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The Best in the News on HCV, HBV, and HIV/HCV Coinfection from October 1st, 2003 thru October 15th, 2003

Alan Franciscus
Editor-in-Chief

1. Roche Has Realigned and Now Is Concentrating Solely On Its Core Pharmaceutical And Diagnostic Businesses
2. Schering Says Puerto Rico Probe is Closed
3. Obesity tied to cirrhosis in non-drinkers
4. Spontaneous Elimination of HCV Documented in a Japanese Population
5. Fisher's SPS is Acquired by Medmark, Inc., a Subsidiary of Highmark, Inc.
6. Immunization with an Adjuvant Hepatitis B Vaccine After Liver Transplantation for Hepatitis B-related Disease
7. Nebraska Revokes Medical License of Doctor Linked to Hepatitis C Outbreak
8. Transfer of Products From CBER To CDER Completed
9. Can Interferon Prolong Life?
10. Cryosurgery: How It Helps Treat Liver Cancer
11. Those with Hepatitis C Still Face Long Odds
12. Poor Survival after Liver Retransplantation
13. Idun Pharmaceuticals Initiates Phase 2 Clinical Trial In Liver Transplantation
14. Slowing the Progression of Chronic Hepatitis B with Early Antiviral Therapy
15. Hepatitis C in Recipients Of Living Versus Cadaveric Liver Grafts
16. Checkup: Hepatitis C
17. In Situ Split-Liver Transplantations
18. Roche to Kick Off Q3 Season With Improving Sales
19. Prospective Analysis of Risk Factors for Hepatocellular Carcinoma in Patients with Liver Cirrhosis
20. Current Therapy for the Treatment of Chronic Hepatitis B
21. Long-term Interleukin 10 (IL-10) Therapy in HCV Patients Has a Proviral and Anti-inflammatory Effect
22. 24 weeks of Therapy with Peginterferon Alfa Plus Ribavirin Are Sufficient to Produce a Sustained Virologic Response In HCV Patients with Genotypes 2 and 3
23. CEO Fred Hassan Is Building A Solid Foundation For Long-Term Growth And A Productive Future For Schering-Plough
24. AAFP: Hepatitis C Offers Unique Challenges for Physicians
25. Needle Exchange Programs for IV Drug Users Gets Nixed in California
26. Schering-Plough Announces FDA Approval of PEG-Intron Redipen for the Treatment of Chronic Hepatitis C
27. Fibromyalgia Syndrome in Patients with Hepatitis C Infection
28. Pre-treatment Laparoscopic Appearance of the Liver Can Predict Response to Combination Therapy with Interferon Alfa and Ribavirin
29. Liver Transplantation with Allografts from Hepatitis B Core Antibody-positive Donors
30. Peripheral Neuropathy in Patients with Liver Cirrhosis
31. Risk of HCV-Infected Allografts "Serious Public Health Threat"
32. Immunization with an Adjuvant Hepatitis B Vaccine After Liver Transplantation for Hepatitis B-related Disease
33. Peg-Intron Redipen Approved In the US
34. Across The Nation | Nebraska Insurance Department Malpractice Fund Could Be Depleted Due to Hepatitis C Outbreak Lawsuits
35. Politics and Policy | California Gov. Davis Signs Two HIV/AIDS-Related Bills, Vetoes Two Needle Access Bills
36. Acute Hepatitis C in the HIV Negative Patient
37. Future Hepatitis C Treatments
38. Hepatitis B in the HIV Negative Patient
39. Long-term Clinical Outcomes of One-year Treatment of Chronic Hepatitis B with Epivir-HBV
40. ICN Plans Job Reductions, Plant Sales
41. Pregnancy Can Be Good for Women with Hepatitis C

October 1st, 2003


Roche Has Realigned and Now Is Concentrating Solely On Its Core Pharmaceutical And Diagnostic Businesses

The road leading Roche to a new direction has been marked by a number of major milestones, including a series of strategically targeted acquisitions, the disposal of noncore businesses, and efforts to strengthen the group's development pipeline and product portfolio. As a result of this systematic reshaping process, Roche has gone from being a niche player in diagnostics to a position of market leadership in five years, managers say. Innovative oncology products have placed Roche first in this key therapeutic since 2001, after moving up from eighth place within three years. The marketing authorizations the company has received recently for Pegasys and Fuzeon have brought Roche a major step closer to its goal of becoming No. 1 in virology, as well. Geographically, the Roche group has been strengthened by its majority interest in Chugai Pharmaceutical in Japan, a transaction that has propelled Roche from 32nd place to No. 5 in the world's second-largest single market for pharmaceuticals.

