects (9.5%) experienced severe hepatotoxicity: 4 of 66 pretreated patients and 6 of 39 untreated patients (24-month survival: 94% +/- 2.9% vs. 85% +/- 5.8%).

After adjusting for baseline CD4 cell counts, ALT levels, histologic scores, HCV and HIV viremia, HCV genotype (genotype 1 in 29% of pretreated patients and 20% of patients not pretreated), and previous anti-HCV therapy, the risk of discontinuing anti-HIV treatment was significantly higher in the anti-HCV untreated patients and in those with increased baseline ALT levels.

The authors' data suggest that previous treatment of chronic active HCV is an independent factor associated with a decrease of severe liver toxicity as the result of a subsequent antiretroviral regimen. The authors also confirm that the baseline level of ALT is an important prognostic factor for increased liver damage during antiretroviral therapy."

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Metanalysis of Interferon Alfa in the Treatment of Children with Chronic HCV Reveals Poor Methodology of Most Published Studies

Children with chronic hepatitis C might be ideal candidates for treatment with interferon alfa (IFN alfa) because they have liver disease at an early stage. However, adverse drug reactions need to be considered.

The aim of this Italian study was to conduct a systematic review of literature on interferon therapy of chronic hepatitis C in children, and to perform a metanalysis of the pooled data.

A computerized search gave 18 articles on IFN alfa therapy in children with chronic hepatitis C; after exclusion of uncontrolled trials and of trials including patients with comorbidities, data from two studies could be pooled (48 patients).

The outcomes assessed were biochemical, defined as normalization of alanine transaminase, and virologic, defined as HCV RNA loss, both sustained at 24 months after enrolment. Results of the studies were homogenous. Risk difference was 37% in favor of IFN alfa-treated children for sustained biochemical response, and 36.8% in favor of treated children for sustained HCV clearance, respectively. The differences were highly significant (P = 0.007 and P = 0.004, respectively).

The histological end-point, as well as side effects, could not be analyzed, due to lack of data.

According to the authors, "This review identifies the poor methodology of the majority of the published trials. The study provides support for the efficacy of IFN alfa in improving both biochemical and virologic outcomes in chronic hepatitis C in children, but evidence is confined to these surrogate end-points. "

Bambino Gesu Chidren's Hospital; Department of Human Physiology and Pharmacology, University 'La Sapienza', Rome, Italy

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No Significant Difference in Rates of Sustained HBV Suppression from Therapy with Intron A Monotherapy and Intron A Plus Epivir-HBV Combination Treatment
By hivandhepatitis.com

There are currently 3 FDA-approved drugs for the treatment of chronic hepatitis B virus (HBV) disease: Intron A (interferon alfa-2b), Epivir-HBV (lamivudine) and most recently, Hepsera (adefovir dipivoxil).

Several randomized controlled trials have shown the efficacy of interferon alfa-2b (IFN-alfa) for the treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B.

In addition, 52 weeks of lamivudine100 mg daily results in suppression of HBV DNA in the majority of patients, but relapse is common. Sustained suppression of HBV DNA and HBeAg occurs in only 16% of patients, and the degree of lamivudine resistance increases with the duration of therapy.

An ideal therapy for chronic HBV would target both viral replication and the immune response. Because IFN alfa and lamivudine have different mechanisms of action, the combination of the antiviral properties of lamivudine with the immunomodulatory properties of IFN alfa might have possible additive effects against HBV that increase its effectiveness, compared with IFN-alfa monotherapy.

To test this hypothesis, Turkish researchers compared the use of prolonged synchronous combination therapy IFN alfa and lamivudine with the use of IFN alfa monotherapy in patients with untreated hepatitis B e antigen (HBeAg) positive chronic hepatitis B virus (HBV) infection.

Thirty-three patients received therapy with lamivudine (100 mg daily) and IFN alfa (10 million U 3 times per week) for 12 months; 16 patients received IFN alfa alone (10 million U 3 times per week for 12 months).

The primary end point was sustained suppression of HBV DNA and HBeAg seroconversion, which was observed in 15 (45%) of 33 patients treated with combination therapy and in 3 (19%) of 16 patients treated with monotherapy (P = .133). Both therapeutic regimens were well tolerated. Combination therapy increased the rate of sustained suppression of HBeAg and resulted in significant improvement in Knodell histologic activity index scores, compared with monotherapy. However, there was no significant difference in rates of sustained suppression between the 2 groups at the end of follow-up.

Unfortunately, despite the impressive HBeAg seroconversion rates achieved at month 24, the difference in sustained response rates between the 2 groups remained non significant at that time. Viral persistence was observed after anti-HBeAg seroconversion in 3 patients in the combination therapy group, and this influenced the level of significance.

In the present study, the effectiveness of IFN alfa and lamivudine combination therapy appears more effective than that of IFN alfa monotherapy and the previously studied sequential administration of IFN and lamivudine. The authors conclude that several factors may possibly explain this difference: a synchronous combination regimen is superior to a sequential combination regimen;
a prolonged course of combination therapy is more effective than shorter course of combination therapy;
combination therapy is better than monotherapy; and
patients enrolled in this study tended to have a higher mean ALT levels, a higher HAI score, and a lower stage of fibrosis.

"We conclude that IFN alfa and lamivudine combination therapy, in combination with a longer duration of therapy [emphasis added] appears to be a therapeutic regimen and might be considered for the initial treatment of patients with chronic hepatitis B."

Division of Hepatology, Department of Internal Medicine, and Department of Biostatistics, Dicle University School of Medicine, and Department of Pathology, State Hospital, Diyarbakir, Turkey

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Combination Treatment with Standard Interferon Alfa Plus Ribavirin Has Poor Virological Efficacy in HIV-HCV Coinfected Patients
HIVandHepatitis.com

Hepatitis C virus (HCV) related liver disease is a leading cause of morbidity and mortality among HIV-HCV coinfected patients. In fact, HIV infection has been shown to accelerate chronic hepatitis C disease progression to cirrhosis. Moreover, HCV-HIV coinfected patients are at higher risk for developing hepatotoxicity associated with HAART.

HCV coinfection has also been reported to alter immune recovery during HAART. As a result, patients receiving HAART who are stable should now consider treatment of chronic hepatitis C, according to many experts.

In patients with HCV monoinfection, the current standard of care for chronic hepatitis C is pegylated interferon (PEG-IFN) plus ribavirin. There are only scarce data available concerning treatment and care for HIV-HCV coinfected patients. In 1999, when the present study was designed, PEG-IFN was not available. However, the pharmacokinetic characteristics of a daily administration of interferon were expected to resemble closely those provided by PEG-IFN.

In the current study, French researchers at multiple medical sites conducted an open-label, randomized trial to compare the efficacy and safety of two regimens of interferon-alfa-2a (IFN-alfa-2a) plus ribavirin for management of chronic hepatitis C virus (HCV) infection in HIV coinfected patients.

Sixty-eight patients were randomized to receive IFN-alfa-2a at a dosage of either (1) 6 MU given 3 times per week for 24 weeks, followed by 3 MU 3 times per week for an additional 24 weeks (group A; 31 patients); or (2) 9 MU per day for 2 weeks, followed by 3 MU per day for 22 weeks, followed by 3 MU 3 times per week for 24 weeks (group B; 37 patients). Ribavirin was added at week 16 of therapy if HCV RNA remained detectable at week 12.

Sustained virological response was achieved in 10 patients (15%; 6 in group A and 4 in group B). HCV genotypes 2 or 3 and a decrease in the HCV load of ?3 log10 copies/mL between inclusion and week 4 were associated with virological response.

The authors conclude that the combination of standard IFN-alfa-2a and ribavirin has poor virological efficacy in HIV-HCV coinfected patients.

The authors also noted the following about their study results:

"The virological response rate obtained in our study was disappointing when we consider that the patients had a satisfactory immune status and that IFN alfa-2a was administered daily. The loading dose was expected to induce a rapid decrease in the HCV load. Indeed, a 3-log10 decrease after 4 weeks of therapy has been shown to be predictive of a sustained response in immunocompetent patients.

"In our study, the delayed addition of ribavirin, which was also proposed by Sauleda et al. one month after the beginning of IFN alfa-2a therapy, may have had a negative effect on the response."

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Nutritional Supplementation in Advanced Cirrhosis

In patients with advanced cirrhosis, long-term nutritional supplementation with oral branched-chain amino acids helps prevent progressive hepatic failure, find researchers from Italy.

The role of oral branched-chain amino acid (BCAA) supplementation in advanced cirrhosis is unclear. It is possible that a nutritional approach could prevent progressive liver failure, and improve nutritional parameters and quality of life.

Researchers performed a multicenter, randomized study to compare 1-year BCAA supplementation with either lactoalbumin or maltodextrins.

The research team's results are published in the June issue of Gastroenterology (Gastroenterology 2003; 124(7): 1792-1801).

The team included 174 patients with advanced cirrhosis.

Average hospital admission rate was lower in the branched-chain amino acid group.

The primary outcomes were the prevention of death and deterioration to exclusion criteria, hospital admission, and duration of hospital stay.

While secondary outcomes were nutritional parameters, laboratory data and Child-Pugh score, anorexia, health-related quality of life, and need for therapy.

The research team found that treatment with BCAA significantly reduced the combined event rates compared with lactoalbumin (odds ratio, 0.43). Combined events were also reduced compared with maltodextrins (odds ratio, 0.51), but this difference was not significant.

They also determined that the average hospital admission rate was lower in the BCAA group, compared with other groups.

The team also found that nutritional parameters and liver function tests were stable or showed improvement during treatment with BCAA. In addition, the Child-Pugh score decreased.

Furthermore, improvements were found in anorexia and health-related quality of life.

However, the team found that long-term compliance with BCAA was poor.

Dr Giulio Marchesini's team concluded, "In advanced cirrhosis, long-term nutritional supplementation with oral BCAA is useful to prevent progressive hepatic failure and to improve surrogate markers and perceived health status". "New formulas are needed to increase compliance".

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June 20th 2003

Diagnosis of Acute Hepatitis C: Test for Anti-HCV or HCV-RNA?
By hivandhepatitis.com

In theory, the optimal method for diagnosing acute hepatitis C is nucleotide amplification. This is because of the significant delay in the emergence of hepatitis C virus (HCV) antibodies.

Researchers at Aalborg University Hospital in Denmark studied whether the use of HCV polymerase chain reaction (PCR) screening for acute HCV infection in a clinical setting would identify otherwise undetected cases.

Patients clinically suspected of having acute viral hepatitis were tested over a 32-month period (n = 2023).

Sixty-four patients were found HCV ribonucleic acid (RNA) positive. Of these, 13 were suffering from an acute infection and 12 of these 13 patients were concomitantly anti-HCV (and HCV-RNA) positive at the time of diagnosis. One patient was HCV-RNA positive and anti-HCV negative. This symptom-free patient was tested because of known exposure to HCV 2 weeks previously.

Conclusion: Anti-HCV is reliable in screening for acute hepatitis C. In cases of known/possible HCV exposure, we find that HCV PCR is the diagnostic of choice.

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Hepatitis induced by Kava (Piper methysticum rhizoma)

The potentially severe hepatotoxicity of Kava (Piper methysticum rhizoma) is reported in a study in the July issue of the Journal of Hepatology. J Hepatol2003; 39(1): 62-7.

Botanical drugs are widely used. However, they often contain highly active compounds.

Kava root (Piper methysticum rhizome) is used frequently in Europe as a remedy against anxiety. It contains kavapyrones which have a sedative effect.

It has been suggested that hepatitis can develop after the intake of Kava.

In this study, researchers from Germany analyzed 29 novel cases of hepatitis along with Kava ingestion, which occurred between 1990 and 2002. The team examined these cases in addition 7 previously published reports.

The cumulative dose was highly variable. They used a clinical diagnostic scale established for adverse hepatic drug reactions.

The research team found that hepatic necrosis or cholestatic hepatitis occurred with both alcoholic and acetonic Kava extracts.

They determined that the majority of the patients, and additional 7 published cases, were women.

However, the cumulative dose was highly variable, as was the latency to when the hepatotoxic reaction emerged.

Overall, the team found that 9 patients developed fulminant liver failure. Of these, 8 underwent liver transplantation.

However, 3 patients died. Of these, 2 occurred after unsuccessful liver transplantation. The researcher observed that a complete recovery occurred in all other patients, once the Kava was withdrawn.

The team considered that, pathophysiologically, both immunoallergic and idiosyncratic factors may be responsible.

Dr Felix Stickel's team concluded, "The present report emphasizes the potentially severe hepatotoxicity of Kava which has recently led to the retraction of Kava-containing drugs".

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Machine Helps Liver Failure Patients Stay Alive
By Alison McCook

Researchers have successfully kept a handful of patients with liver failure alive long enough to receive an organ transplant using a machine that contains liver cells from organs deemed not fit for transplant.

Dr. Jorg C. Gerlach, author of a study released Thursday and inventor of the machine, which is a type of bioreactor, told Reuters Health that many extra livers cannot be used for transplant because they are not sufficiently healthy, often a result of disease.

During the newest technique, patients whose livers no longer function properly are hooked up to the machine, which serves as their makeshift liver, enabling them to survive until a healthy liver becomes available for transplant, Gerlach said.

Gerlach, who is based at the University of Pittsburgh in Pennsylvania, noted that this strategy is intended for patients with acute liver failure, many of whom will need a liver transplant to survive.

He estimated that acute liver failure patients could survive between one and two weeks on the bioreactor, and that extra window of time could save their lives.

Gerlach, who has also patented the device used in the current study, said that he and his colleagues need to continue improving the machine and to conduct further studies to determine if it helps a larger number of patients with liver failure.

He added that the technique is being used at the University Hospital of Berlin in Germany and the University of Pittsburgh Medical Center.

Unlike chronic liver failure, which develops gradually, acute liver failure occurs when a person with no apparent liver disease suddenly experiences a severe deterioration in liver function. Approximately 2,000 Americans develop acute liver failure each year.

The causes of acute liver failure include hepatitis virus infections, pregnancy and drugs.

Gerlach and his colleagues presented their findings Thursday during a joint meeting of the American Society for Artificial Internal Organs and the International Society for Artificial Organs, held in Washington, D.C.

Gerlach and his colleagues were able to use the bioreactor to grow functional liver cells from cells extracted from discarded organs and to keep eight liver failure patients alive until they could receive a new organ.

In an interview, Gerlach said that he hopes this technique may one day help patients avoid liver transplant altogether.

Transplantation is a risky procedure, he said, and patients have to take toxic drugs to thwart the body's tendency to reject the foreign organ. However, given enough time, livers that have undergone acute failure are able to regenerate themselves, Gerlach noted.

Consequently, patients with acute liver failure may one day be able to use the bioreactor to give their livers the opportunity to heal enough to take over the job themselves, he said.

"In this situation, we would use the machine ... for the waiting time until (the patient's) own liver regenerates, and then transplantation would not be required anymore," Gerlach said.

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June 23rd 2003

Schering's Dr. Feelbetter? Fred Hassan Is Out To Revive The Drugmaker. It's A Big Job
Amy Barrett

Fred Hassan had been running Schering-Plough Corp. for all of one month when he received the letter. On May 28, the U.S. Attorney's Office in Massachusetts notified the company that the federal government was planning to indict it for a number of alleged violations, including improper marketing and obstruction of justice. If the company settles, which is likely, the fine could come to hundreds of millions of dollars.

Just what he needed. Schering-Plough was already in trouble with regulators: In May, 2002, it agreed to pay a $500 million fine to the Food & Drug Administration for manufacturing lapses.

Then, in December, the patent on the company's most important drug, the allergy medicine Claritin, expired, which could cost Schering more than $1 billion in lost sales this year. None of its other products can possibly make up for that. "Don't see how you turn [Schering] around quickly,'' warns Dr. John R. Borzilleri, portfolio manager at State Street Research & Management Co., which recently sold some of its Schering stock. "There is not enough to work with."

Hassan, a 57-year-old Pakistani-born executive who has been in the business for more than three decades, has never said anything about being able to revive Schering quickly. In fact, it could be a long, grueling process that still results in a much-diminished company. And that's assuming Schering can survive on its own. But for Hassan, it sure beats what he faced after selling Pharmacia Corp. to Pfizer Inc. this year: the prospect of becoming vice-chairman and watching Henry A. McKinnell Jr. run the show. "I like adventure, and I like a challenge," he says.

Even before news of Schering's possible indictment (which he declines to discuss), Hassan had identified festering problems. "his company was lulled into a false sense of comfort for too long,'' he says. "We need to change the culture.'' Certainly, Schering had been too lax in supervising its plants-one in New Jersey shipped a few asthma inhalers without any medicine in them-but it had also been too stingy when it came to spending on science. Hassan intends to exert more control over the manufacturing operations; he says he devotes about a quarter of his time to monitoring the changes that the FDA has required. And he has appointed the head of R&D to the senior management committee in hopes that a greater focus on science will help the company fill in its product portfolio.

He has also tried to infuse the company with some of his own personality, which can most easily be described as effusive. "I'm like the CEO at Mercedes who has a passion for cars," he says. "I have a passion for the products.'' At Pharmacia, he often went home with a stack of trade publications to read and sent managers handwritten notes about everything from drugs they might want to license to tax issues they might want to study. When he joined Schering, he turned the very formal executive suite into a meeting room and moved into the office of the former chief operating officer (whom he's not going to replace). He says he has given up his one after-hours activity, golf, because there are no after hours anymore. But he does make sure to have tea with his wife every morning.

Still, none of that will ease Schering's immediate predicament. Claritin sales are expected to fall to just $800 million this year, from $1.9 billion in 2002, according to Morgan Stanley analyst Jami Rubin. And Schering's franchise of hepatitis C drugs is expected to decline as rivals enter the market. In all, Schering's sales could drop 16% this year, to $8.6 billion, while net income sinks 55%, to $932 million. Meanwhile, the company will probably increase its reserves because of its legal woes and could cut its dividend.

Hassan's short-term cure for the company is the conventional one: Spend more on marketing what drugs it has, and buy whatever it can. What Schering has already is Clarinex, the follow-up to Claritin, and Zetia, a cholesterol-lowering drug Schering discovered and markets with Merck & Co. But Clarinex has been a disappointment so far, and sales growth of all cholesterol drugs are slowing. So even though Hassan wants to develop the company's own scientific expertise, he is also scouting for products to license and acquire. "Half of what we sell should come from other people's labs,'' he asserts.

