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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