"Of critical importance for the group's future is the fact that we have not only substantially improved our operating performance but have also significantly strengthened our pharmaceutical pipeline in terms of both project quality and the number of projects being pursued,"says Franz B. Humer, the CEO and chairman of Roche (roche.com). "We have increased the number of new molecular entities in development from 23 to 40. In Phase II clinical development alone, the number of projects has risen from two to 12. Roche Diagnostics is recognized as having the strongest pipeline in the industry. And the pipeline will be enhanced by agreements signed in the first quarter of 2003 with Affymetrix and Epigenomics and by the forthcoming acquisition of Disetronic. With its tight focus on health care and extensive network of alliances, Roche is ideally placed to meet today's and tomorrow's challenges in the health-care market."

With the recent sale of the vitamin and fine chemical business, Roche has completed its strategy of focusing on two high-technology, high-value-added health-care businesses: pharmaceuticals and diagnostics. The company is now promising investors that it will sustain organic growth in both of these innovative businesses. The Swiss company also plans to grow through targeted alliances, acquisitions, and license agreements.

Initiatives to strengthen the core businesses in the long term are bearing fruit, and as of the first half of 2003, Roche sales were growing at a double-digit rate and significantly faster than markets. Analysts believe that with Roches renewed focus on pharmaceuticals and diagnostics, exposure to business risk will decrease and growth will be the result.

According to managers, the integration of Chugai (chugai.co.jp) has contributed to growth, as has the strong sales performance of the new and established Roche products. U.S. approval of the novel HIV medicine Fuzeon and the latest strategic moves by the diagnostic division (Disetronic, Affymetrix, and Epigenomics) are major milestones on the road to making Roche an even stronger innovation-driven company with a sharp focus on health care.

After divesting its vitamin and fine chemical unit in 2002, Roche now operates two business units: pharmaceuticals and diagnostics. The pharmaceutical and diagnostic divisions have performed strongly, posting above-market growth rates and increases in profitability. At the same time, Roche has suffered financially from charges for litigation and investment losses.

Although gross cash flow reached a new record high for Roche, action to address significant forward, Sanford C. Bernstein & Co. (bernstein.com) analysts expect continued growth. "We see Roche's business risk as decreasing and we see growth from diagnostics," analysts say.

In 2002, Roche generated sales of SFr29.73 billion ($19.09 billion), a 1.9% increase compared with 2001. Roche posted a net loss of SFr4.03 billion ($2.59 billion) in 2002 after generating net income of SFr3.7 billion ($2.38 billion) the previous year. Loss per share was SFr4.80 ($3.08) after Roche earned SFr4.37 ($2.81) per share in 2001. Roche increased research and development spending 9.4% in 2002 to a total of SFr4.26 billion ($2.73 billion).

During the year, Roche addressed a number of unresolved issues from the past: notably, issues relating to the vitamin division, outstanding lawsuits, and—owing to the dramatic downturn on stock markets—financial assets. This resulted in a number of substantial one-time charges in the 2002 financial statements.

"Painful as the corrective measures we have taken are, they were necessary to reposition Roche as a highly focused health-care company," Mr. Humer says. "Taking this action has meant recording a net loss of 4.02 billion Swiss francs, despite Roche's significant strategic and operational progress and solid operating results."

Roche is moving steadily toward the medium-term goal of achieving an operating profit margin for pharmaceuticals that approaches 25%. The diagnostic division's operating profit margin improved again in 2002, from 14.4% to 15.6%, and is thus on track to reach managers' medium-term target of 20%.

Roche's pharmaceutical division, including over-the-counter products, recorded 2002 sales of SFr19.31 billion ($12.4 billion). Worldwide sales of Roche prescription medicines increased 2% to SFr17.75 billion ($11.4 billion) in 2002. When adjusted for local currencies, Roche's prescription-drug sales increased 10%, ahead of the global market average of 7%.