This isn't the first time Hassan has come in to run an ailing company. He led a cultural overhaul at Pharmacia in the late 1990s. The company, formed by the 1995 merger of Pharmacia and Upjohn, hadn't integrated operations. When Hassan joined two years later, he centralized control in a new headquarters in New Jersey and remade the upper ranks almost from scratch.

Hassan also had a knack for spotting untapped potential. He and his marketing staff took what was supposed to be a modest seller, bladder control medicine Detrol, and turned it into a $757 billion drug by 2002.

But Hassan's time at Pharmacia was not without problems. After orchestrating a merger with Monsanto Co. in 2000, Hassan failed to deliver on Wall Street's earnings expectations. He concedes that some shareholders may have been disappointed on that score but points out that Pharmacia's stock performed much better than its peers' during his tenure.

At Schering, Hassan doesn't have to worry about keeping expectations in check. All most investors hope for is that he can get the company out of its legal mess and in reasonably good shape so that someone will buy it. That someone could be Merck, which is counting on the success of a new cholesterol-fighting product it will share with Schering to get it out of its slump. Merck officials won't comment. But "[the drug] has too much potential for Merck not to be interested,'' says Dr. Kris H. Jenner, an analyst at T. Rowe Price Associates Inc., which holds Schering shares. For now, Hassan deflects such notions, saying: "By nature I'm a builder, not a seller.'' Certainly he wouldn't want to watch yet another CEO run what had been his company. But that could be wishful thinking.

Fred Hassan

BORN
Nov. 12, 1945, in Multan, Pakistan.

CHILDHOOD
Raised in Lahore, where his father was a civil servant and his mother was a women's rights activist.

EDUCATION
BS in chemical engineering, Imperial College of Science, Technology & Medicine at the University of London, 1967; MBA, Harvard Business School, 1972.

CURRENT POSITION
CEO of Schering-Plough for two months.

CAREER PATH
After seven years at Wyeth, formerly American Home Products, he was tapped to overhaul the ailing Pharmacia & Upjohn. Merged with Monsanto, nabbing that company's arthritis drug, Celebrex. Its success prompted Pfizer to buy Pharmacia.

FAMILY
Married for 34 years to Noreen; they have two daughters and a son.

Hassan's Headaches
Schering-Plough's condition just keeps getting worse

• On May 28, Schering was notified by the U.S. Attorney's Office in Massachusetts that the federal government intends to indict the company on a umber of issues, including improper marketing and obstruction of justice.
• Claritin's patent expired at the end of 2002, and sales are expected to drop more than 50%. Clarinex, Schering's follow-on allergy product, has been a disappointment.
• While Zetia, a cholesterol-lowering drug that Schering markets with Merck, looks promising, Hassan has few potential big sellers in development.

Court: Hepatitis C Treatment Not Improperly Denied Inmate
By Joel Stashenko

State prison administrators did not improperly deny an inmate treatment for hepatitis C, in large part because the prisoner has failed to undergo drug treatment first, a state appeals court ruled.

The ruling upheld the state Department of Correctional Services' rules on which prisoners get treatment for hepatitis C, one of the leading health concerns among the 66,000-inmate population in state prisons.

Andrew Sandsom had argued that the refusal of prison administrators to supply him with hepatitis C drugs constituted cruel and unusual punishment.

But the Appellate Division of state Supreme Court said Sandsom has to prove that there was "deliberate indifference" on the part of prison officials for the inmate's cruel-and-unusual-punishment claim to stand.

On the contrary, the judges said Sandsom failed to meet some "reasonable" treatment prerequisites for inmates set down by prison administrators. The court said Sandsom failed to demonstrate "continuing abstinence from substance abuse by successfully completing a substance abuse treatment program."

"Not only has petitioner (Sandsom) failed to complete such a program, but it appears that he has continued to abuse controlled substances during his incarceration," the five-judge panel wrote in a ruling dated June 19.

Prison records show that Sandsom, serving an 8-to-10-year sentence for robbery, was found guilty of prison drug use in April 2001 and May 2002. Officials said he was removed from a drug treatment program at Great Meadow state prison in January 2003 for disciplinary reasons, and that he is now in a program at Attica state prison.

Inmate advocates have criticized the state prison system for the fact that only about 200 of the 9,000 inmates suspected of having been exposed to hepatitis C are receiving treatment.

"It is a real significant issue," said Robert Gangi, head of the state Correctional Association prison watchdog group. "There are a significant number of people in the state prison system who, in our judgment, should be getting treatment and are not."

Department of Correctional Services spokesman James Flateau said exposure to hepatitis C does not necessarily mean inmates are infected with the liver-damaging disease. Only about 10 percent of those exposed will get hepatitis C, Flateau said, but it may take decades for the disease to develop.

Prison health administrators follow guidelines by the National Institutes of Health when deciding hepatitis C protocols, Flateau said. They also consult with the Centers for Disease Control and Prevention, he said.

The NIH had recommended against starting hepatitis C drug treatment for intravenous drug users, but the institutes last September said limited evidence suggests that treatment may still be effective for active drug users. Flateau said prison officials believe the bulk of the evidence still indicates that inmates should be drug-free before getting hepatitis C treatment.

The state also says inmates must have enough time left in their sentences to assure that the treatment regimen can be completed while the prisoner remains behind bars. Starting the drug treatments but not completing them -the process takes about one year - essentially assures that the drugs will be ineffective against hepatitis C if treatment is tried again in the future, health experts say.

"While inmates and their lobbyists might feel more inmates should be in treatment, we follow federal guidelines and not the wishes of inmates and their advocates," Flateau said.

The court said Sandsom, who argued his case himself, wrongfully sought for his immediate release under a writ of habeas corpus on the claim of cruel and unusual punishment. The judges said Sandsom more properly should have filed an "Article 78" proceeding challenging the legality of an action by a state agency. But they also indicated that the state did not act improperly and that such an action should fail.

Nineteen inmates died in prison of hepatitis C in 2002 one more than the number who died of AIDS.

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IDEC To Acquire Biogen in $6.5 Billion Biotech Deal
Jed Seltzer and Ransdell Pierson

NEW YORK (Reuters) IDEC Pharmaceuticals Corp. Monday said it would pay $6.5 billion in stock to acquire Biogen Inc. in the biggest biotechnology deal in 18 months, merging two companies facing declining sales growth of their blockbuster drugs.

Wall Street failed to embrace the deal, sending shares of both companies down over 5 percent in heavy morning trade on the Nasdaq.

The Biogen-IDEC combination would be the largest U.S. biotechnology deal since Amgen agreed in December 2001 to snap up Immunex for about $10 billion, and is the latest in a string of recent biotech mergers.

The companies are looking to diversify the diseases they treat. Biogen currently sells products to treat multiple sclerosis and psoriasis, and IDEC sells cancer drugs to treat non-Hodgkin's lymphoma.

The merger comes amid concerns that Biogen's earnings growth is too dependent on Avonex for multiple sclerosis, whose sales growth has been hurt by U.S. introduction over a year ago of Serono SA's rival multiple sclerosis drug Rebif.

In the first quarter, sales of Avonex edged up 3 percent to $274 million, compared with 21 percent growth in the same quarter of 2002.

"The price IDEC is paying looks a little rich considering that Biogen has become so dependent on Avonex and its sales are now sputtering,'' said David Saks, chief investment officer of the Saks MedScience Fund at Ladenburg Thalmann.

Even as the deal was announced, Biogen Monday warned its second-quarter earnings would fall short of Wall Street estimates because of lower-than-expected royalties on hepatitis C drugs sold by Schering-Plough Corp.

Under the terms of the deal, Biogen shareholders would receive 1.15 IDEC shares for each Biogen share. The companies said IDEC holders would own about 50.5 percent of the stock of the combined company.

Based on IDEC's share price Monday, Biogen shareholders would get about $43.25 for each share owned, compared with Biogen's current stock price of $42.25. The new entity, Biogen IDEC Inc., will have revenue of about $1.55 billion this year and more than $1.5 billion in cash on its balance sheet. The merger would provide cost savings of almost $500 million through 2007. IDEC's main product is Rituxan for non-Hodgkin's lymphoma, whose U.S. sales rose 32 percent in the first quarter to $310 million. That reflects a slowdown from growth of 39 percent in 2002 and 83 percent in 2001.

IDEC co-markets Rituxan with Genentech Inc., a larger biotech that keeps over half of profit from the blockbuster medicine.

Saks said the merger makes sense despite its price because both companies are focused too narrowly, IDEC on cancer and Biogen on multiple sclerosis, and each could become vulnerable in the event insurers cut back on reimbursement for their respective products or cheaper generic rivals hit the scene.

"By being a big, broad powerhouse biotech company, and with the cost savings from the merger, the combined company will be less vulnerable,'' said Saks.

Shares of Biogen were down $2.40 to $41.40, or 5.4 percent, while IDEC fell $2.39 to $36.58, or 6 percent, in heavy morning trade on the Nasdaq. Their declines helped drag down the biotech sector by nearly 4 percent amid a moderate decline in the broader stock market.

IDEC said the deal, which is expected to close by the end of the third quarter or early fourth quarter, would add to its net earnings within two to three years.

The chairman and CEO of IDEC, William Rastetter, will be chairman of the new company and the top official at Biogen, James Mullen, will serve as the CEO.

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Experiment: Hospitals try giving organs to people once thought doomed by AIDS and unworthy of extensive treatment.
By A Baltimore Sun Staff Writer

Not long ago, the thought of transplanting a kidney into salesman Derek Kee, a heart into statistician Robert Zackin or a liver into playwright Larry Kramer would have defied all reason.

All suffered from HIV infection before their organs went bad, and under the old rules, the drugs needed to protect their transplants would surely have crippled their immune systems even more. Giving scarce organs to patients who didn't have long to live was considered wasteful, even unethical.

Like so many things about AIDS, that view is slowly giving way to another, articulated by Dr. Stephen T. Bartlett, a surgeon at the University of Maryland Medical Center who performed Kee's transplant last month.

"Now, the question is whether we can ethically exclude these patients," says Bartlett.

The unofficial moratorium on transplants for HIV-infected patients, in force since the 1980s, is slowly being lifted as hospital after hospital has found ways to push boundaries once thought inviolable.

Kee, for instance, sought a transplant just as the University of Maryland Medical Center was recruiting patients for a nationwide trial in which 75 HIV-infected patients will receive kidney or liver transplants.

Other hospitals have forged out on their own to test the idea. That was the case with the Cleveland Clinic, which gave Zackin a heart last year, and the University of Pittsburgh Medical Center, which gave Kramer a transplant in December 2001 but has offered livers to infected patients since 1997.

The argument for performing organ transplants on such patients was strengthened by a study presented this year by researchers at the University of California-San Francisco. Among 23 patients who had at least a year of follow-up after their transplants, the survival rate was about 85 percent. Outcomes overall were no different than one would expect among people without the virus.

Several forces are converging to change the prospects for HIV-infected patients needing transplants. For starters, the revolutionary drug combinations introduced in the mid-1990s are enabling many patients to live healthy, robust lives with their virus at undetectable levels.

With their immune systems restored, such patients can often survive a transplant and even the immune-suppressing drugs that prevent patients from rejecting a foreign organ, doctors say.

That some patients with HIV infection even need transplants is testimony to the strides made against the disease, which was once considered a death sentence. Now, some patients are living so long that their organs are succumbing to other diseases or the long-term side effects of anti-AIDS medications.

Larry Kramer, 67, a New York playwright and AIDS activist, suffered liver failure because of his long bout with hepatitis B, an infection that along with hepatitis C plagues many AIDS patients. Derek Kee's kidneys may have been damaged by high blood pressure. Zackin's heart was weakened by drugs that had been used to treat Kaposi's sarcoma, a cancer that sometimes preys upon AIDS patients.

Zackin's quest for a new heart began in 1999, when he started to need 24-hour infusions of a medication to boost his failing heart. An AIDS researcher, the 39-year-old Zackin had colleagues across the country who put out feelers at the institutions where they worked.

Hopkins and Harvard were just two of many institutions that rejected him, saying they had a categorical ban against such transplants. Zackin said two medical centers, which he declined to identify, agreed to present his case to their transplant boards but ultimately turned him down as well.

Finally, the Cleveland Clinic accepted him and gave him a new heart in February 2001. Though he has suffered several bouts of rejection, doctors say he has overcome them and has not had any renewed problems with AIDS.

"In many ways, he's done much better than many transplant patients," said Dr. James Young, a cardiologist who treated Zackin and co-wrote an article with him on the case in the New England Journal of Medicine this month.

Young says he is encouraged that Zackin's immune system was healthy enough to attack the new organ. For his part, Zackin says he quickly returned to work, resumed exercising at the gym, and put on weight and muscle.

"More successes will lead to more people trying, " said Zackin. "I'm not sure it's really an ethical issue anymore. You can't decide who is worthy and who is not worthy."

Kee, a 31-year-old shoe salesman in Clearwater, Fla., almost got a kidney two years ago when Hahnemann University Hospital in Philadelphia offered him one in the middle of the night. Kee, however, knew he couldn't make the trip fast enough, so the hospital gave it to someone else.

Then he began a frustrating search in Florida. "At least three places said they wouldn't even consider it, that they wouldn't touch it," said Kee, who was diagnosed with HIV infection a decade ago but never developed AIDS. "There were many times when I felt I was really being devalued as a human being. "

About a year ago, Kee enrolled in the Maryland program after learning about the clinical trial. On May 2, he received a kidney donated by a longtime friend, and Kee was out of the hospital in four days.

"I feel amazing," he said. "I feel like nothing was ever wrong with me."

While welcoming to HIV patients, doctors at the University of Maryland Medical Center applied strict criteria before offering Kee a transplant. Fortunately, he met them all.

His viral load - the amount of viral particles in his bloodstream - was undetectable. His immune system was in a healthy state. He was free of the myriad "opportunistic" infections that can prey upon people with weakened immune systems.

"He's been an enormous success," said Bartlett, explaining that the transplant has done nothing to worsen Kee's HIV infection.

One purpose of the clinical trial is to determine which anti-rejection drugs and which antivirals should be used and in what doses. Many doctors believe that certain anti-rejection drugs do nothing to worsen HIV infection while others should be avoided.

"It turns out some of the antiretroviral drugs [used against AIDS] are inhibited by renal transplant medicine," said Dr. Robert Redfield, who runs the AIDS clinical services at the Maryland and conducts research for the university's Institute of Human Virology. "There are other medicines that actually work better."

For all the promise, many if not most hospitals still bar HIV-infected patients into their transplant programs.

Dr. John Conte, who heads the heart transplant program at Hopkins, said heart transplants for people with HIV infections remain risky and should be done only by institutions participating in a clinical trial. For now, he said, the Hopkins program is staying out of trials, preferring to reserve the procedure for patients who stand the best chance of succeeding.

"This is an experimental approach, and a program is at risk if there is a bad outcome," said Conte. "It's all guesswork in patients like this. This is new territory."

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June 24th 2003

Roche Says May Raise Pegasys Sales Guidance after Strong Uptake
Ben Hirschler

LONDON, June 24 (Reuters) - Roche Holding AG said on Tuesday it may increase its sales guidance for hepatitis C treatment Pegasys because demand for the Swiss group's biggest new drug in years has proved stronger than expected.

Charles Sabbah, strategy chief for drug marketing, told Reuters the current peak sales forecast of 1.5 billion Swiss francs ($1.1 billion) was "probably conservative" and may be revised up when half-year results are published on July 23.

"There is a distinct possibility that we will address Pegasys, taking into account the developments in market share," he said in an interview ahead of a presentation on the company's virology business to analysts in London.

Latest weekly data show Pegasys, which was launched in the United States last December in competition to Schering-Plough Corp's Peg-Intron, now accounts for 35 percent of new U.S. prescriptions, he said.

"It's a very fast uptake. It's certainly better than we anticipated ourselves and probably better than what analysts were expecting," Sabbah said.

In Germany, Europe's biggest market, Pegasys has won a 50-60 percent share while in Britain the figure is estimated at around 30-50 percent. The interferon drug was recently also launched in France and will be rolled out in Italy very soon.

Shares in Roche rose 1.7 percent to 103.50 Swiss francs by 1315 GMT, outperforming the European drugs sector, which was off 0.1 percent.

FOURFOLD RISE IN ANTIVIRALS

Virology has emerged as a top strategic focus for Roche, which is already the world leader in cancer treatments and traditionally focuses on medicines prescribed by specialist doctors in hospitals.

The company also recently launched Fuzeon, a novel HIV/AIDS treatment designed to treat patients resistant to existing therapies, which is expected to generate sales of up to one billion Swiss francs.

Together, Pegasys and Fuzeon are expected to jump-start Roche's virology business, which last year brought in some 800 million francs in revenues, or four percent of the group total.

"These two products are likely to transform our position, probably multiplying sales by a factor of four in the mid-term," Sabbah said.

Roche currently sells AIDS drugs Viracept and Invirase, together with flu drug Tamiflu.

Production constraints mean Roche and its partner Trimeris Inc will have enough Fuzeon for only 12,000 to 15,000 patients by the end of 2003, although Sabbah said he was confident supply would be towards the upper end of this range.

Roche aims to complement its antiviral drug line-up with a range of diagnostic tests, including a kit to detect the virus that causes Severe Acute Respiratory Syndrome (SARS).

Diagnostics head Heino von Prondzynski said separately the SARS test would be launched in July, but he cautioned sales of the product would be modest, at under $10 million.

Roche has already received several thousand Asian orders for the product, which will cost $10 to $15 per test, depending on the quantity ordered.

Roche's test will compete against rivals from smaller companies, but Von Prondzynski expects it to become the most widely used because it is designed to run on Roche machines found in many laboratories around the world.

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Lamivudine During Pregnancy To Prevent Perinatal Transmission Of HBV


In highly viraemic HBsAg-positive mothers, lamivudine therapy may reduce the risk of child vaccination breakthrough, find researchers in the July issue of the Journal of Viral Hepatitis (J Viral Hepat 2003; 10(4): 294-7).

The vertical transmission of hepatitis B virus (HBV) can occur, despite vaccination of the child. This vaccination breakthrough is associated with high maternal viraemia.