For the first half of 2003, the core pharmaceutical and diagnostic businesses grew faster than the market and significantly improved profitability. Total sales totaled SFr15.33 billion ($11.62 billion), a 4% increase compared with the same period in 2002. Net income was SFr1.3 billion ($985.1 million), a 28% decrease in local currency compared with the first half of 2002. Earnings per share decreased 29% to SFr1.52 ($1.15). Roche maintained the 14% increase in R&D spending established for full-year 2002.

Roche's pharmaceutical and diagnostic divisions generated combined sales of SFr13.88 billion ($10.52 billion) in the first half of 2003, a 6% increase from first-half 2002. Chugai contributed about 8% to the increase in local currency sales.

The provisions recorded and announced in the fall of 2002 for settling litigation, primarily with U.S. customers, in the vitamin case increased SFr570 million ($366.2 million) to SFr1.77 billion ($1.14 billion). Although the merger of Nippon Roche, Roche's Japanese subsidiary, and Chugai resulted in a net gain, this was offset by an impairment charge in connection with the sale of the vitamin division. The net effect of these two transactions was a loss of SFr1.06 billion ($680.9 million).

Roche's pipeline is delivering, with sales of the hepatitis drug Pegasys helping to propel above-market-average pharmaceutical growth. The 2003 launches of Fuzeon for HIV and Xolair for asthma have yet to substantially add to sales. Bank Julius Baer & Co. analysts expect that the 2004 launch of Avastin for colon cancer will be a key growth driver. Possible expansion of the hepatitis C market could boost sales of Pegasys higher than current assumptions.

Roche's oncology franchise continues to drive growth through its partnership with the biotechnology company Genentech Inc. Roche owns more than 59% of Genentech (gene.com). Genentech's operating profit margin increased more than nine percentage points to 11.8%.

Roche's anticancer medicines generated sales of SFr2.9 billion ($2.20 billion) in the first six months of 2003, achieving a growth rate of 36%. The oncology portfolio accounts for about one-third of Roche's prescription pharmaceutical sales. MabThera/Rituxan, Herceptin, and Xeloda were the main growth drivers.

MabThera/Rituxan, the world's first therapeutic monoclonal antibody for non-Hodgkin lymphoma, continues to post strong double-digit sales growth. Sales of the product for indolent and aggressive non-Hodgkin lymphoma are expected to benefit from recently published data from clinical trials.

In addition, promising early data from Phase II trials show MabThera/Rituxan to be effective and well-tolerated in rheumatoid arthritis. Herceptin, a product prescribed for the targeted treatment of advanced breast cancer, continued to experience strong double-digit sales growth in all key regions.

Xeloda sales were significantly higher for the first six months of 2003. This oral, tumor-activated medicine is used in the treatment of breast and colorectal cancer. In May, the National Institute for Clinical Excellence in the United Kingdom endorsed the use of Xeloda in both these indications.

Other products in Roche's oncology portfolio posted gains in 2002. Sales of NeoRecormon, for the treatment of anemia in end-stage renal disease and for managing anemia in cancer patients, grew 59.8% in 2002 to SFr1.19 billion ($766 million). In the first half of 2003, NeoRecormon posted sales of SFr970 million ($735.1 million), 130% more than in first-half 2002. The product is marketed as Epogin by Chugai in Japan, where it posted first-half 2003 sales of SFr365 million ($276.6 million).

Sales of Kytril, a potent antiemetic used to control nausea and vomiting in chemotherapy patients, returned to growth in 2002, increasing 12% to SFr451 million ($289.7 million). In August 2002, the product was approved by the U.S. Food and Drug Administration for the prevention and treatment of postoperative nausea and vomiting. Sales of Kytril slipped 7% to SFr200 million ($151.6 million) in the first half of 2003.

Roche's virology franchise was expanded in the first half of 2003 by the approval of a combination therapy with Pegasys and Copegus for the treatment of adults with chronic hepatitis C who have compensated liver disease and have not previously been treated with interferon alpha. The therapy gained U.S. approval in December 2002. Pegasys combined with Copegus is now approved in more than 80 countries worldwide.

Combined sales of Pegasys and Copegus in first-half 2003 were SFr335 million ($253.9 million). Pegasys is approved in more than 80 countries worldwide. A Japanese filing is receiving fast-track review, and approval is expected by the end of 2003. Bernstein analysts believe that Pegasys will be one of Roche's key growth drivers and have predicted the product will generate sales of SFr733 million ($555.5 million) for full-year 2003 and sales of SFr1.19 billion ($901.8 million) in 2008.