In this study, researchers from the Netherlands treated 8 highly viraemic (HBV-DNAb %1.2 x 109 geq/ml) mothers in their last month of pregnancy. They were given 150 mg of lamivudine daily.

The research team measured the babies' HBV-DNA, hepatitis B surface antigen (HBsAg), anti-HBs and anti-HBc levels at birth, and at 3, 6 and 12 months.

The team used 24 children, who were born to untreated HBsAg-positive mothers with HBV-DNA levels b 1.2 x 109 geq/ml, as historical controls.

All the children received passive-active immunization at birth and the team followed them for 12 months.

he researchers found that 1 child in the lamivudine group was HBsAg and HBV-DNA positive at 12 months.

Perinatal transmission of HBV:
lamivudine group = 13%
control group = 28%

However,all the other children seroconverted to anti-HBs, and maintained seroprotection.

In 3 children, HBV-DNA was temporarily detected by PCR.

The researchers found that in the untreated control group, perinatal transmission occurred in 28% of the children.

Dr van Zonneveld's team concluded, "In highly viraemic HBsAg-positive mothers, reduction of viraemia by lamivudine therapy in the last month of pregnancy may be an effective and safe measure to reduce the risk of child vaccination breakthrough".

"This approach should be evaluated in a large controlled trial".

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June 25th 2003

HCV-associated Hypobeta-lipoproteinemia Is Correlated with Plasma Viral Load, Steatosis and Liver Fibrosis
By hivandhepatitis.com

A relationship between chronic hepatitis C virus (HCV) infection and lipid metabolism has recently been suggested. The aim of this study was to determine the correlation between lipid profile and virology, histologic lesions, and response to alpha interferon therapy in non cirrhotic, non diabetic patients with hepatitis C.

A total of 109 consecutive untreated chronic hepatitis C patients were studied to assess the following:

The effects of HCV genotype, viral load, steatosis, hepatic fibrosis, and body mass index (BMI) on lipid profile; and Whether lipid parameters could predict response to antiviral therapy.

The control group showed a significantly higher apolipoprotein B (apo B) concentration compared with patients with chronic hepatitis C. Hypobeta-lipoproteinemia (apo B <0.7 g/L) was found in 27 (24.7%) chronic HCV patients and in five (5.3%) control subjects (p = 0.0002).

Levels of apo B were negatively correlated with steatosis and HCV viral load (r = -0.22; p = 0.03). This last correlation was strong for non-1 genotype and genotype 3 (r = -0.48; p = 0.0005, and r = -0.47; p = 0.007, respectively) but was not found in genotype 1.

In multivariate analysis, low apo B concentration was significantly associated with fibrosis grade 2 or 3 versus grade 0 or 1 (p < 0.001), steatosis >5% (p < 0.001), low body mass index (p < 0.001), and high HCV viral load (p < 0.014).

No correlation was found in the 76 treated patients between apo B and response to interferon therapy.

The authors conclude, "In chronic HCV patients, hypobeta-lipoproteinemia occurs already in the early stages of HCV infection before the development of liver cirrhosis. The correlation between apo B levels and HCV viral load seems to confirm the interaction between hepatitis C infection and beta-lipoprotein metabolism."

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June 26th 2003

ICN Sues Ribapharm over Takeover Defense

ICN Pharmaceuticals Inc. has filed a lawsuit challenging Ribapharm Inc.'s stockholder rights plan meant to stave off ICN's $168 million takeover bid, Ribapharm said on Thursday.

Ribapharm, already 80 percent-owned by ICN, on Monday said its board had rejected ICN's bid for the rest of the company, saying the offer price of $5.60 per share was inadequate.

Shares of Ribapharm closed at $6.52 on Wednesday on the New York Stock Exchange.

Under its shareholder rights plan, Ribapharm would flood the market with preferred shares in the form of a dividend, increasing the cost of an ICN takeover.

ICN is accusing Ribapharm of breach of contract and breach of fiduciary duty, Ribapharm said. Ribapharm said it believes the ICN lawsuit is without merit and it expects to prevail.

Ribapharm was once a unit of ICN, but the larger company spun off 20 percent of Ribapharm in April 2002.

Bringing Ribapharm back in-house is part of ICN's restructuring after the 2002 retirement of founder Milan Panic, who received a $33 million bonus in connection with the partial spin-off.

Ribapharm's only product is the hepatitis C drug ribavirin, and ICN reaps royalties from sales of the drug, accounting for about 30 percent of its own revenue. But ribavirin faces the threat of generic competition as early as this year, which could significantly erode sales.

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SciClone Cites Favorable Hepatitis Drug Result

SciClone Pharmaceuticals Inc. on Wednesday said 20 percent of patients taking its hepatitis B drug in a Japanese clinical trial were deemed cured of the virus, compared with 16 percent of Asian patients in a different study taking the standard treatment lamivudine.

"These results are even more impressive when we consider that this study included some of the more difficult to treat hepatitis B patients," the San Mateo, California-based biotech company said in a release.

Its lead drug, called Zadaxin, was tested in a Phase III trial that lasted 18 months.

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June 27th 2003

HBV Superinfection Has a Severe Clinical Course and Strongly Suppresses HCV in Chronic Carriers
By hivandhepatitis.com

It is not uncommon for HCV-infected individuals to become infected with HBV (HBV superinfection). The aim of the current study was to evaluate the effect of the superinfection on HCV and the clinical course of co-infection with HBV-HCV.

Researchers enrolled 44 patients with hepatitis B virus (HBV) acute infection, 21 anti-hepatitis C virus (HCV)positive for at least 1 year (case BC group), 20 anti-HCVnegative (control B group), and 3 with HBV/HCV acute concurrent infection. For each case BC, a subject with chronic HCV infection alone was selected (control C group).

At the first observation, 85.7% of patients in case BC group and 85% of those in control B group were HBV-DNA positive (polymerase chain reaction [PCR]), with a similar trend towards a decrease and negativization in about 20 days; in the case BC group, seroconversion to antibody to hepatitis B e antigen (anti-HBe) was more rapid. HCV-RNA (PCR) was undetectable in all case BC patients but 1, who shortly became negative, whereas 85.7% of subjects in control C group were positive (P < .001).

Severe acute hepatitis was more frequent in the case BC group than in the control B group (28.6% vs. 0%, P < .05).

Of the 14 patients in the case BC group and of the 16 in the control B group followed up for more than 6 months, 1 in the first and 1 in the second group became hepatitis B surface antigen (HBsAg) chronic carriers.

Of the 13 patients in case BC group who recovered, 1 cleared both anti-HCV and HCV-RNA, 6 became HCV-RNA positive, and 6 remained HCV-RNA negative.

In patients with HBV/HCV acute concurrent infection, HBV-DNA became undetectable in 15 days, and HCV-RNA and anti-HCV became positive at days 30 and 45, respectively; these patients developed HCV-RNA positive chronic hepatitis.

The authors conclude, "HBV superinfection in chronic HCV carriers has a severe clinical course and strongly and persistently depresses HCV."

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HBV Genotype B Is Associated with Better Response to Interferon Therapy in HBeAg(+) Chronic Hepatitis Than Genotype C
By hivandhepatitis.com

Hepatitis B virus (HBV) genotype and precore/core promoter mutations have been implicated in spontaneous and interferon alfa (IFN-alfa)-related hepatitis B e antigen (HBeAg) seroconversion.

Researchers performed a retrospective analysis of a previously reported randomized controlled trial to determine the effects of HBV genotype and precore/core promoter mutations on IFN-alfa response in patients with HBeAg-positive chronic hepatitis.

Clinical data and stored sera from 109 (95%) patients in the original trial were analyzed. Seventy-three patients received IFN-alfa and 34 received no treatment (controls).

Almost all patients had HBV genotypes B (38%) and C (60%). Antiviral response was achieved in 39% and 17% of IFN-a treated patients (P = .03) and in 10% and 8% of untreated controls (P = .88) with HBV genotype B and C, respectively.

Multivariate analysis identified HBV genotype B, elevated pretreatment alanine aminotransferase (ALT) levels, and low pretreatment HBV-DNA levels but not IFN-alfa treatment as independent factors associated with antiviral response.

Among the 66 patients with elevated pretreatment ALT level, antiviral response was achieved in 57% and 21% of IFN-alfatreated patients (P = .019), and in 25% and 8% of untreated controls (P = .45) with HBV genotype B and C, respectively. Multivariate analysis showed that genotype B and low pretreatment HBV-DNA levels were independent predictors of antiviral response.

The authors conclude, "Our data showed that HBV genotype B was associated with a higher rate of IFN-induced HBeAg clearance compared with genotype C. Stratification for HBV genotypes should be considered in future clinical trials of antiviral therapy of chronic hepatitis B."

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Nonalcoholic Fatty Liver Disease (NAFLD) May Be a Common Underlying Liver Disease in Patients with Hepatocellular Carcinoma in the US
By hivandhepatitis.com

The incidence of hepatocellular carcinoma (HCC) in the United States is increasing, but the clinical characteristics of American patients with HCC have not been well described.

The aims of this study were to determine the etiology of liver disease and short-term outcome among HCC patients presenting to a single center in the United States.

One hundred five consecutive patients with HCC were studied; mean age was 59 years, 67% were men, and 76% were non-Hispanic white.

The most common etiology of liver disease was hepatitis C (51%) and cryptogenic cirrhosis (29%). Half of the patients with cryptogenic cirrhosis had histologic or clinical features associated with nonalcoholic fatty liver disease (NAFLD).

Fifty-three (50%) patients had HCC detected during surveillance (group I), whereas the remaining patients had symptomatic tumors (group II). Group I patients had smaller tumors (P = .01), were more likely to be eligible for surgical treatment (P = .005), and had a better median survival compared with patients in group II (P = .001). Patients with cryptogenic cirrhosis were less likely to have undergone HCC surveillance and had larger tumors at diagnosis.

In conclusion, hepatitis C and cryptogenic liver disease are the most common etiologies of diseases in our patients with HCC. NAFLD accounted for at least 13% of the cases. Patients who underwent surveillance had smaller tumors and were more likely to be candidates for surgical or local ablative therapies.

Because of the increasing incidence of NAFLD, further studies are needed to determine the risk of HCC in patients with NAFLD.

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Impact of Immunosuppression in Hepatitis C Recurrence After Liver Transplantation: A Controllable Factor?
By hivandhepatitis.com

The current outcome typical of hepatitis C virus-infected liver recipients after a first transplant is worrisome. Prophylaxis with antivirals has yielded a low rate of success. Without effective prophylaxis, the attention should be focused on the one factor that can be controlled: immunosuppression.

In the current study, a summarized review of the impact of immunosuppressive agents used for the past few years is presented in the context of hepatitis C virus recurrence.

Steroids have been blamed for years as the main culprit in the higher incidence of hepatitis C virus recurrence reported in some series. New experience with these agents may prove the opposite.

Purine synthesis inhibitors such as azathioprine and mycophenolate mofetil may help to reduce the incidence of hepatitis C virus recurrence after liver transplantation, although further studies are needed to confirm these recent reports.

Antilymphocytic therapy with monoclonal or polyclonal antibodies does not seem to be harmful when used at induction. Most reports have analyzed these agents in the context of steroid-resistant rejection, a confounding factor in many studies.

The calcineurin-inhibitors, cyclosporine and tacrolimus, appear with similar incidences of hepatitis C virus recurrence and their current use is only center-dependent.

Newer agents like sirolimus and antibodies against IL-2 receptors still need to pass the test of time before firm recommendations can be given in any sense.

Larger, randomized studies will finally answer questions concerning the best immunosuppressive agent combinations for treating the high-risk hepatitis C virus-infected population of liver transplant recipients.

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July 2nd 2003

The Management of Ascites in Cirrhosis: Report on the Consensus Conference of the International Ascites Club
By hivandhepatitis.com

Ascites refers to fluid accumulation around the liver and other abdominal organs. Ascites occurs in more than 50% of cirrhotic patients within 10 years of the diagnosis of cirrhosis.

Cirrhotic ascites accounts for over 75% of patients who present with ascites, with the remaining 25% being due to malignancy (10%), cardiac failure (3%), pancreatitis (1%), tuberculosis (2%), or other rarer causes.

There have been several changes in the clinical management of ascites over recent years. An International Ascites Club Consensus Meeting on the management of ascites agreed on the recommendations reviewed here. The consensus meeting was supported by an unconditional educational grant from Searle, Spain.

These recommendations have been updated in line with subsequent recent publications of controlled clinical studies. The full consensus document is published in the July 2003 issue of Hepatology. Following is a brief summary of the consensus observations and recommendations:

"Ascites is a common complication of cirrhosis, and heralds a new phase of hepatic decompensation in the progression of the cirrhotic process. The development of ascites carries a significant worsening of the prognosis."

"It is important to diagnose non cirrhotic causes of ascites such as malignancy, tuberculosis, and pancreatic ascites since these occur with increased frequency in patients with liver disease."

"The International Ascites Club, representing the spectrum of clinical practice from North America to Europe, have developed guidelines by consensus in the management of cirrhotic ascites from the early ascitic stage to the stage of refractory ascites."

"Mild to moderate ascites should be managed by modest salt restriction and diuretic therapy with spironolactone or an equivalent in the first instance. Diuretics should be added in a stepwise fashion while maintaining sodium restriction."

"Gross ascites should be treated with therapeutic paracentesis followed by colloid volume expansion, and diuretic therapy."

"Refractory ascites is managed by repeated large volume paracentesis or insertion of a transjugular intrahepatic portosystemic stent shunt (TIPS). Successful placement of TIPS results in improved renal function, sodium excretion, and general well-being of the patient but without proven survival benefits."

"Clinicians caring for these patients should be aware of the potential complications of each treatment modality and be prepared to discontinue diuretics or not proceed with TIPS placement should complications or contraindications develop."

"Liver transplantation should be considered for all ascitic patients, and this should preferably be performed prior to the development of renal dysfunction to prevent further compromise of their prognosis."

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Can Serum HBV-DNA Levels Serve As a Primary End Point to Assess the Efficacy of New HBV Treatments?
By hivandhepatitis.com

Three drugs have been approved by the US FDA for the treatment of chronic hepatitis B: Intron A (interferon (IFN) alfa-2b), available since the early 1980s; Epivir-HBV (lamivudine; 3TC), a nucleoside analog introduced in the late 1990s; and the recently approved Hepsera (adefovir dipivoxil), a nucleotide analog with efficacy similar to lamivudine but with a more favorable resistance profile with efficacy against lamivudine-resistant HBV.

A number of other compounds are currently investigated in phase II/III clinical trials. Most are nucleos(t)ide analogs and include entecavir, emtricitabine, clevudine, beta-1 L-nucleoside, and other molecules. Other studies are assessing different ways of combining anti-HBV therapies (IFN and PEG-IFN plus lamivudine or adefovir, lamivudine plus adefovir, other nucleos(t)ide analogs combinations) with the hope of improving the effectiveness of monotherapy.

An article by Mommeja-Marin et. al. in the June 2003 issue of Hepatology argues in favor of using HBV DNA levels to assess the effectiveness of new HBV treatments. However, the July 2003 issue of Hepatology contains an editorial that argues such use of HBV DNA testing would be "premature." The editorial is written by Alfredo Alberti, MD, of the Venetian Institute of Molecular Medicine at the University of Padova in Padova, Italy. Selected sections of his commentary follow:

"Faced with [an] expanding armamentarium of potentially useful treatments, there is the need to identify parameters that accurately reflect their clinical efficacy. The final goal of therapy in chronic hepatitis B is to prevent cirrhosis and its complication, hepatocellular carcinoma, and HBV-related death."

"In clinical trials, it is unrealistic to assess for these 'true' end points due to the slow course of initially compensated chronic hepatitis B. Therefore, 'surrogate' end points need to be used. However, identification of surrogates that adequately describe clinically significant events is not an easy task in chronic hepatitis B, due to the great virologic and clinical heterogeneity of the disease, its complex pathogenesis, and the type of response obtainable with therapy in most patients, i.e., short-term suppression rather than complete eradication of HBV."

"The difficulties and uncertainties in proposing a well-defined parameter/time point as gold standard of response to antiviral therapy in chronic hepatitis B are reflected by the conclusions of the 2000 HBV Workshop organized by the National Institutes of Health and of the 2002 European Consensus Conference on Hepatitis B."

"These documents describe a number of types (virologic, biochemical, histologic, composite) and time points (early, end-of-therapy, maintained during long-term therapy, sustained after therapy) of response to be considered without indicating a specific type/time point to be adopted as a primary efficacy end point."

In recent registration trials of nucleos(t)ide analogs, liver histology, defined as a decrease in histologic activity index (HAI) by 2 or more points with no worsening of fibrosis score, was adopted as the primary efficacy end point. This approach, however, has a number of limitations:

• "it requires an invasive procedure, to be performed twice, with the potential for bias when the percent of patients agreeing to a repeat biopsy is low;
• it uses a poorly standardized semiquantitative assessment of a noncontinuous variable such as HAI;
• it implies the unproven assumption that an HAI reduction of 2 points or more is clinically relevant and that improvement in liver histology after a certain duration (usually 1 year) of therapy can be maintained if treatment is stopped;
• it does not allow early prediction of response; and (5) it is unsuitable in every day clinical practice."

"Recently, highly sensitive polymerase chain reaction-based methods that measure serum HBV-DNA levels with a wide dynamic range have become available and can now be used to precisely assess and compare the potency of different anti-HBV treatments in suppressing HBV replication."

"Since improvement of liver disease with antiviral therapies is thought to depend on suppression of HBV replication, can we consider serum HBV-DNA measurement a surrogate of clinically significant events and use it as a primary end point of efficacy in clinical trials, as in the case of antiviral therapy for chronic hepatitis C?

"The use of virologic end points is fully justified in hepatitis C based on the high (>50%) rate of virus eradication that can be obtained with therapy,11-12 the demonstration that virus eradication can be accurately predicted by HCV-RNA testing at well-defined time points during therapy,13 the very high (>95%) rate of durability of sustained response, and the correlation between sustained virologic response and improvement in long-term clinical outcomes."

"Unfortunately, this is not the case with hepatitis B. All types of anti-HBV treatments evaluated so far have resulted in long-term virus suppression with a finite course only in a small minority of patients. Virus eradication is rarely if ever achieved as the vast majority of patients remain hepatitis B surface antigen positive. Most cases need prolonged therapy to suppress liver disease activity and progression."