In July, the labeling for Pegasys was expanded as a result of a pivotal study that demonstrates that the duration of combination therapy and dose of Copegus or chronic hepatitis C patients depends on viral genotype. This labeling means patients will only continue on therapy for as long as needed to obtain benefit, depending on genotype.

The European Commission recommends that patients infected with genotype 1 hepatitis C should receive 12 months of therapy with standard-dose Copegus, while patients with genotype 2/3 only need six months of Pegasys therapy and a lower dose of Copegus. The decision was based on the unanimous positive opinion adopted by the Committee for Proprietary Medicinal Products in April.

"We are pleased that the European Commission has approved the label to reflect this new and important data on how best to treat hepatitis C patients who are prescribed Pegasys and Copegus," says William M. Burns, head of Roche's pharmaceutical division. "It's not only a competitive label but one that provides benefits to patients."

Analysts predict that Roche's pipeline will deliver an increasing amount of product launches through 2005. Julius Baer (juliusbaer.com) predicts the launch of two new molecules in 2003, three new molecules in 2004, and four in 2005. In addition, these analysts predict eight line extensions and six product roll-outs between 2003 and 2005.

One of Roche's most-anticipated products, the HIV infection medicine Fuzeon, was approved in March in the United States and in May in Switzerland. The product is the first fusion inhibitor and has proven to be extremely effective even in patients who no longer respond to other retroviral therapies.

Roche continues to grow its pipeline, pursuing 135 research projects. Twelve new molecular entities entered preclinical development in 2002, and seven entered Phase I clinical testing. The pharmaceutical division has 65 new molecular entities in its development pipeline. This includes nine option agreements with other companies, six potential new medicines from Genentech, and 10 Chugai projects. Roche has the right to inlicense any projects for which Chugai seeks a partner outside Japan and South Korea. The sharp rise in new molecular entities compared with 2001 is a result of structural adjustments in the pharmaceutical research and development organization. In the last two years, the number of projects in Phase II clinical development has increased significantly. In addition, the company has arranged 25 license agreements of which nine are product transactions.

The higher hurdles Roche has put in place for moving compounds to the next stage of development have increased the quality of pipeline projects. Roche expects that with the assignment of rigorous product profiles, these products will bring value to patients, physicians, and payers.

Roche's partner Genentech is pursuing a broad late-stage clinical development program with Avastin, including its potential use in the treatment of metastatic colorectal cancer. Avastin is in Phase III clinical trials for the treatment of colorectal, breast, and lung cancer. Under the existing agreement with Genentech, Roche has licensed the rights to Avastin for all countries outside the United States. Genentech will retain all rights to market the product in the United States.

Analysts believe that the presentation of positive Avastin clinical data was a major highlight for Roche and Genentech.

In addition to being developed for colorectal cancer, Avastin will be developed for treating other tumor types, including renal cell carcinoma, nonsmall cell lung cancer, and metastatic breast cancer. Clinical trials for Avastin are continuing for other solid and hematological tumors.

"We are very excited about this agreement, as Avastin is an ideal supplement to our existing range of highly innovative and effective cancer medicines," Mr. Humer says. "It also confirms the strengths of our decade-long network strategy with Genentech that shows impressive results. The combined R&D resources of Roche, Genentech, and Chugai form the core of our group's innovation capacity. Together with our network of strategic alliances and partnerships we build a strong team enabling us to offer new options in areas of unmet medical needs."

Bernstein analysts predict Avastin sales of SFr1.22 billion ($925 million) in 2005, climbing to SFr1.56 billion ($1.18 billion) in 2008. The analysts tap Avastin as one of Roche's key growth drivers.

The next partnered product to come from Roche's pipeline will be Tarceva, scheduled to be filed for approval in 2004. Potentially the biggest news for Roche could come from Tarceva, which is concluding four Phase III clinical trials, three in nonsmall cell lung cancer and one for pancreatic cancer. The first Phase III clinical-trial results are forecast by Roche to come in August/September 2003. Tarceva was discovered by OSI Pharmaceuticals Inc. (osip.com) and inlicensed by Genentech for the U.S. market and by Roche for other markets.