"Unfortunately, an initial response can be lost with time if drug resistance develops. If the virus cannot be completely eliminated, the question is to which levels and for how long its replication should be suppressed to ensure a significant benefit on clinical outcomes.

"To propose HBV-DNA measurement as a primary end point of response to anti-HBV therapies, several criteria need to be fulfilled:

• serum HBV-DNA changes should correlate with the end points for which surrogacy (i.e., improvement in clinical outcome) is proposed;
• the extent and timing of "clinically significant" HBV-DNA suppression should be precisely defined; and
• HBV-DNA changes should predict changes in "true" end points at the individual patient level, as assessed by the "percent of effect explained."
• Last but not least, HBV-DNA quantitative assays should be standardized as in the case of HCV-RNA assays. Unfortunately, most of these issues have not been yet solved."

"In conclusion, while serum HBV-DNA measurement by polymerase chain reaction-based assays is already a most useful tool to assess and compare the antiviral potency of different anti-HBV compounds and strategies, to monitor the virologic response in individual treated patients, and to identify cases with a reduced response or emergence of drug resistance, its implementation as the primary surrogate end point of efficacy in the assessment of new anti-HBV therapies appears premature."

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July 3rd 2003

Innogenetics announces additional positive liver histology results for its hepatitis C therapeutic vaccine

On the occasion of the 38th Annual Meeting of the European Association for the Study of the Liver (EASL), Innogenetics today announced the presentation of additional positive results supporting the previously published positive histological findings of its E1-based therapeutic candidate vaccine for hepatitis C.

As part of its phase IIa study that started in 35 chronic hepatitis C patients, positive histological results were communicated in October 2002 for 24 out of the 26 patients who underwent two vaccination courses followed by liver biopsy. The 9 remaining patients have now completed two courses of Innogenetics' E1candidate therapeutic vaccine and have undergone liver biopsy. These biopsies have now been analyzed by two expert pathologists, and compared with the biopsy at study start, some 28 months before. Histological scoring was performed under strict procedures of blinding.

The results showed that for 78% (7/9) of the patients, the overall Ishak histology score either improved (3/9) or remained stable (4/9) as compared to pre-study scores. Another significant finding was that on average, a regression (improvement) of liver fibrosis of minus 0.22 points on the Ishak fibrosis scale was observed. Over the 28 months since the initiation of the study, this group of patients was expected to have shown, on average, a progression (worsening) of fibrosis, amounting to plus 0.75 points. These results are an independent confirmation of the previously reported phase IIa results in 24 patients, and strengthen the evidence that the E1 therapeutic vaccine may not only halt, but actively induce regression of HCV-related liver disease. In summary, we can state that after two courses of E1-based therapeutic vaccination in a total of 33 (24 + 9) patients, an improvement of liver histology was seen in 12 patients (37%), while the overall Ishak score was stabilized in another 14 patients (42%).

According to Professor Dr. F. Nevens, the principal investigator, "These new liver biopsy results, obtained in the same rigorously monitored manner as previously, strengthen the evidence that the E1-based therapeutic vaccine not only has the potential to halt disease progression towards liver cirrhosis, but appears to demonstrate a possible anti-fibrotic effect."

Beyond these interim results of the phase IIa extension study, the entire cohort of patients is scheduled to receive further E1 therapeutic vaccination in the coming months. This open-label extension of the phase IIa study will generate relevant clinical data over a 3-year period. Its aim is to further explore the long-term disease-modifying effects of E1-based therapeutic vaccination. The next liver histology results on the other 24 patients of this phase IIa extension study are expected in the second quarter of 2004.

According to Philippe Archinard, Chief Executive Officer of Innogenetics, "These outstanding results strengthen the previous positive results already achieved with our E1 candidate therapeutic vaccine, and this mostly in patients who failed to respond to current standard therapy. We eagerly await the outcome of our two ongoing phase II studies, with the fullest confidence that the therapeutic vaccine approach will provide a well tolerated, practical, and effective option for the treatment of HCV patients."

Notes to Editor

The initial phase IIa trial started in the spring of 2001 and entailed 35 patients with chronic hepatitis C virus of genotype 1.Twenty-six patients received five 20-microgram injections of the E1 protein on alum at weeks 0, 4, 8, 12, and 24, while 9 patients received placebo at similar intervals. In the spring of 2002, a study extension was initiated in which 34 of the previously enrolled 35 patients took part. Based on the promising immunological results, all 34 patients received six 20-microgram injections of the same vaccine at 3-week intervals. Thus, 25 patients received two vaccination courses. A total of 24 out of these 25 patients then underwent a liver biopsy after the second vaccination course. In the phase IIa extension study, the 9 placebo patients underwent two course of E1 therapeutic vaccination, followed by a liver biopsy, of which the results are covered in this press release. The other 24 are undergoing a third and fourth vaccination course, followed by a liver biopsy with results expected in the second quarter of 2004.

To date, the phase II studies have also demonstrated that the therapeutic candidate vaccine is well tolerated, as supported by the very low dropout rates over at least 28 months.

Liver biopsy remains the gold standard to assess liver disease. Histology is the science of examining such biopsies.

The Ishak scoring method was used to evaluate the liver histology. A histological improvement or worsening is characterized by a change of at least two points according to the overall Ishak scale (i.e. sum of liver inflammation and fibrosis scores). The Ishak score is a widely accepted tool for the semi-quantitative assessment of liver biopsies in therapeutic trials.

About Innogenetics

Innogenetics is an international biotechnology company building two businesses in the areas of speciality diagnostics and therapeutic vaccines. The Company's advanced therapeutic vaccine for the treatment of hepatitis C virus - a global unmet medical need - is currently considered to be two years ahead of the competition. In its diagnostics division, Innogenetics develops a large number of speciality products covering 3 disease areas: infectious diseases, genetic testing, and neurodegeneration. In 2002, diagnostics sales increased by 17% to 47 million and total revenues reached 62 million. With a strong commercially oriented management team and distinctive dual business model, Innogenetics provides a low-risk biotech investment with potentially high returns. Founded in 1985, Innogenetics has been listed on NASDAQ Europe since 1996 and on Euronext Brussels since December 2002. The Company's headquarters are in Gent, Belgium, and it has sales affiliates in France, Germany, Italy, the Netherlands, Spain, and the USA. Innogenetics employs 600 people worldwide and has a market capitalization of approximately 300m.

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July 4th 2003

Alcohol Diminishes Therapeutic Effect of Interferon Alfa and May Be Cofactor in HCV Disease Progression
By hivandhepatitis.com

Results of prior studies demonstrate that alcohol consumption accelerates liver damage, diminishes therapeutic response to interferon alfa (IFN-a), and increases the rate of hepatocellular carcinoma in patients with chronic HCV infection.

Alcohol added in vivo and in vitro also impairs liver parenchymal cells and various functions of immune cells, including monocytes, T cells, and natural killer cells, which contribute to hepatocyte damage in chronic HCV infection.

Alcohol consumption and viral hepatitis infection, both recognized as major causes of liver disease worldwide, frequently coexist in patients with chronic liver disease. Alcohol and HCV most likely act synergistically to promote the development and progression of liver damage.

However, there is little direct information available concerning the effects of alcohol abuse on HCV replication in hepatic cells. This lack of knowledge about the impact of alcohol abuse on HCV is a major barrier to fundamental understanding of HCV-related morbidity and mortality in alcohol abusers with HCV infection. It is critical to investigate the impact of alcohol abuse on HCV replication in the target cells such as hepatic cells.

Japanese researchers investigated whether alcohol enhances HCV RNA expression in HCV replicon containing cell lines. They also studied whether the in vitro addition of alcohol to these cells compromises the anti-HCV effect of IFN-a.

Alcohol, in a concentration-dependent fashion, significantly increased HCV replicon expression. Alcohol also compromised the anti-HCV effect of IFN-a. Investigation of the mechanism(s) responsible for the alcohol action on HCV replicon indicated that alcohol activated nuclear factor KB (NF-kappa B) promoter.

Caffeic acid phenethyl ester (CAPE), a specific inhibitor of the activation of NF-Kappa B, abolished alcohol-induced HCV RNA expression. In addition, naltrexone, an opiate receptor antagonist, abrogated the enhancing effect of alcohol on HCV replicon expression.

In conclusion, alcohol, probably through the activation of NF-Kappa B and the endogenous opioid system, enhances HCV replicon expression and compromises the anti-HCV effect of IFN-a. Thus, alcohol may play an important role in vivo as a cofactor in HCV disease progression and compromise IFN-a-based therapy against HCV infection.

Abbreviations

HCV: Hepatitis C virus
IFN: interferon alfa
CAPE: caffeic acid phenethyl ester
4-MP: 4-methylpyrazole
IgG: immunoglobulin G
RT-PCR: reverse-transcription polymerase chain reaction
Mrna: messenger RNA
NF- B: nuclear factor kappa B
54-NCR: 54-noncoding region
MB: molecular beacon

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Treatment with Peginterferon or Interferon Alfa and Ribavirin Leads to Reduction or Disappearance of Liver Steatosis, Especially in Genotype 3 Sustained Responders
By hivandhepatitis.com

It has been suggested that hepatitis C virus (HCV) and especially genotype 3 is associated with steatosis (fatty liver). In an international, multicenter, randomized trial, researchers assessed the effect of treatment with peginterferon or interferon alfa-2b (Intron A) and ribavirin on steatosis.

The investigators analyzed 1,428 naive patients included in a randomized trial. A single pathologist scored steatosis at baseline and 24 weeks after the treatment.

At baseline, steatosis was present in 935 of 1,428 patients (65%), including 175 (83%) of 210 patients with genotype 3 versus 760 (62%) of 1,218 with other genotypes.

The variables associated with steatosis in logistic regression were genotype 3, triglycerides greater than 1.7 micromolar/L, body mass index greater than 27, age greater than 40 years, and septal fibrosis.

Patients were randomized to 1 of 3 treatment arms:

• standard interferon (interferon alfa-2b [Intron A], 3 million units 3 times a week subcutaneously) plus ribavirin 1,000 to 1,200 mg/d for 48 weeks;
• peginterferon alfa-2b [PEG-Intron] 1.5 microgram per kg per week for the first 4 weeks, followed by 0.5 microgram/kg per week for the next 44 weeks plus ribavirin 1,000 to 1,200 mg/d;
• peginterferon alfa-2b 1.5 microgram/kg per week plus ribavirin 800 mg/d.

For patients in the groups receiving ribavirin 1,000 to 1,200 mg/d, the dose was adjusted for body weight (1,000 mg for <75 kg and 1,200 mg for 75 kg).

Liver biopsy specimens were processed using standard techniques and evaluated for stage of fibrosis and grade of activity according to the METAVIR scoring system. In genotype 3-infected patients, steatosis was associated with high viral load and with lower serum cholesterol. Steatosis was associated with lower sustained response rate, even after taking into account other factors.

Among virologic responders, steatosis was much improved in genotype 3, improvement of at least 1 grade in 77%, and disappearance in 46% compared with other genotypes, 46% and 29%, respectively. In genotype 3 responders, the baseline low serum cholesterol was corrected by treatment.

Commentary

This study confirms the high prevalence (65%) of steatosis among patients with chronic hepatitis C and the association with genotype 3, overweight, high fasting serum glucose, triglycerides, male gender, and age. Steatosis was also associated with fibrosis stage.

There was an expected association between fibrosis and male gender, glucose, and BMI. Therefore, the inclusion of fibrosis in the multivariate model reduces the strength of the association between steatosis and male gender, BMI, and glucose.

Serum glucose and serum triglycerides also had significant impact on steatosis, independent of BMI, suggesting that insulin resistance without being overweight may be associated with steatosis.

For the first time, it has been clearly demonstrated that effective treatment of HCV leads to a reduction or disappearance of liver steatosis. The impact was particularly observed in patients with HCV genotype 3 infection.

In patients infected with genotype 3 HCV, most will be sustained responders, and the steatosis will disappear in half of them. In contrast, in patients infected by non-3 genotype HCV, steatosis is mainly associated with metabolic factors. The management of overweight, diabetes, and hypertriglyceridemia must be particularly encouraged.

The authors conclude, "The better understanding of factors related with steatosis will permit us to improve the management of patients. In patients infected with genotype 3 HCV, most of them will be sustained responders, and the steatosis will disappear in half of them. In contrast, in patients infected by non-3 genotype HCV, steatosis is mainly associated with metabolic factors. The management of overweight, diabetes, and hypertriglyceridemia must be particularly encouraged."

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Moderate Alcohol Consumption Increases Oxidative Stress That May Contribute to HCV Disease Progression
By hivandhepatitis.com

Chronic hepatitis C progresses to cirrhosis or to hepatocellular carcinoma in 20% to 25% of patients within 20 years from infection. Alcohol consumption is receiving more attention as a significant factor that contributes to the progression of hepatitis C.

Alcohol intake exceeding 40 g/d for women and 60 g/d for men increases the risk of developing cirrhosis by 2- to 3-fold, independently from the duration of HCV infection. According to Corrao and Aricr, the interaction between ethanol and hepatitis C virus (HCV) in promoting cirrhosis is additive for lifetime daily alcohol intake of 50 g/d but becomes synergistic when alcohol consumption exceeds 125 g/d.

However, a recent report suggests that even moderate alcohol intake (below 30-40 g/d) can promote the progression of fibrosis in patients with HCV infection. In addition, heavy alcohol consumption has also an additive effect with chronic hepatitis C in increasing the risk of hepatocellular carcinoma.

Despite the finding that the capacity of ethanol to worsen the evolution of HCV infection is well documented, the mechanisms involved are still poorly understood. It has been proposed that alcohol might favor viral replication; however, other mechanisms are also likely to be involved. Recent studies have documented an association between HCV infection and the presence of both liver and serum markers of oxidative stress.

Italian researchers investigated the possible interaction between hepatitis C virus (HCV) and ethanol in promoting oxidative stress. A preliminary report of this work was presented as oral communication at the 2002 AASLD.

Circulating IgG against human serum albumin (HSA) adducted with malondialdehyde (MDA-HSA), 4-hydroxynonenal (HNE-HSA), or arachidonic acid hydroperoxide (AAHP-HSA) and against oxidized cardiolipin (Ox-CL) were evaluated as markers of oxidative stress in 145 CHC patients with different alcohol consumption, 20 HCV-free heavy drinkers (HD) without liver disease, and 50 healthy controls.

Anti-MDA IgG was increased in CHC patients irrespective of alcohol intake as well as in the HD group. CHC patients with moderate alcohol intake (<50 g ethanol/d), but not HD, also had significantly higher values of anti-AAHP-HSA, anti-HNE-HSA, and anti-Ox-CL IgG (P < .05) than controls.

A further elevation (P < .001) of these antibodies was evident in CHC patients with heavy alcohol intake (>50 g ethanol/d). Anti-AAHP and anti-Ox-CL IgG above the 95th percentile in the controls were observed in 24% to 26% of moderate and 58% to 63% of heavy drinkers but only in 6% to 9% of the abstainers.

The risk of developing oxidative stress during CHC was increased 3-fold by moderate and 13- to 24-fold by heavy alcohol consumption. Heavy drinking CHC patients had significantly more piecemeal necrosis and fibrosis than abstainers. Diffuse piecemeal necrosis was 4-fold more frequent among alcohol-consuming patients with lipid peroxidation-related antibodies than among those without these antibodies.

In conclusion, authors note, "The data presented are the first evidence that even moderate alcohol consumption worsens oxidative stress in patients with chronic hepatitis C and suggest that oxidative injury might be one of the mechanisms by which alcohol contributes to the progression of chronic hepatitis C."

Abbreviations

HCV: hepatitis C virus
Ox-CL: oxidized cardiolipin
CHC: chronic hepatitis C
ELISA: enzyme-linked immunosorbent assay
MDA: malondialdehyde
HNE: 4-hydroxynonenal
HAS:Human serum albumin
PBS: phosphate-buffered saline
AAHP: arachidonic acid hydroperoxide
ROS: reactive oxygen species

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July 6th 2003

Donor-Crisis Hospitals Gamble on Bad Organs
By SUSAN EDELMAN

Desperate patients at New York transplant centers are being offered "high-risk" and sometimes infected livers and kidneys because of a severe shortage of organ donors, The Post has learned.

NYU Medical Center, New York-Presbyterian Hospital and Mount Sinai Medical Center say they routinely use "expanded donors," including organs from the aged, overweight, drug or alcohol abusers and those infected with hepatitis. Some organs accepted here are rejected by other states, surgeons said.

Surgeons are taking chances on risky organs, they say, because New York has a list of about 8,000 patients waiting for organs. And many die waiting - about 200 organs from brain-dead donors are given each year.

The race for a liver has come at a steep price for some.

At NYU, a 37-year-old Bronx father of six died of cancer just a year after receiving a cancerous liver, his widow alleges.

In another NYU case, a 49-year-old Queens woman got hepatitis C from an infected donor liver - and now needs another liver to survive.

"She's a victim of the system," said Dr. Hillel Tobias, one of her doctors at NYU.

While transplant centers rule out livers with the AIDS virus and those from known cancer victims, they now routinely transplant livers with signs of hepatitis B and the more dangerous C strain, a chronic disease that causes liver failure.

But such livers are nearly always given to patients already infected with hepatitis - and rarely to those without it.

"We have never given a liver with hepatitis C to someone who doesn't have it, because we'd be giving them a disease," said Dr. Robert Brown, medical director of New York-Presbyterian's Center for Liver Disease and Transplantation. "It would violate our Hippocratic oath: 'First, do no harm,' except in a life-or-death situation."

At NYU, where Delfina Balan had a transplant last October, surgeons took the risky, but not prohibited, step of offering a hepatitis C liver because they thought her death was "imminent."

"Instead of grieving her loss, we have kept her alive, and she still has a chance," said Dr. Lewis Teperman, chief of NYU's liver-transplant center.

Since her transplant, however, Balan has sickened. Barely recognizable as the pretty, energetic office manager she once was, her skin is dark and eyes yellow with jaundice. She has shriveled to 100 pounds and has been hospitalized for 11 months.

"I'm glad they tried to save me, but if I had known it was a bad liver, I would have said 'no,' " she said in a trembling, barely audible voice.