Tarceva and AstraZeneca Plc.'s potential competitor, Iressa, belong to the same class of drugs, have similar structures, and have closely related Phase III combination clinical-trial designs. Because Iressa's Phase III clinical trials initially produced poor results, some have concluded that Tarceva's Phase III clinical trials would fail. Analysts say because of Iressa's difficulty getting through Phase III development, expectations are low for Tarceva, making the upside potentially larger than the downside. In addition, with four Phase III clinical trials, investors have four chances of gaining a positive result, any one of which could turn Tarceva into an important drug. If Tarceva is effective in the first-line setting, peak sales could reach SFr1 billion ($757.8 million), depending on the strength of the efficacy and toxicity data.

Roche received positive pipeline news about another of its products, Bondronat, in July. The European Committee for Proprietary Medicinal Products has issued a positive opinion for the use of oral and intravenous Bondronat for the prevention of skeletal events such as pathological fractures and bone complications requiring radiotherapy or surgery in patients with breast cancer and bone metastases. This will be an additional major indication for Bondronat, which is approved for treating hypercalcemia of malignancy. This indication significantly increases the number of cancer patients who can benefit from Bondronat.

"Bondronat"s main attributes include unsurpassed oral and I.V. efficacy and a much-improved safety profile compared with other bisphosphonates currently in use for the treatment of metastatic bone disease," says Stefan Manth, Ph.D., director of oncology at Roche. "Moreover, patients' quality of life is greatly enhanced by the pronounced and lasting relief of pain from bone metastases."

The availability of oral Bondronat eliminates unnecessary hospital visits for patients and allows hospitals to better manage resources for administering intravenous infusion therapy. This should also help save on long-term treatment costs.

Becoming even more entrenched in the diagnostic business, Roche's most recent acquisition was Igen International Inc., which develops and markets biological detection systems based on its proprietary Origen technology. This technology provides a unique combination of sensitivity, reliability, speed, and flexibility. Origen-based systems are used in a wide variety of applications, including clinical diagnostic, pharmaceutical research and development, life-science research, biodefense testing, and testing for food safety and quality control.

Roche uses Origen in its Elecsys line of diagnostics. Igen and Roche have reached definitive agreements to resolve their dispute on the rights to Origen. The transaction, which has been approved by the boards of directors of Igen and Roche, will enable both companies to independently maximize the value of their assets and businesses.

Through the acquisition of Igen, Roche will secure new nonexclusive worldwide rights that will permit Roche to continue to commercialize Origen technology in the human in vitro diagnostic field and continue to sell and develop its Elecsys products for centralized laboratories, hospital laboratories, and blood banks. In addition, Roche generally will be able to sell certain Origen-based immunochemistry systems into point-of-care sites and physician offices.

Roche's electrochemiluminescence-based lab diagnostic business had sales in 2002 of about SFr560 million ($359.74 million), with a compound annual growth rate in local currencies of 23% during the last three years.
Upon completion of the acquisition, the new company to be spun off by Igen to its shareholders will hold Igen's patents and assume its biodefense, life-science, and industrial businesses, as well as opportunities in the clinical-diagnostic field. The new company will be able to address the entire clinical-diagnostic market, including the hospital, blood bank, and reference lab markets that were previously exclusively held by Roche. The new company will receive rights to certain improvements relating to Roche's Elecsys product line and royalty-bearing licenses to polymerase chain reaction technology for use in most fields.

The new company, which will be named before closing the transaction, will be managed by Igen's current management team and based in Gaithersburg, Md. The new company's shares are expected to be listed on Nasdaq upon completion of the spin-off.

As part of the purchase agreement, Roche will immediately pay Igen $18.6 million in cash for compensatory damages as confirmed July 9, 2003, by the U.S. Court of Appeals for the Fourth Circuit. Roche will immediately pay to Igen the royalties owed to Igen for the quarter ended June 30, 2003. There will be no further royalties owed to Igen, and Roche will pay a fixed fee of $5 million per month to Igen for the use of Origen technology pending completion of the transaction. The transaction is expected to close by the end of 2003, subject to the approval of Igen shareholders and receipt of necessary regulatory approvals and other limited closing conditions.

"Through this acquisition, we have been able to resolve this legally and contractually highly complex dispute in the best interest of both companies and their shareholders," Mr. Humer says.