Her husband, Ion, an electrical contractor, is heartsick and furious. He says an NYU surgeon, who told him about "a possible donor who was exposed" to hepatitis C, did not explain the risks and complications. NYU claims the husband was informed before consenting.

In the cancer case, the Bronx security guard with six kids, ages 3 to 21, was rushed into surgery at NYU in March 2002 for acute liver failure. Eight months later, he was diagnosed with cancer.

"I want answers," said his widow, who asked to remain anonymous. "This should not have happened."

Her lawyers, who are preparing a suit, say NYU failed to detect a tumor inside the donor liver, which spread cancer throughout her husband's body.

"Before they put it in his body, they had an obligation to screen the organ for possible tumors," attorney Marvin Fuhrman said.

NYU officials said the man received a "healthy, normal" liver and later developed a tumor that spread to the liver.

For information on becoming an organ donor, go to http://www.donatelifeny.org

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July 7th 2003

Study: 99 Percent of Pegasys Responders Virus Free Up to Four Years Later

Ninety nine percent of the hepatitis C patients who responded to treatment with Pegasys (peginterferon alfa-2a) have remained virus free up to four years later, according to results presented at the 38th Annual Meeting of the European Association for the Study of the Liver.

"This information tells us that when a patient achieves a sustained virological response, they are indeed really 'cured,'" says Dr. Mark Swain, Associate Professor of Medicine at the University of Calgary in Canada. "This is a critical message for patients whether they are about to start therapy or in the midst of it-the end result is worth it."

Researchers for Roche, which markets the drug, said a possible explanation for the success of Pegasys may be found in another study showing that levels of the drug-which hepatitis C patients take once weekly-remain constant in the body over the seven-day period thereby suppressing the virus on a constant basis.

The researchers said that in contrast, half of patients treated with PEG-Intron (peginterferon alfa-2b)-a rival drug marketed by Schering-had no detectable drug in their bodies by the fifth day after their weekly injection, potentially resulting in renewed virus replication.

"Our study demonstrated a difference in drug levels between the two pegylated interferons," said Dr. Raffaele Bruno, University of Pavia, Italy. "We concluded that Peg-Intron should be intensified from its current once weekly dose to a twice-weekly dose to avoid the hepatitis C virus from replicating."

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Pegasys (peginterferon alfa-2a) Is More Effective Than Current Standard Therapy for Chronic Hepatitis B
By hivandhepatitis.com

Hepatitis B is a blood-borne virus that attacks the liver and is the most common serious liver infection in the world. The hepatitis B virus (HBV) is highly contagious and is relatively easy to transmit from one infected individual to another. It is 100 times more infectious than the HIV virus. More than 300 million people worldwide are infected with HBV.

The first published study on the use of Pegasys (peginterferon alfa-2a) for the treatment of chronic hepatitis B virus (HBV) appears in the July issue of the Journal of Viral Hepatitis.

The study found that Pegasys (peginterferon alfa-2a) is more effective than standard interferon (interferon alfa-2a), the initial therapy for chronic HBV recommended by a recent International Consensus Conference EASL (European Association for the Study of the Liver) International Consensus Conference on Hepatitis B (1).

The 194 patients in the Phase II study were treated with either conventional interferon injected three times weekly or Pegasys (at 90 g, 180 g or 270 g) injected once weekly for a 24-week-period, and were then observed with no further treatment for another 24 weeks.

The study evaluated the "combined response" of patients. This response includes the loss of viral protein, suppression of HBV DNA levels and the normalization of the liver function, all strong indicators of treatment efficacy.

Overall, 28% of patients who received Pegasys for six months at the180 gram dose achieved a "combined response." Only 12% of patients who received standard interferon achieved a combined response.

"The viral reduction achieved with Pegasys is substantially more pronounced than what's achieved with conventional interferon. It appears that Pegasys enhances the patient's immune response against the virus as well as profoundly inhibiting the virus," said Professor Graham Cooksley, a principal author of the study and Senior Principal Research Fellow, Clinical Research Center, Royal Brisbane Hospital, Australia.

"One reason this study was undertaken was because of the short-comings with current therapies, including nucleoside analogues, which offer less than optimal efficacy, often require long-term or continuous administration and have been associated with drug resistance," said Dr. Cooksley.

More Profound Impact on HBV Than Standard Interferon their article, the authors note that the beneficial effects of Pegasys were also observed in difficult to treat patients, for example those with cirrhosis, those with low ALT or high HBV DNA levels at baseline, and those with HBV genotype C.

The rapid and sustained reductions in HBeAg and HBV DNA levels indicated that Pegasys has a more profound impact on HBV than conventional interferon alfa-2a.

Promising Seroconversion Rate with Pegasys

Dr. Cooksley and colleagues note the primary treatment goal in chronic hepatitis B remains sustained suppression of HBV replication in the absence of therapy. HBeAg loss and "e" seroconversion (antibodies against the viral antigens) are indicative that this goal has been reached.

Significantly, seroconversion significantly lowers a patient's risk of developing end-stage liver disease or death. "For this reason, the documented seroconversion rate of 33% in 6 months seen in this study with peginterferon alfa-2a (40KD) [Pegasys], an agent with both antiviral and immunomodulatory properties, is eminently promising."

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Early Responders to PEG-Intron (peginterferon alfa-2b) Plus Ribavirin Have a Significant Reduction in HCV RNA at 48 hours That May Be Pivotal in Achieving a Sustained Viral Response
By hivandhepatitis.com

Currently, interferon alfa and ribavirin are the mainstay of therapy for patients with chronic hepatitis C. Recently the pegylation of interferon has allowed once weekly dosing, resulting in an increased sustained viral response (SVR) rate and a better quality of life for patients.

The analysis of serum HCV dynamics has been shown useful in predicting clinical effects and optimizing the treatment regimen. The aim of the present study was to assess early serum HCV RNA changes in patients with chronic hepatitis C treated with PEG-Intron (peginterferon alfa-2b) plus ribavirin.

Male and female patients aged 18 to 65 years with chronic hepatitis C were eligible for the study. All patients received peginterferon alfa 2b 1.5 micrograms/kg once weekly for 4 weeks and then peginterferon alfa 2b 0.5 microgram/kg once weekly until the completion of the 48 week trial period, plus ribavirin orally with meals, adjusted to body weight. HCV RNA was determined at base-line, 48 hours, 4 and 12 weeks of therapy.

Data were obtained from 20 patients with chronic hepatitis C treated with peginterferon alfa 2b and ribavirin; 16 male, 4 female, with a mean age of 44.4 +/- 11.9 years, 16 patients (80%) were infected with HCV genotype 1, the remainder were infected with genotype 2.

Mean baseline HCV RNA for the total group was 1,091,405 +/- 972,715 IU/mL. Mean reductions in viral load at 48 hours, 4 and 12 weeks for the 20 patients were 1.31 +/- 0.91 log, 1.99 +/- 1.27 log and 2.31 +/- 1.25 log, respectively.

A > 2 log reduction in HCV RNA was noticed in 12/20 patients (60%) at 4 weeks (early viral responders), in 9 of them (45%) HCV RNA was undetectable. This response in HCV RNA persisted at 12 weeks of therapy.

Early viral responders had a significant reduction in HCV RNA at 48 hours after the initial peginterferon alfa 2b injection (> 1 log reduction). Early viral response was observed in 8/16 patients with HCV genotype 1, and in all genotype 2 patients.

The authors conclude, "Treatment with peginterferon alfa 2b and ribavirin produces significant changes in the early HCV viral dynamics supporting the concept that such changes may be pivotal in achieving a sustained viral response."

Department of Health Sciences, Universidad Nacional Autonoma Metropolitana-Iztapalapa.

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New Pegasys Trial to Enroll Hepatitis C Patients Not Helped by PEG-Intron

Hepatitis C patients who failed to respond to the first pegylated interferon combination therapy (peginterferon alfa-2b and ribavirin) are being recruited for a new global trial of peginterferon alfa-2a and ribavirin, it was announced at the 38th Annual Meeting of the European Association for the Study of the Liver.

Roche, which markets peginterferon alfa-2a as Pegasys, said the trial, which ultimately expects to enroll 1,000 patients in this study from Europe, North America and Latin America, will be known as REPEAT (REtreatment with Pegasys in pATients not responding to prior Peginterferon alfa-2b/Ribavirin combination therapy).

"Non-responders," as these hepatitis C patients are called, are those who failed to achieve a sustained virological response (increasingly regarded as a "cure") as a result of their treatment, and who continued to have virus present throughout their course of therapy.

The trial will be the first to compare repeat treatment of "non-responders" who previously were treated with peginterferon alfa-2b, which is marketed by Roche competitor Schering. Previous studies using pegylated interferon to retreat "non responders" have measured themselves against earlier therapies.

Today, the standard of care is pegylated interferon and ribavirin, and most hepatitis C patients receive one of the two pegylated interferon combination therapies.

"The two pegylated interferons are different drugs, with different properties and we know that Pegasys with Copegus (ribavirin) has yielded impressive results in hepatitis C patients," said William M. Burns, head of the pharmaceutical division at Roche. "We feel it is important for this pivotal trial to show how Pegasys with Copegus can help that sizeable group of patients who have not responded to the first pegylated interferon combination therapy."

The REPEAT study will evaluate the efficacy and safety of the combination of Pegasys and Copegus given for a longer, 72-week period, as well as examining the role of an induction regimen in this treatment- resistant population, Roche said.

"We've already seen that Pegasys in combination with Copegus is a highly effective treatment in [first-time] patients with some of the most difficult-to-treat strains of the virus,"said the European lead researcher Dr. Patrick Marcellin from Hospital Beaujon in France. "Given this performance, Pegasys may prove to give these particular patients another chance to respond and be cured."

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38Hepatotoxicity Associated with Nimesulide and Other Nsaids

The risk of liver injury in patients taking nimesulide and other non-steroidal anti-inflammatory drugs is small, find researchers in this week's issue of the British Medical Journal (BMJ 2003; 327: 18-22)

In this study, researchers from Italy estimated the risk of acute hepatotoxicity associated with nimesulide, compared with other non-steroidal anti-inflammatory drugs (NSAIDs).

The Original Nimesulide registered trademarks in the world are:

Ainex., Aulin., Donulide., Edrigyl., Eskaflam., Guaxan., Heugan., Mesulid., Nexen., Nimed., Nimedex., Nisulid., Plarium., Scaflam., Scaflan., Sulidene..

The team performed a retrospective cohort and nested case-control study.

Current NSAID use was associated with a 1.4 increased risk of hepatopathy.--British Medical Journal

They evaluated 400,000 current, recent, and past users of NSAIDs, between 1997 and 2001.

The team measured admission to hospital for acute non-viral hepatitis, incidence of all hepatopathies, and liver injury among users of nimesulide and other NSAIDs.

The researchers found that current use of NSAIDs was associated with a 1.4 increased risk of hepatopathy, compared with past use.

They determined that the rate ratio was 1.3 for all hepatopathies, and 1.9 for more severe liver injury, in current users of nimesulide.

Dr Giuseppe Traversa's team concluded, "The risk of liver injury in patients taking nimesulide and other non-steroidal anti-inflammatory drugs is small".

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Study: Half of Cirrhosis Patients Respond to Pegasys and Ribavirin


The largest-ever analysis of data on hepatitis C patients with cirrhosis, or advanced liver disease, concluded that half of them respond to treatment with Pegasys in combination with Copegus (ribavirin), according to results presented at the 38th Annual Meeting of the European Association for the Study of the Liver.

Dr. Patrick Marcellin, a hepatologist at the Hospital Beaujon in France, said a meta-analysis of two Phase-III Pegasys combination studies involving hepatitis C patients with cirrhosis found that:

• Among those treated with a standard dose of Pegasys plus 1000/1200 mg of ribavirin for 48 weeks, 49 percent achieved a sustained viral response, as compared to 33 percent who received conventional combination therapy;
• Among those who also had the genotype 1 virus -- the most difficult to treat but most common form of hepatitis C - 38 percent achieved a sustained viral response using Pegasys combination therapy versus 25 percent with conventional combination therapy.
• Among those with genotype 2/3 virus, the rate of cure rose to 72 percent with Pegasys combination therapy versus 45 percent with conventional combination therapy.

Schering-Plough Sets Dimmer Earnings View
By Jed Seltzer and Ransdell Pierson

NEW YORK (Reuters) - Schering-Plough Corp. on Monday warned that 2003 earnings will plunge by at least two thirds, well below already dismal Wall Street forecasts, as rival products cut deeper into sales of its drugs for allergies and hepatitis C.

Schering-Plough, struggling amid a battery of probes into its marketing and manufacturing practices, as well as the loss of U.S. patent protection for allergy pill Claritin, expects second-quarter earnings of 12 cents a share. That compares with the average estimate of 18 cents among analysts polled by Thomson First Call.

The company, whose stock fell nearly 4 percent, said second-half 2003 earnings could be lower than results in the first half, which are now projected at 24 cents a share. Analysts have estimated second-half earnings at 37 cents per share.

Last October, the company predicted per-share earnings of $1.00 to $1.15 for 2003. Its latest math indicates earnings could actually be lower than 48 cents per share -- representing at least a 66 percent decline from last year's operating profit of $1.42 per share.

The earnings warning was the latest dose of bitter news from Schering-Plough, whose 2001 profit fell 4 percent in large part due to quality control lapses at its plants that delayed U.S. approvals of new drugs and curtailed production of existing ones.

Profit in 2002 fell 10 percent as the company's hepatitis C drugs met competition from a new treatment sold by Roche Holding AG (ROCZg.VX) and as Claritin became available without a prescription at a third its former price.

Other drugmakers, meanwhile, are selling even cheaper copycat forms of Claritin, which once boasted annual sales of over $3 billion but has now virtually evaporated. Schering-Plough's newer and slightly altered version of the drug, called Clarinex, is not selling as well as the company had hoped.

THIRD WARNING

Monday's earnings forecast from the Kenilworth, New Jersey-based company was the first since Fred Hassan was appointed its chief executive officer in April. It was, however, the company's third 2003 earnings warning since October.

Hassan, previously the CEO of Pharmacia Corp., had rescinded Schering-Plough's previous earnings projections in May -- saying he needed to review the company's finances to get a realistic picture of earnings prospects.

"I welcome this earnings guidance from Fred Hassan, even if the numbers are far below anyone's expectations," said Neil Sweig, an analyst at Fulcrum Global Partners. "But I would urge great caution on this stock because next year's earnings could crater."

Shares of the company fell 72 cents to $18.34 on the New York Stock Exchange.

U.S. regulators last year slapped Schering-Plough with a $500 million fine for slipshod manufacturing. The company acknowledged in May it expects a federal criminal indictment for its sales practices, including marketing drugs for unapproved uses and submitting false pricing information on their drugs.

Few industry observers think Schering-Plough's problems will be easy to fix. The company's best bet, they said, is the new cholesterol drug Zetia, which was approved last year by U.S. regulators and is co-marketed with Merck & Co. Inc.

Many analysts expect Zetia to generate sales of more than $1 billion by 2006, and to rake in many times that amount if U.S. regulators eventually approve a pill combining the new medicine with Merck's older cholesterol drug Zocor.

"The great hope is that Merck will buy for a high price the 50 percent of Zetia that it does not already own or that it will buy all of Schering-Plough," Sweig said.

Schering-Plough's former CEO, Richard Kogan, resigned amid an investigation by securities regulators into his possible improper disclosure of the company's dim earnings prospects to selected analysts and investors last October. (Additional reporting by Toni Clarke)

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July 8th 2003

Schering-Plough Says 2003 Net May Sink 64 Percent Due to Competition
Peter Landers

Schering-Plough Corp. warned that net income in 2003 may fall by more than 64% compared with 2002, as it faces new competition on its top-selling hepatitis C drugs and its Claritin brand of over-the-counter allergy medicine.

The new profit forecast was below Wall Street's scaled-back expectations for Schering-Plough, which has struggled to overcome the loss of its patent on Claritin last year. The company, based in Kenilworth, N.J., also faces the threat of criminal indictment by the U.S. attorney in Boston over alleged marketing violations.

Schering-Plough shares were down amid an overall rise in the market, declining 72 cents to $18.34 in 4 p.m. New York Stock Exchange composite trading.

Chief Executive Fred Hassan, who took over in April, said his turnaround plan is still on track. "Our objective for Schering-Plough is to build a solid foundation for growth -- it's not about making quick fixes," Mr. Hassan said in a statement. He announced new heads for Schering-Plough's consumer and overseas businesses. The company also said several executives are retiring, including its longtime head of investor relations, Geraldine Foster, who will retire in March.

In a news release, Schering-Plough said it expects net income of 12 cents a share in the second quarter of 2003 following 12 cents a share in the first quarter. The release also said that, as a result of more intense competition, "earnings in the 2003 second half may not reach the levels achieved in the first half."

If that warning comes true, net income for the entire year would be less than 48 cents a share, or at least 64% below 2002 net income of $1.34 a share. On average, Wall Street analysts had been estimating that Schering-Plough would earn 68 cents a share in 2003, according to Thomson First Call.

The company's forecast excludes possible charges for "unusual items." A number of drug companies that faced similar probes by U.S. attorneys have taken one-time charges of several hundred million dollars to pay for settlements.

Claritin sales continue to be under attack. Schering-Plough recorded $125 million in over-the-counter sales of Claritin in the first quarter of 2003, the first full quarter that the drug was available in U.S. stores without a prescription. Over-the-counter Claritin has been selling in stores for more than a dollar a pill because generic competition is limited, but the company said it expects additional competition in the second half of 2003.

Generic drugs with the same active ingredient as Claritin are likely to be available by the end of this year for 10 cents to 25 cents a pill, said Gale Bensussen, president of Leiner Health Products Inc., which makes and markets generic drugs. Mr. Bensussen said his price estimate is based on contracts his company has signed with major national retail chains to supply a generic version of Claritin manufactured by an affiliate of Germany's Merck KGaA.

In its earnings warning, Schering-Plough also cited heavy competition from Roche Holding AG in hepatitis C treatment. U.S. sales of Schering-Plough's hepatitis C drugs fell a 18% year-to-year in the first quarter, although the company blamed that partly on inventory adjustments. Also, Schering-Plough faces generic competition for Rebetol, one of its hepatitis C drugs, in the second half of this year.

On a bright note, Mr. Hassan said he is encouraged by the progress of Zetia, a cholesterol drug that Schering-Plough is selling with Merck & Co. More than 1.5 million Zetia prescriptions have been filled since it went on sale in the U.S. in November, Schering-Plough said, citing data from market researcher IMS Health.

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US Report Questions Early Treatment Of Hepatitis C

People with hepatitis C whose livers remain healthy may be better off not undergoing drug treatment, which can produce severe side effects such as nausea and depression and does not always work, researchers said on Tuesday.

The recommended 48-week course of treatment for the blood-borne virus - injections of interferon and oral ingestion of ribavarin - is effective in, at most, 60 percent of patients. It also has potentially severe side effects such as nausea, fatigue, depression and, in some cases, suicidal impulses.

The treatment, which costs in excess of $20,000, has been shown to lengthen the lives of hepatitis C sufferers with existing liver damage, a condition which can lead to deadly cirrhosis or cancer.

But a majority of hepatitis C patients do not develop liver damage before dying of other causes, so the drug treatment may not be cost-effective or helpful for them, the report from the Harvard School of Public Health's Center for Risk Analysis said.

In the United States, 2.7 million people have chronic cases of hepatitis C and there are about 25,000 new cases each year, most infected through needle sharing or from receiving blood from an infected donor. But four out of five have no signs or symptoms and many of them are unaware they have it.

The disease's progression varies considerably and milder cases, especially among women, may never progress to cirrhosis. The report's analysis of U.S. health data showed that the probability of infected men developing cirrhosis over a 30-year period was between 13 percent and 46 percent, and among women the probability was between 1 percent and 29 percent.

"There has been a huge effort over the last few years to identify people infected with (hepatitis C), but this wider group of patients will likely include those who are least likely to develop advanced liver disease," Sue Goldie, author of the report published in this week's issue of the Journal of the American Medical Association, said in a statement.

"For patients at low risk of progressing, the overall health gain from treatment may be minimal given the potential for toxic side effects," she said.

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July 9th 2003

Pilot Study of Interferon Alfa and Ribavirin in Liver Transplant Recipients with Recurrent Hepatitis C
By hivandhepatitis.com

Although interferon alfa (IFN-a) and ribavirin are widely used in the treatment of hepatitis C, their role in the transplant recipient is unclear. Researchers conducted a pilot study to determine the efficacy and safety of this therapy in transplant recipients with recurrent hepatitis C.

Patients at least 6 months post transplantation were treated with IFN-a 3 million units 3 times a week subcutaneously and ribavirin 800 mg daily by mouth for 48 weeks followed by ribavirin monotherapy for 24 weeks.

The primary end point was sustained virologic response, and secondary end points included biochemical, virologic, and histologic responses at the end of combination treatment.

Thirty-eight patients initiated therapy but 16 withdrew due to adverse effects, including 2 with myocardial infarction. Median age was 50 years; 74% were men, and 91% had genotype 1. The median interval between transplantation and enrollment was 23 months. On an intention-to-treat basis, 7 patients (18%) had a biochemical and 5 (13%) had a virologic response at the end of combination treatment.

Inflammatory activity did not change, but fibrosis worsened in virologic non responders. Ribavirin maintenance caused a further decrease in serum alanine aminotransferase levels, but hepatitis C virus (HCV) RNA levels increased.

Only 2 of the 38 patients (5%) had a sustained virologic response. Several patients required treatment with erythropoietin for anemia.

In conclusion, IFN-a and ribavirin are effective in a small proportion of liver allograft recipients with recurrent hepatitis C. Adverse effects occur commonly, requiring dose reductions and treatment withdrawal.

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Researchers Rethink Options in Treating Hepatitis C
By Angela Stewart

People with hepatitis C who show no signs of liver disease may be better off not undergoing drug treatment because of the severe side effects, hefty cost and probability it may not work, according to a new study published today.

Researchers from the Harvard School of Public Health's Center for Risk Analysis concluded that the recommended, 48-week course of treatment for the blood-borne virus may not be the right choice for thousands of people with asymptomatic infection. In the study, they reason that in otherwise healthy individuals, the benefits of early therapy may not outweigh side effects such as nausea, fatigue and depression, which may lead to suicidal impulses.

Therapy also carries a $20,000 price tag for the three-times-a- week injections of interferon and oral ribavirin, the study on cost-effectiveness concludes.

"This may lead to a re-evaluation of the way decisions are made for people who have infection, but no evidence of liver damage as of yet," said lead researcher Joshua Salomon, assistant professor of international health at the Harvard School of Public Health.

The research appears in today's issue of the Journal of the American Medical Association.

Some liver experts strongly disagree with any suggestion that asymptomatic people shouldn't undergo treatment, especially with the big push in recent years to identify infected persons.

"Anyone who tests positive should receive anti-viral therapy at the earliest possible time so we can try and eliminate hepatitis C as a major health problem in the United States," said Carroll B. Leevy, director of clinical affairs for the liver center based at the University of Medicine and Dentistry of New Jersey in Newark.

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Serum Leptin Levels Correlate with Hepatic Steatosis in Chronic Hepatitis C
By hivandhepatitis.com

Hepatic steatosis (HS) has been associated with obesity and fibrosis in chronic hepatitis C (CHC). The aim of this study was to determine the role of leptin in HS development.

Patients (n = 131) with biopsy-proven CHC, positive HCV RNA, and elevated ALT were enrolled. Body mass index, percentage of body fat by skin fold measurement, and bioelectrical impedance analysis was calculated and serum leptin concentration measured. Intrahepatic HCV RNA, HS, necroinflammatory activity, and fibrosis were determined in liver biopsy tissue.

HS was present in 63 patients (48.1%). Steatosis was evident in 32 of 91 patients (35.2%) infected with genotype 1 and in 22 of 27 patients (81.5%) with genotype 3a. In patients infected by genotype 3a, HS correlated significantly with intrahepatic HCV RNA load. However, in genotype 1, HS was associated with host factors such as leptin, body mass index, percentage of body fat and visceral obesity.

Multivariate analysis showed genotype, leptin and fibrosis as independent variables of HS development.

The authors conclude, "Hepatic steatosis was related to genotype, fibrosis degree, and serum leptin levels. Genotype 3 seems to have a viral specific steatogenic effect. Leptin seems to be a link between obesity and steatosis development in CHC genotype 1-infected patients."

Hepatology Unit, Hospital Universitario de Valme, Sevilla, Spain.

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As Testing Campaigns Identify More People with Asymptomatic Hepatitis C Infection, Benefits, Risks and Cost-Effectiveness of Early Treatment Uncertain

In the first analysis that takes into account the variety in progression of hepatitis C infection, researchers at Harvard School of Public Health's Center for Risk Analysis looking at the clinical benefit and cost effectiveness of the latest treatment for the disease have concluded that early treatment may not be the right choice for many thousands of people with asymptomatic hepatitis C infection.

Their analysis is described in the July 9, 2003 issue of the Journal of the American Medical Association (JAMA) "Cost-Effectiveness of Treatment for Chronic Hepatitis C Infection in an Evolving Patient Population."

Hepatitis C virus (HCV) is a largely asymptomatic disease that after a long latency period, usually spanning decades, can damage the liver and eventually cause cirrhosis and liver cancer.

While it is currently a leading cause of liver transplantation in the U.S., many infected patients will never develop advanced liver disease. HCV infection is most commonly transmitted through shared needle use and also had been passed along through blood transfusions before testing of blood donations largely eliminated that route in the early 1990s.

The current treatment recommended for HCV is an injected long-acting interferon plus oral ribavirin. Treatment has improved considerably in the last decade but is still only effective in 40 to 60 percent of patients, has potentially severe side effects (e.g., nausea, severe fatigue, depression and, in some cases, suicidal impulses), and a single 48-week treatment course costs more than $20,000. Previous analyses have found that treating HCV is clinically beneficial and cost-effective, on average, in patients infected with HCV and with evidence of existing liver disease. For patients without evidence of liver damage, the effects of early therapy on life expectancy and particularly on patient quality of life are less clear.

In the United States an estimated 2.7 million individuals are chronically infected with HCV, but many of these people remain unaware of their infections. Rising interest in HCV from patient advocacy groups, public health advisory groups, and the lay press has been accompanied by a range of policy initiatives such as a government 'lookback' campaign launched in 1998 to notify people who received blood from potentially infected donors and an open letter from the Surgeon General in July 2000 warning the public about the 'silent epidemic' and encouraging at-risk individuals to get tested.

In this analysis, HSPH researchers, led by Joshua Salomon, assistant professor of international health, looked at a patient population of HCV seropositive but otherwise healthy individuals--people with the mildest form of the disease and the group most likely to be turned up in larger numbers by the HCV testing campaigns. Additionally, the researchers examined the latest information on the progression of the disease in several subgroups of patient by gender, age and other factors. This data showed that progression is highly variable, and some 30 to 70 percent of infected individuals may never progress to liver cirrhosis before dying from other causes.

In women in particular HCV appears to progress especially slowly. The probability of developing cirrhosis during a 30-year period was estimated to be between 13 and 46 percent for men and between one and 29 percent for women. Progression rates to cirrhosis and its complications are probably also substantially lower among those individuals infected at relatively young ages.

"Taking into account this lowered assessment of risk for some groups, the possible toxic side effects of therapy, and the limited efficacy of current regimens, the benefits of early therapy may not outweigh the substantial costs and decreases in quality of life for some individuals," said Sue Goldie, associate professor of health decision science and senior author of the paper. "As the pool of patients eligible for treatment expands to the more general population, it will be imperative for patients and their physicians to consider these factors in approaching treatment decisions at the individual level."

"Policy makers need to carefully consider the implications that public health campaigns targeted at HCV will have on the individual clinical decisions that follow," said Salomon. "There has been a huge effort over the last few years to identify people infected with HCV, but this wider group of patients will likely include those who are least likely to develop advanced liver disease. For patients at low risk of progressing, the overall health gain from treatment may be minimal given the potential for toxic side effects."

The research was supported in part by a grant to Dr. Salomon from the former Agency for Health Care Policy and Research. Coauthors Drs. Goldie, Milton Weinstein and James Hammitt are members of the Harvard Center for Risk Analysis and the Department of Health Policy and Management at HSPH.

Harvard School of Public Health is dedicated to advancing the public's health through learning, discovery, and communication. More than 300 faculty members are engaged in teaching and training the 800-plus student body in a broad spectrum of disciplines crucial to the health and well being of individuals and populations around the world. Programs and projects range from the molecular biology of AIDS vaccines to the epidemiology of cancer; from risk analysis to violence prevention; from maternal and children's health to quality of care measurement; from health care management to international health and human rights.

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Prison Health-Care Costs Still Going Up

The cost of providing medical care to inmates in Nebraska's prison system has risen from $8.8 million in fiscal year 2000 to around $18 million for the last fiscal year which ended June 30.

Rising medical costs, more inmates and a legislative mandate to provide inmates with better health care are behind the skyrocketing costs, the Lincoln Journal Star reported in Thursday editions.

The prison system has about 34 inmates who have been exposed to HIV the virus that causes AIDS with 23 under treatment for a cost of $345,000 last year, said Dr. Randy Kohl, correctional services medical director.

The state's prison system spent $280,000 last year treating eight inmates with hepatitis C.

Those costs could rise dramatically as more of the nearly 500 inmates with hepatitis C reach the point where they need treatment.

The agency could be spending $700,000 on hepatitis C treatment next year if 20 people need the $35,000-a-year combination of medicines, lab tests and specialist oversight, Kohl said.

The average cost of medical care per inmate has almost doubled. In fiscal 2000 the Department of Correctional Services spent an average of $2,471 on medical care per inmate.

Last year that figure jumped to about $4,375 per inmate. A number of moves did cut about $3.5 million in costs last year, said Robin Spindler, the department's budget analyst.

The department negotiated contracts with hospitals in Lincoln and Creighton University Medical Center in Omaha so the agency is no longer paying the highest rates.

"We were paying 100 percent of the bill charges,'' Kohl told the Journal Star.

The agency hopes to negotiate more contracts this year with additional hospitals and physician groups, just like insurance companies do, Kohl said.

The department now has a list of preferred drugs that makes it harder to prescribe newer and most expensive medicines. It is moving toward a central pharmacy for use by all prisons.

Still, medical costs will likely continue to rise, due in part to the high number of inmates with hepatitis C which can cause liver failure and a growing number of inmates who are HIV positive.

The system's health care costs also rose after the Legislature mandated in 2001 that inmates be provided the same level of care most insured Nebraskans receive.

That came after the state Ombudsman's Office and a special task force found the prison system sometimes offered substandard care and that a lack of training had led to at least one inmate's death.

The department should be in full compliance with the mandate by the end of the year, Kohl said.

In August the department will begin annual testing of the prison population for tuberculosis. Screening of inmates leaving prison will be screened for hepatitis in the fall.

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Comparison of Assays for HCV RNA Using the International Unit Standard
By hivandhepatitis.com

The present study was performed to evaluate the impact of the international unit standard for measuring HCV RNA in the management of patients with chronic hepatitis C virus (HCV) infection.

The three assays used were Amplicor Monitor PCR, the National Genetics Institute PCR assay, and branched chain DNA.

HCV RNA was measured at four time points (baseline, 3 months after the start of therapy, at the end of treatment, and 6 months after discontinuation of therapy) in 106 consecutive patients who received interferon and ribavirin for chronic HCV.

The mean age of the patients was 44 years. Of the patients, 62% were male, 24% were African American, 38% had bridging fibrosis or cirrhosis, and 75% were HCV genotype 1.

Of the 424 samples analyzed, 82-89% of values were within 1 log unit and 85-92% were within 2 log units by the various assays. This variability was not dependent upon HCV genotype.

HCV RNA was undetectable in 1.4-6.8% of samples when virus was detected by another assay. The mean HCV RNA in these discordant samples was 1.47-6.33 log IU/ml (30-2,100,000 IU/ml).

These data demonstrate that approximately 90% of serum values for HCV RNA were within 1 log unit by the international unit standard regardless of which virological assay was used.

The researchers conclude, "False positive and false negative results as well as variations in the HCV RNA level of more than 1 to 2 log units can occur with any of the assays, and these results may have an impact upon the management of patients receiving interferon therapy. It is therefore unwise in clinical practice to base important treatment decisions upon a single HCV RNA determination."

Source: Hepatology Section, Virginia Commonwealth University Health System-Medical College of Virginia, Richmond, Virginia.

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Stigma of Hepatitis C and Lack of Awareness Stops Americans from Getting Tested and Treated

Landmark survey shows need to shatter myths surrounding hepatitis C

Americans' misunderstanding of the potential dangers of hepatitis C is causing many with risk factors to forgo testing and treatment, according to a landmark survey commissioned by the American Gastroenterological Association (AGA). HCV, a virus that attacks the liver, infects four times as many Americans as HIV and is expected to kill more Americans than HIV by the year 2010.

"Hepatitis C can be detected with a simple test, yet it is estimated that the vast majority -- 70 percent -- of four million Americans infected with HCV do not know they have the disease," said Dr. Mitchell L. Shiffman, co-chair of AGA's new hepatitis C education effort and Chief of Hepatology, Virginia Commonwealth University Health System.

Hepatitis C is a potentially life-threatening viral disease of the liver transmitted through blood and blood products. Over time, chronic infection can lead to cirrhosis, liver failure, and liver cancer. The survey findings indicate the need for increased awareness and education about hepatitis C, the most common blood-borne disease in the US. While only about half of the general public believes it is a public health threat, more than 80 percent recognize HIV poses a serious threat. In contrast, physicians and hepatitis C sufferers surveyed view HCV as a threat on par with HIV.

The survey is part of AGA's "Be Hep C S.M.A.R.T." (Shattering Myths And Reinforcing Truths) campaign to educate the public and healthcare providers about the prevention, diagnosis and treatment of hepatitis C.

A Need to Reinforce Truths:

The survey of physicians, people with HCV and the public revealed lack of awareness of the facts about HCV and some new truths:

HCV is spread through blood-to-blood contact

Many adult Americans (32 percent) incorrectly think HCV can be spread through fecal contaminated water or food; 42 percent of Americans do not know that hepatitis C can be contracted through any contact with infected blood.

No vaccine for hepatitis C exists

Twenty percent of Americans and 15 percent of hepatitis C sufferers believe there is a vaccine for the disease.

A Need to Shatter Myths:

The stigma attached to hepatitis C is far less than those infected think

Although 74 percent of hepatitis C sufferers believe that most people think that the disease mostly afflicts drug addicts and people with unhealthy lifestyles, only 30 percent of the public actually holds this belief. Only 12 percent of the general public believes that people like themselves don't get diseases like hepatitis C.

"Since my diagnosis with hepatitis C in 1999, I have been dedicated to sharing my story and encouraging others to do the same so that we can bring the attention to this disease that it deserves," said David Marks, original Beach Boy and the official Be Hep C S.M.A.R.T. campaign spokesperson. "Until people with hepatitis C unite and speak up, this disease will remain a silent epidemic."

A Need to Manage the Disease:

Hepatitis C is curable, not only treatable

While over half of hepatitis C cases are cured with treatment, 34 percent of Americans and 17 percent of hepatitis C sufferers are unaware that prescription medications are available to treat the disease. Only 24 percent of Americans, 24 percent of patients and 15 percent of primary care physicians believe that available treatments can cure some patients with the disease.

In contrast, 65 percent of gastroenterologists and hepatologists say that hepatitis C can be cured in some patients.

"With the newest prescription treatment combination, at least 50 percent of patients have a sustained virological response. Clinical research now suggests that this response, where the virus can no longer be detected in the patient's blood, is permanent. I consider it to be a cure," said Dr. Michael Fried, Be Hep C S.M.A.R.T. campaign co-chair and Director of Clinical Hepatology, University of North Carolina Liver Program.

Side effects are the biggest hurdle in treatment

Of the hepatitis C patients surveyed, 47 percent have taken prescription therapy for the disease. When asked what they would change about their medication if they could do so, 61 percent said they would decrease the side effects. Of the patients who received treatment, 21 percent did not complete treatment. The reason given by 82 percent was because of side effects or a bad reaction to the treatment. For the 53 percent of patients who never received prescription treatment, 21 percent said concern of side effects was one of the reasons.

"Patients believe that hepatitis C therapy is more difficult than is actually the case as newer, more tolerable treatments have come to market with fewer side effects," said Fried.

Patients and physicians are not discussing hepatitis C risk factors

Only 55 percent of primary care physicians routinely inquire about risk factors in their patients and only 15 percent of patients believe that they have any of the risk factors. However, most people, 85 percent, say they are likely to seek medical attention if they thought they had been exposed.

About the survey

This survey was conducted online by Harris Interactive(R) for AGA in the United States between February 19 and March 5, 2003, among a nationwide cross- section of adults ages 18 and older. Sample included 493 infected with HCV; 1,226 not infected with the condition and 415 physicians (198 primary care physicians and 217 specialists). Figures for age, sex, race, education and number of adults in the household were weighted where necessary to bring them into line with their actual proportions in the population. "Propensity score" weighting was also used to adjust for respondents' propensity to be online.

With probability samples of this size, one could say with 95 percent certainty that the results have a statistical precision of plus or minus 3 percentage points (for the non-infected general public sample), plus or minus 4 percentage points (for the HCV-infected sample), and plus or minus 7 percentage points (for each physician sample) of what they would be if the entire population had been polled with complete accuracy. This online sample was not a probability sample.

Survey results are available on the AGA Web site, www.gastro.org

The AGA Be Hep C S.M.A.R.T. campaign is funded through an unrestricted educational grant from Roche.

About AGA

Founded in 1897, the American Gastroenterological Association is one of the oldest medical specialty societies in the United States. Its members include physicians and scientists who research, diagnose, and treat disorders of the gastrointestinal tract and liver. Representing almost 14,000 gastroenterologists worldwide, the AGA serves as an advocate for its members and their patients, supports gastroenterology practice and scientific needs, and promotes the discovery, dissemination, and application of new knowledge, leading to the prevention, treatment, and cure of digestive and liver diseases. AGA does not endorse or favor any specific product or company. Trade, proprietary, or company names appearing in this document are used only because they are considered necessary in the context of the information provided.

About Harris Interactive(R)

Harris Interactive (www.harrisinteractive.com) is a worldwide market research and consulting firm best known for The Harris Poll(R), and for pioneering the Internet method to conduct scientifically accurate market research. Headquartered in Rochester, New York, U.S.A., Harris Interactive combines proprietary methodologies and technology with expertise in predictive, custom and strategic research. The Company conducts international research through wholly owned subsidiaries-London-based HI Europe (www.hieurope.com) and Tokyo-based Harris Interactive Japan-as well as through the Harris Interactive Global Network of local market- and opinion-research firms, and various U.S. offices.

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July 10th 2003

Roche Investigates Pegasys in Failed Pegintron Patients

Roche has launched a new study to look at the use of Pegasys (peginterferon alfa-2a) in re-treating hepatitis C patients who have failed on therapy with rival pegylated interferon, Pegintron (Schering-Plough's peginterferon alfa-2b).

Therapy with a pegylated interferon plus ribavirin has become the gold standard for hepatitis C patients, but there is no established treatment strategy for the 46% of patients who do not achieve a sustained viral response (SVR). Showing a benefit in this difficult population would provide a new pool of patients for Roche's product, which is already taking market share from Pegintron.

The rationale for the new REPEAT (re-treatment with Pegasys in patients not responding to prior peginterferon alfa-2b/ribavirin combination therapy) trial is that non-responders may have a different pattern of viral clearance than those who did achieve a SVR, which could mean they need a longer treatment duration or higher doses for effective therapy. Although they are both pegylated alpha-interferons, Pegasys is a much larger molecule than Pegintron and they have different pharmacological properties, which could have an effect on clinical outcomes.

The life cycles of the two products - Pegasys followed Pegintron onto the market - has meant that although there is a growing number of patients who failed on Pegintron combination therapy and are now looking for the next therapeutic option, there is as yet no clear-cut population of patients who have failed on Pegasys combination therapy but have not received Pegintron, and Schering-Plough has no plans for a similar study of its own.

1,000 patient trial

REPEAT will enrol nearly 1,000 patients from 12 countries in Europe, North America and Latin America into four arms comparing different doses and durations of Pegasys therapy in combination with 1,000mg/day or 1,200mg/day of ribavirin. Patients in arm A will be treated with weekly doses of 360 micro g of Pegasys for 12 weeks followed by 180 micro g/week up to 72 weeks; arm B patients will receive 12 weekly doses of 360 micro g followed by 180 micro g up to 48 weeks. Arm C will receive 180 micro g once weekly for 72 weeks and arm D 180 micro g for 48 weeks.

The study's researchers are pragmatic about the fact that the trial will not contain any comparative arms looking at higher doses or longer treatment options for Pegintron in these patients. The lead investigator, Professor Marcellin of the Hopital Beaujon in France, told Scrip, "It would have been interesting but I think the chance of seeing any benefit [for Pegintron] is small. I agree that to be rigorous and answer the question of whether Pegasys is superior to Pegintron it would be needed, but this is not a superiority study. It's a study to see how best to use Pegasys in non-responders."

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Cost-Effectiveness of Treatment for Chronic Hepatitis C Infection

Newer treatment options for hepatitis C are reasonably cost-effective, but results vary widely across patient subgroups and depend on quality-of-life assumptions, find researchers in this week's issue of the Journal of the American Medical Association (JAMA 2003; 290(2): 228-37).

Over 2.5 million people in the United States have chronic hepatitis C virus (HCV) infection.

However, as public health campaigns are pursued, a growing number of treatment candidates are likely to have minimal evidence of liver damage.

In this study, researchers examined the benefits and cost-effectiveness of treatments for chronic hepatitis C infection in asymptomatic, HCV sero-positive, but otherwise healthy individuals.

The team performed a cost-effectiveness analysis using a Markov model of the natural history of HCV infection and impact of treatment.

Probability of developing cirrhosis over a 30-year period was between 13% and 46% for men, and 1% and 29% for women. Journal of the American Medical Association

They derived natural history parameters from an epidemiologic model. These were empirically calibrated to provide a good fit to observed data on both prevalence of HCV seropositivity and time trends in outcomes.

The researchers assessed cohorts of 40-year-olds who had elevated levels of alanine aminotransferase, positive HCV RNA assays and serologic tests for antibody to HCV. Subjects had no histological evidence of fibrosis on liver biopsy.

The subjects were treated using either standard or pegylated interferon alfa-2b, or combination therapy with standard or pegylated interferon plus ribavirin.

The team evaluated the lifetime costs of treatment, life expectancy, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios.

The researchers found that the probability of patients with chronic HCV developing cirrhosis over a 30-year period was between 13% and 46% for men, and 1% and 29% for women.

They determined that the incremental cost-effectiveness of combination therapy with pegylated interferon for men was between $26,000 and $64,000 per QALY for genotype 1, and between $10,000 and $28,000 for other genotypes.

The cost-effectiveness for women was between $32,000 and $90,000 for genotype 1, and between $12,000 and $42,000 for other genotypes.

The research team found that the benefits of treatment were largely improvements in health-related quality of life, rather than prolonged survivorship, meaning that cost-effectiveness ratios expressed as dollars per year of life were substantially higher.

In addition, results were most sensitive to assumptions about the gains and decrements in health-related quality of life associated with treatment.

Dr Joshua Salomon's team concluded, "While newer treatment options for hepatitis C appear to be reasonably cost-effective on average, these results vary widely across different patient subgroups and depend critically on quality-of-life assumptions".

"As the pool of persons eligible for treatment for HCV infection expands to the more general population, it will be imperative for patients and their physicians to consider these assumptions in making individual-level treatment decisions."

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July 11th 2003

Roche To Release A New Drug Each Year In Japan

Following their recent merger (Marketletters passim), Swiss drugs and diagnostics major Roche is planning to release at least one new drug onto the Japanese market per year through its local subsidiary Chugai Pharmaceutical, says chief executive Franz Humer.

The company is targeting the aggressive introduction of new products with the aim of growing at a rate above Japan's current market expansion level, and hopes to boost its market share in Japan to 5% from the current 4% by 2005-2006, reports the Nikkei Weekly.

Clinical trials are currently underway at Chugai in Japan relating to some 10 Roche compounds, while the latter firm is expected to increase the amount of product candidates as it carries out an appraisal of the local market and targets therapeutic areas with strong growth potential.

New Roche products poised to hit the Japanese market include: Renagel (sevelamer HCl) for the treatment of hyperphosphatemia observed in hemodialysis patients, which was National Health Insurance price-listed on April 1; Pegasys (peginterferon alfa-2a) for chronic hepatitis C; the selective estrogen receptor modulator Evista (raloxifene) for osteoporosis; and the antimetabolite Xeloda (capecitabine).

On the back of this rash of proposed product introductions, Chugai is targeting consolidated sales of around 315 billion yen ($2.67 billion) for calender year 2005, compared with 237.4 billion yen during the last fiscal year ended March 2003. Earlier this year, Chugai chief executive Osamu Nagayama reportedly estimated that peak sales for these new agents will be 13 billion yen for Renagel, 10 billion yen for Xeloda (in both breast and colon cancer indications) and 15-20 billion yen each for Pegasys and Evista (Marketletter April 28).

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Combination Therapy with Interferon Alfa Plus Ribavirin Seems to Be an Important Advance in the Treatment of Children and Adolescents with Chronic HCV
By hivandhepatitis.com

Treatment with interferon alfa alone has yielded poor results in children with chronic hepatitis C and has not been generally recommended.

Given the limited clinical experience with combination therapy in children, the aim of the current study was to evaluate the efficacy and tolerability of interferon alfa-2b (PEG-Intron) in combination with ribavirin in these patients with different routes of viral transmission.

In an uncontrolled pilot study, 41 children and adolescents ranging from 3 to 16 years were treated with interferon alfa at a dose of 3 or 5 MU/m2 3 times weekly in combination with oral ribavirin (15 mg/kg/d) for 12 months.

The mode of infection was unknown in 4, parenterally transmitted in 16, and vertically transmitted in 21 children. Forty patients completed the study. Eleven children, who remained hepatitis C virus (HCV)-RNA positive 6 months after the beginning, discontinued therapy. One boy stopped treatment because of side effects.

At the end of treatment, 25 patients were HCV-RNA negative (61%). All individuals remained HCV-RNA negative during the 6-month follow-up period. Nine of 15 children with parenteral (56.3%), 14 of 21 with vertical (66.6%), and 2 of 4 with unknown route of infection responded.

Side effects included minor clinical signs such as fever, flu-like symptoms, anorexia, and more severe signs (21.4%), such as the development of thyroid autoantibodies and impairment of thyroid function.

In conclusion, combination of alfa-interferon with ribavirin seems to be an important advance in the treatment of chronic hepatitis C in children and adolescents. This also is true for both vertically infected patients and for individuals with normal transaminase levels before therapy.

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Factors Associated with HCV Infection in Injection and Non injection Drug Users
By hivandhepatitis.com

Injection drug users (IDUs) constitute the largest group of persons at high risk for acquiring hepatitis C virus (HCV) infection in developed countries. During the past 2 decades, there have been large increases in the numbers of noninjection heroin users in several parts of the world, including the United States and Europe, including Italy.

There have been relatively few studies of HCV infection among these non injection heroin users. These studies have, however, shown substantial prevalence of HCV infection, with prevalence rates of 10% 20%. The reasons for these substantial rates are not clear. Sexual transmission involving high-risk sex partners and blood borne transmission are both possible sources of infection.

Here, we report the prevalence of HCV infection among non injection drug users (NIDUs) in a large cohort of drug users in northern Italy. We also compare the prevalence of HCV infection among these NIDUs with the prevalence among IDUs recruited from the same sites.

Patient Characteristics

The NIDUs were generally younger, had used drugs for less time, were better educated, and were less likely to have been infected with HIV, HBV, or HCV. The anti-HCV prevalence was >4 times higher among IDUs than among NIDUs (81.6% vs. 20%, respectively).

The mean age (1SD) was 30.0 1 7.0 years for NIDUs and 33.0 1 6.4 years for IDUs. The mean duration of drug use (1SD) was 9.0 1 6.0 years for NIDUs and 14.5 1 6.6 years for IDUs. The prevalence of HIV infection was 1.5% among NIDUs and 13.6% among IDUs, and the prevalence of HBV infection among NIDUs was 13%, compared with 46.5% among IDUs.

Among IDUs, 419 (43.4%) of 965 subjects were coinfected with HCV and HBV, compared with 9 (6.9%) of 130 NIDUs. The proportion of subjects with absence of any serological markers of viral hepatitis was higher among NIDUs (48 [36.9%] of 130) than among IDUs (60 [6.2%] of 965).

Among the IDUs, 127 (13.2%) of 965 subjects were coinfected with HCV and HIV, compared with 1 (0.8%) of 130 NIDUs. The rate of positive results of treponema pallidum hemoagglutination tests was higher among IDUs (16 [1.7%] of 965) than among NIDUs (no positive results among 130 patients).

Level of education, duration of drug use, and HBV infection status were all significantly related to HCV seropositivity.

HBV infection status was the only meaningful independent predictor of HCV infection status among these NIDUs. Although HIV infection status was found to be significant, the number of NIDUs who were HIV seropositive was too small for interpretation.

Age, duration of drug use, level of education, living situation, having a regular sex partner who is a drug user, and HBV and HIV infection status were all associated with HCV seropositivity among IDUs. In multiple logistic analysis, only duration of drug use and HBV and HIV infection status were independent predictors of HCV seropositivity.

Commentary

In this study, the investigators found a substantial prevalence of HCV infection (20%) among NIDUs in the 16 PCDUs in the Veneto region of northern Italy. This rate of positivity was high, compared with that for the general population of the same area (3%), but it was much lower than the prevalence among IDUs, who are 11 times more likely to have anti-HCV.

The seroprevalence of HCV infection among NIDUs in the study is toward the lower end of the range of the prevalences of HCV infection among drug users who never inject drugs reported by van den Hoek et al. (4 [10%] of 42 subjects), Gyarmathy et al. (42 [12%] of 337 subjects), Fingerhood et al. (50 [21%] of 241 subjects), and Santana Rodriguez et al. (92 [35%] of 168 subjects).

The pattern of a higher prevalence of HBV infection than HCV infection among NIDUs was also observed in a New York study, which found a 23% prevalence of HBV infection and a 12% prevalence of HCV infection among NIDUs. In the New York study, the duration of heroin use (>5 years) and having been tattooed were associated with HCV seropositivity. Although it is not possible to fully compare the results from the New York study with the results of the present study, there does appear to be considerable consistency across the 2 studies.

Presence of antibody to HBV was the best predictor of presence of anti-HCV among both NIDUs and IDUs in this study. This suggests that the modes of transmission of the 2 viruses were similar among all drug users, although the difference in the prevalences of HCV and HBV infection among the IDUs and NIDUs also suggests important differences in the frequency of transmission through various routes.

Transmission through unprotected sexual activity may have occurred among the NIDUs in this study: of the 75 subjects in this group who declared that they had a stable sex partner, 27 (36%) had a partner with a history of or current drug use.

It has been reported that practices such as tattooing and perhaps also piercing may be a route of HCV transmission; however, these possibilities were not analyzed in the present study.

For noninjection drug use, transmission through the sharing of equipment, which could convey the virus to denuded nasal mucosa, may have occurred. Moreover, the sharing of injecting equipment may not be reported, as described elsewhere, and could be a means of transmission.

Additional research on HCV infection among NIDUs is needed to develop a strategic prevention program for this patient subgroup.

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Millions Unaware They Have Hepatitis C

Millions of people have been unknowingly infected with hepatitis C, some of them from contaminated blood during transfusions, according to health officials.

"We know that many people are infected with hepatitis C and are unaware that they have the disease," said newly appointed US Surgeon General Dr. David Satcher.

"Unfortunately, many of them cannot be readily identified because the disease does not cause symptoms until it is far advanced."

"Many with hepatitis C virus have no reason to believe they are infected," researchers say. "Many of those at high risk are average people -- middle-aged housewives who had a cesarean section delivery, young adults who had transfusions as high-risk babies or middle-aged men who served in Vietnam."

It is believed that millions are infected with hepatitis C by transfusions.

Hepatitis C is a potentially deadly disease that infects the liver, causing extreme fatigue, nausea, loss of appetite and abdominal pain. It can eventually cause cirrhosis of the liver and death.

It is considered a silent epidemic because many people don't develop symptoms for decades. The Centers for Disease Control and Prevention (CDC) in Atlanta estimates that 40 to 70 percent of those exposed to tainted blood become infected with hepatitis C. Symptoms of Hepatitis C are nausea and vomiting, weakness, Fever, muscle and joint pain, yellowing of eyes and skin, dark urine and tenderness in upper abdomen.

It is spread most commonly through intravenous drug use, blood transfusions and organ transplants. It can also be spread through sexual contact, although it is a less likely means of transmission.

Satcher said that those who were infected from contaminated blood transfusions could be tracked through hospital and blood bank records.

An estimated 8,000 to 10,000 people die from hepatitis C each year.

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July 13th 2003

Drug Earnings a Pill for Investors Schering-Plough Sets a Pessimistic Trend
By David Schwab

For big drug makers, the best part about the second-quarter earnings announcements is things can only get better.

Citing increasing competition for two of its important products, Kenilworth-based Schering-Plough informally launched the quarterly ritual last week by announcing its earnings will be two-thirds less than Wall Street analysts expected -- down a whopping 72 percent from a year ago -- and warning things may get worse before they get better.

Other major pharmaceutical companies are expected to do better when they begin reporting financial results this week, but this won't be a stellar quarter for the industry, according to analysts. Earnings for the eight biggest U.S. drug makers are expected to decline on average by more than 1 percent, according to a report by Michael Krensavage, an analyst at Raymond James.

Compared with earnings growth of about 4 percent for companies in the Standard & Poor's 500, this will be the fifth consecutive quarter in which the big drug makers delivered "inferior earnings," according to Krensavage. Before this recent downturn, the drug stocks had outperformed the S&P 500 for at least seven years.

"It's just a confluence of problems that have taken a toll on the drug industry," he said.

For example, the expiration last year of the patent on Claritin, Schering-Plough's blockbuster allergy medicine, severely cut into earnings as cheaper generic versions enter the market.

As recently as 2001, Claritin's yearly sales reached $3.2 billion, including $2.7 billion in the United States. Now sold in the United States without a prescription, Claritin accounted for just $125 million for the first quarter.

At Madison-based Wyeth, Krensavage estimated earnings will rise just 1 percent to 47 cents per share -- less than the Wall Street consensus forecast of a 4 percent gain -- thanks to health concerns that have hurt sales of hormone replacements Premarin and Prempro. And he expects Merck, of Whitehouse Station, to post an earnings increase of 7 percent, less than the Wall Street consensus of 9 percent.

Wall Street analysts polled by Thomson First Call expect Pfizer, a New York company with big New Jersey operations, to post second-quarter earnings that dropped 12 percent to 29 cents per share, due to the Pharmacia acquisition and slowing sales of Lipitor, its blockbuster cholesterol medicine.

Adding to the uncertainty about drug stocks is the debate in Washington about creating a prescription-drug benefit for Medicare patients. The industry is concerned a government program could amount to a form of price controls.

"I am one of those who really worry about the intrusion of more government in the purchasing of drugs," said David Saks, president of the Saks MedScience Fund. "There will be more volume, but I think the volume will be less profitable."

In addition, some analysts are concerned about a slowdown in prescriptions.

In a note to investors, Girish Tyagi, an analyst at Thomas Weisel Partners, attributed the slowdown to a number of factors, including fewer product launches, rising costs and more consumers getting lower-priced medicines from Canada.

One bright spot among the earnings announcements is expected to be Johnson & Johnson, which Tuesday kicks off a string of formal announcements that will continue for the following nine days.

Earnings at the New Brunswick company are expected to rise 15 percent to 69 cents per share, thanks to sales of Cypher, its drug-coated stent, a tiny device that helps keep arteries unclogged.

And Wall Street analysts expect Bristol-Myers Squibb earnings to rise 65 percent to 38 cents per share, though that may be due mostly to poor results a year ago, according to analysts. Analysts will be watching sales of Abilify, a schizophrenia drug approved last November. Bristol-Myers has its research headquarters in New Jersey.

"Although still confusing, the earnings picture is beginning to clear for Bristol-Myers Squibb," Tyagi wrote.

David Schwab can be reached at dschwab@starledger.com or (973) 392-5835.

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July 14th 2003

Interferon May Help to Prevent and Treat Hepatocellular Carcinoma Associated with Hepatitis C Virus
By hivandhepatitis.com

The possibility that interferon-alfa might be effective for the prevention or treatment of hepatocellular carcinoma is suggested by its efficacy against the associated hepatitis B and C viruses, by its efficacy in the treatment of some other human tumors, and by evidence that interferon-alfa may inhibit the growth of human hepatocellular carcinoma cell lines and their production of hepatitis B surface antigen.

Few studies support the use of interferon-alfa for preventing hepatitis B virus-associated hepatocellular carcinoma. In contrast, benefit from the use of interferon-alfa to prevent hepatitis C virus-associated hepatocellular carcinoma is suggested in a large number of studies, but most of these studies have weaknesses of study design that preclude definitive conclusions.

Nevertheless, most of these studies suggest that the incidence of hepatocellular carcinoma is lower in hepatitis C virus-infected patients receiving interferon-alfa, particularly in patients with a sustained response to interferon-alfa, compared to nonresponders.

As a treatment for hepatocellular carcinoma, interferon-alfa was only evaluated in a small number of patients with advanced disease. "Partial responses' and prolongation of survival times in a few of these studies suggest that additional studies should be done in patients with less advanced disease."

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Non Liver-related Manifestations of HCV infection
By hivandhepatitis.com

Hepatitis C virus infection is associated with various extra-hepatic manifestations that include mixed cryoglobulinemia, membranoproliferative glomerulonephritis and porphyria cutanea tarda (photosensitive skin lesions).

The link between mixed cryoglobulinemia and hepatitis C virus infection is actually well known.

Interferon alpha therapy decreases hepatitis C viremia and improves the clinical signs and biochemical abnormalities of cryoglobulinemia. The rare combination of hepatitis C and panarteritis nodosa (inflammatory disorder of the arteries) has still not been confirmed. The sicca syndrome (dry skin) also seems to be associated with hepatitis C virus, but this is not the typical Sjogren's syndrome.

It is not yet well established if hepatitis C virus plays a pathogenic role in the development of thyroid dysfunction and autoimmune thyroiditis. Probably interferon therapy may be implicated in the development in this and other extra-hepatic manifestations of hepatitis C virus infection.

Although an epidemiological association of hepatitis C with lichen planus, neuropathies and other diseases has been observed, the etiological role and the pathogenic involvement of the hepatitis C infection remains unclear.

The authors conclude that extra-hepatic clinical manifestations are frequently observed in hepatitis C virus patients and involve primarily the joints, muscles, and skin. The most frequent immunological abnormalities include mixed cryoglobulins, antinuclear antibodies, and anti-smooth muscle antibodies.

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Does Prior Hepatitis A Virus (HAV) Infection Affect the Progression of Chronic Hepatitis C?
By hivandhepatitis.com

The aim of the current study was to evaluate the effect of previous infection with hepatitis A virus on histopathological and biochemical changes in chronic hepatitis C.

Anti-hepatitis A virus antibodies, liver histopathology and alanine aminotransferase activity were determined in 82 patients with chronic hepatitis C. The liver biopsy specimen of each patient was examined according to Scheuer's classification to indicate the severity of the inflammatory cell infiltration in a 0-4 scale and fibrous stage (staging) in a 0-4 scale.

The overall prevalence of anti-hepatitis A virus antibodies was 63.1%. Anti-HAV-positive patients were significantly older than anti-HAV-negative ones (mean age 42.5 and 33.1 years respectively, p < 0.05).

After stratifying the study sample into two age groups (< 40 years and > or = 40 years) the percentage of anti-HAV-positive individuals was similar irrespective of grading, staging score or presence of steatosis. No remarkable differences were observed between the anti-HAV-positive and -negative group in the mean ALT activity.

The authors conclude, "The results of our study indicate that previous hepatitis A is not associated with progressive course of chronic hepatitis C."

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High Rate of Both Spontaneous and Treatment-induced Viral Clearance in Acute HCV Infection
By hivandhepatitis.com

Acute hepatitis C virus infection currently accounts for approximately 20% of cases of acute hepatitis today. The aim of the present study was to define the natural course of the disease and to contribute to the development of treatment strategies for acute hepatitis C virus.

The diagnosis of acute hepatitis C virus in 60 patients was based on seroconversion to anti-hepatitis C virus antibodies or clinical and biochemical criteria and on the presence of hepatitis C virus RNA in the first serum sample.

Fifty-one of 60 (85%) patients presented with symptomatic acute hepatitis C virus. In the natural (untreated) course of acute symptomatic hepatitis C (n = 46), spontaneous clearance was observed in 24 patients (52%), usually within 12 weeks after the onset of symptoms, whereas all asymptomatic patients (n = 9) developed chronic hepatitis C.

The start of antiviral therapy (interferon-alfa with or without ribavirin) beyond 3 months after the onset of acute hepatitis induced sustained viral clearance in 80% of treated patients.

The management of acute hepatitis C has to take into account the high rate of spontaneous viral clearance within 12 weeks after the onset of symptomatic disease. Treatment of only those patients who remain hepatitis C virus RNA positive for more than 3 months after the onset of disease led to an overall viral clearance (self-limited and treatment induced) in 91% of patients, and unnecessary treatment was avoided in those with spontaneous viral clearance.

Patients with asymptomatic acute hepatitis C virus infection are unlikely to clear the infection spontaneously and should be treated as early as possible.

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Bleeding Complications After Percutaneous Liver Biopsy

In patients with particular risk factors for bleeding, biopsy-related bleeding occurs more frequently and later than commonly observed, find researchers in the latest issue of Digestion (Digestion 2003; 67(3): 138-45)

In this study, researchers from Germany retrospectively assessed the risk of bleeding after percutaneous liver biopsy.

They analyzed 629 procedures, paying particular attention to patients with an increased a priori bleeding risk.

58% of the bleeding events occurred in patients with particular risk factors for bleeding.--Digestion

Any factors which may have been related to the risk of bleeding were analyzed by univariate analysis.

The team used a forward conditional logistic regression to further analyze any variables which were significant in the univariate analysis.

The team identified biopsy-related bleeding events in 2% of patients, an unexplained drop in serum hemoglobin concentration of more than 2 g/dl in 7%, and an intra- or extra-hepatic hematoma assessed by ultrasound in 3%.

The researchers found that 58% of the bleeding events occurred in patients with particular risk factors for bleeding.

They determined that biopsy-related mortality in this cohort was 0.48%.

They identified several independent risk factors for bleeding using logistic regression analysis. These included mycobacterial infection (OR 24.0), pre-biopsy prophylactic platelet substitution (OR 9.9), acute liver failure (OR 9.1), heparin administration on the day of biopsy (OR 8.7), advanced liver cirrhosis (OR 5.1), therapy with corticosteroids (OR 3.5) or metamizole (OR 2.8), and leukemia or lymphoma (OR 2.8).

Furthermore, the team found that delayed bleeding (more than 24 hours after biopsy) occurred in 70% of the bleeding events.

Dr Birgit Terjunga's team concluded, "In our study cohort which comprised a high proportion of patients with particular risk factors for bleeding, biopsy-related bleeding occurred more frequently and later than commonly observed.

It "was associated with only a few prognostic factors".

"Considering these predictors before liver biopsy will aid to reduce the rate of bleeding complications".

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County Recognized for Work on Hepatitis C
The Daily Telegram

The Douglas County Department of Health & Human Services will take its message of hepatitis C awareness on the road this fall.

The department was one of eight in the nation to receive a $10,000 National Association of County & City Health Officials (NACCHO) grant for hepatitis C training. It will be used to hold conferences in Superior, Hayward and Minocqua.

"Hats off to the Douglas County Health Department for writing this grant, taking the chance of getting one in eight grants," said John Kunz program manager for the Center for Continuing Education/Extension at the University of Wisconsin-Superior.

Douglas County is in the front ranks of the fight against hepatitis C, which can cause chronic liver disease as well as cirrhosis and cancer of the liver.

The county's Health & Human Services department held a hepatitis C conference in Wisconsin last fall. It was, said Public Health Nurse Michele Hughes, the first in the state. The Superior conference was attended by 70 regional health care providers, and many others had to be turned away.

In addition, nearly 30 area residents attended an open forum meeting to discuss hepatitis C. One woman from Washburn County, said organizers, brought with her a picture of her husband, who had died of the disease.

Last year's efforts also included hepatitis C testing at high-risk bars and the administration of 400 immunizations for hepatitis A and B. There is no immunization for hepatitis C.

The large scope of activities was made possible by a partnership between the UWS Extension Office, pharmaceutical companies Roche, Schering and Glaxo-Smith-Kline, and the DCDHHS.

Hughes has been pulling in community partners to help stretch the reach and impact of the coming program, as well.

The training programs will take place Sept. 30 in Minocqua, October 1 in Hayward and October 2 in Superior. They will touch on Hepatitis C control, emerging trends, medical management, treatment and tribal perspectives on the epidemic.

"We are very pleased to be partners in this program which will probably be a model to be replicated (nationwide)," said Kunz.

According to the Centers for Disease Control and Prevention (CDC), hepatitis C is the most common blood borne infection in the United States. DCDHHS Nursing Director Judi Walker said it kills five times as many people each year than HIV/AIDS.

According to Marjorie B. Hurie, Epidemiologist with the Wisconsin Division of Public Health, Douglas County has the highest rate of hepatitis C in the state. She attributed that to the amount of testing done in the area.

The disease is often called the silent killer because a person can carry the infection with no symptoms for as long as 20 years. According to Hurie, 60 percent of hepatitis C infections derive from intravenous drug use. Hurie said that 15-25 percent of people who get the infection recover. She also said that 84 percent of infected people will carry the virus without serious health consequences to themselves.

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July 15th 2003

Vaccine Fund Gets $1 Billion to Immunize Kids

A public-private fund set up to gather money to vaccinate children around the world said on Tuesday it has received $1 billion in pledges.

Dr. Tore Godal, executive secretary of the Global Alliance for Vaccines and Immunization, said more than 30 million children had benefited from nearly $250 million spent on new vaccines, infrastructure and supplies spent so far by GAVI.

"Approximately 30 million more of the world's children are now protected against hepatitis B, 4.3 million children are now protected against Haemophilus influenzae type b and 1.6 million children are now protected against yellow fever," the group said in a statement.

"Furthermore, GAVI estimates that countries have been able to provide basic vaccination to 8.3 million children who would otherwise have not been reached with any vaccines at all. It is estimated that as many as 300,000 deaths will be prevented because of the resources provided so far."

Members of GAVI include the United Nation's Children's Fund UNICEF the World Health Organization, The World Bank the Bill & Melinda Gates Foundation and several governments.

Immunization experts say vaccines save 3 million lives a year. But GAVI said 33 million infants do not get vaccinated and 1.5 million of them will die before age five of a disease that could have been prevented by a vaccine.

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Adefovir Dipivoxil Improved Liver Abnormalities in Patients with Chronic Hepatitis B
Source: 411Cancer.com "Cancer Experts leading the way to optimal cancer care."

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

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

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

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

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

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

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

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

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Interferon Treatment Causes Major Depression in Many Hepatitis C Patients
Source: VA Research Communications Service

Portland Veterans Affairs Medical Center researchers and their colleagues have found that many people develop major depression while taking interferon, the most effective drug against the life-threatening liver disease hepatitis C.

The majority of patients developed at least some symptoms of depression and 33 percent met criteria for major depression, said study leader Peter Hauser, M.D., Chief of Psychiatry and Associate Director of the Northwest Hepatitis C Resource Center at the Portland VA Medical Center, and Professor of Psychiatry at Oregon Health & Science University.

"The good news is that in most cases we could successfully treat the depression," Hauser said, "and patients could continue their interferon therapy."

Studies have noted interferon-associated depression, but the incidence remained poorly understood, Hauser said. "Also, the usual and customary practice has been to take patients off interferon if they become depressed. We're saying there's an alternative."

Hauser and his colleagues report on their findings in the November 2002 issue of the journal Molecular Psychiatry. The researchers studied 39 patients infected with the hepatitis C virus (HCV) and taking interferon therapy.

Patients were monitored weekly with the Beck Depression Inventory, a commonly used assessment tool for depression, and those who became depressed were treated with the antidepressant citalopram. Thirteen of the patients (33 percent) developed interferon-induced major depression, with the average onset about 12 weeks after starting therapy. When treated with citalopram, however, 11 of these patients (84 percent) improved significantly and could continue their interferon therapy.

No differences were noted in age, gender, past history of major depression, or substance abuse between those who became depressed and those who did not. For unknown reasons, Hauser noted, there were significantly fewer African American patients in the depressed group.

An estimated 4 million Americans harbor HCV. Because symptoms of liver disease may take decades to develop, however, exact numbers are unknown and doctors consider hepatitis C a "hidden epidemic." HCV often was spread by transfusions before a test for the virus became available in 1992, allowing blood supply screening.

Although the organism can be spread by needle sharing among IV drug users, the source of infection in many cases is unknown. Liver failure caused by HCV is the leading reason for liver transplants, and chronic hepatitis C has been linked to a form of liver cancer.

No vaccine is available, and only about 15 percent of people infected with the virus are able to fight it off on their own and never develop chronic hepatitis C. Interferon response rates depend on the HCV genetic type, Hauser said, ranging from about 50 percent to as many as 80 percent of infected patients with the most recent combinations therapies.

"So it's very important to keep people on treatment if at all possible," he emphasized.

The research team will soon begin a new study to determine whether antidepressant treatment early in interferon therapy can prevent the development of depression.

In addition to Hauser, co-authors of the Molecular Psychiatry paper include Ashlee J. Thornton and Rachel L. Schultz of the Portland VA Medical Center/OHSU; Jaswinder Khosla, Havinder Aurora, Jacqueline Laurin, Mitchel A. Kling, Jo Ann Hill, Mangla Gulati and Charles D. Howell of the Baltimore VA Medical Center/University of Maryland School of Medicine; and Alan D. Valentine and Christina A. Meyers of the MD Anderson Cancer Center in Houston, Texas.

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Researchers Probe Promising Liver Cancer Treatment
Source: Indiana University

A new non-invasive therapy for liver cancer patients who cannot be helped by surgery or organ transplantation is being evaluated by researchers at the Indiana University School of Medicine. The Phase I clinical trial at the IU Cancer Center uses extracranial stereotactic radioablation (SRA) as a potential new treatment for hepatocellular carcinoma, a cancer that originates in the liver, or for liver metastasis from other sites.

The technique evaluates the effects of escalating doses of radiation, which delivers highly focused, precisely targeted, radiation to destroy tumors with minimal damage to surrounding health tissues.

For this procedure, a 3-D computer generated grid system is used to precisely map the tumor location where the therapy will be directed. The patient is positioned in a specially fitted, lightweight body frame that allows perfect immobilization of the patient and stereotactic target localization which is essential in order to accurately deliver the radiation to the target with high precision.

The patient then receives multiple "shots" of photon beams produced by a linear accelerator, a technology similarly used in Gamma Knife radiosurgery, which has been highly effective in treating brain tumors.

"SRA may prove to be an option for patients with liver metastases who are not good candidates for conventional therapy," notes principal investigator Higinia Cardenes, M.D., Ph.D., associate clinical professor in the IU Department of Radiation Oncology.

Adds Dr. Cardenes, "This technique is entirely non-invasive and makes it very attractive when compared with currently available therapies for the same patient population such as radio frequency ablation or chemoembolization, which is the delivery of drugs through the hepatic artery directly to the tumor followed by blocking the artery."

Hepatocellular carcinoma is becoming a common clinical problem and its incidence is on the upswing in the United States because of the hepatitis C virus, which causes inflammation of the liver.

"In Phase I of the study we are evaluating the toxicity of the therapy on patients," says Dr. Cardenes. "Our end goal is to determine if higher doses allowed with SRA kill the tumor without damaging healthy tissue or causing other side effects. We will closely monitor each patient's response, toxicity derived from the therapy and, of course, final outcome in terms of tumor control and patient's survival, in order to compare the effectiveness of this treatment with other therapies." The SRA study also is being conducted at the University of Colorado Cancer Center. For possible enrollment in the trial, contact Tia Whitford at 317-278-7267.

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