"Roche will be able to provide unrestricted access to all its diagnostic products for all its customers, and Igen's shareholders are offered an attractive price and will own a solid business with excellent prospects. Putting this long period of uncertainty to an end will allow both Roche and the new spin-off company to fully focus on their respective businesses and to further develop them independently of each other."

The announcement of this agreement followed a July 9, 2003, ruling by the U.S. Court of Appeals for the Fourth Circuit in litigation that began in 1997, when Igen filed a lawsuit charging Boehringer Mannheim with multiple breaches of a license agreement relating to Igen's ECL technology. Roche inherited the case in its acquisition of Boehringer Mannheim in 1998.

The July ruling eliminated damages of $486.8 million previously awarded to Igen by the jury of the District Court of Maryland while affirming $18.6 million in compensatory damages, Igen's right to terminate the license agreement between the companies, and Igen's right to certain improvements developed by Roche in certain fields under the license agreement. As part of the agreements between Roche and Igen, Igen has agreed to suspend its patent infringement actions against Roche in Maryland and Germany pending consummation of the proposed acquisition, with the right to resume the actions should the transaction not close. Roche has agreed to file a motion to withdraw its petition for rehearing before the Fourth Circuit, and both companies have agreed not to file any further appeals of the opinion issued by that court.

The acquisition of Igen is just the most recent strategic move made by Roche to expand its diagnostic business. Following other recent strategic moves to acquire Disetronic Holding AG and a license agreement with Affymetrix Inc., the diagnostic division is more broadly positioned for continued growth and expansion into new markets. The division plans to launch more than 10 new products in the second half of 2003. Helped by new product rollouts and the inclusion of Disetronic in the consolidated results from May on, full-year sales and operating profit in the division are expected to rise by double-digits in local currencies. Roche Diagnostics has reaffirmed its goal of achieving an operating profit margin of slightly more than 20% in 2006.

In February 2003, in a move aimed at strengthening Roche's lead in diabetes care, the company made a tender offer to acquire the Swiss medical-device supplier Disetronic, the world's second-biggest maker of insulin pumps. Roche's public tender offer for Disetronic was accepted, and 97.96% of Disetronic's shares were tendered to Roche within the offer period ended April 28, 2003.

By signing a license agreement at the beginning of 2003 with Affymetrix (affymetrix.com) on the use of its GeneChip technology, Roche has laid the foundation for future growth in this newly created marketplace. The AmpliChip P450, which was introduced in June, is the first DNA chip-based diagnostic test that provides information on patients' metabolic status.

Roche also has signed an agreement with the German-based diagnostic company Epigenomics AG (epigenomics.com) to jointly develop a range of diagnostic tests for the early detection of cancers, their characterization, and prediction of treatment response.

In addition to working with other companies, Roche Diagnostics will invest more than $135 million and create about 600 new jobs at its Indianapolis campus on the northeast side of the city during the next 10 years. The company expects to grow and expand its research and development, laboratory, manufacturing, distribution, information technology, and corporate headquarters operations during the next several years, which will support five diagnostic business areas: Diabetes Care, Central Diagnostics, Applied Sciences, Molecular Diagnostics, and Point of Care. Roche Diagnostics will receive up to $22.2 million of local and state economic development incentives in the next 10 years.

The expansion of the pharmaceutical and diagnostic businesses was made a primary objective in 2002 to address a number of unresolved issues relating to the vitamin and fine chemical division, continuing litigation, and the impact of the stock market situation on the company's financial assets. Roche management was able to resolve some of the company's challenges and gain the flexibility to maneuver and strengthen the company in the long term.

The contract to divest Roche's vitamin, carotenoid, and fine chemical business has been signed. The sale of the vitamin and fine chemical business to DSM NV (dsm.nl) is progressing and is expected to close in the third quarter of 2003. DSM is based in Heerlen, Netherlands. Additionally, Roche has succeeded in settling all litigation with U.S. direct customers on a vitamin price-fixing case.

"The sale of the division and the litigation settlement bring a significant part of our history to an end," Mr. Humer says. "For Roche, this agreement allows us to further focus our group on our two high-tech pillars, pharmaceuticals and diagnostics, to further establish our position as a leading, innovation-driven health-care company."

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Schering Says Puerto Rico Probe is Closed

Schering-Plough Corp. on Wednesday said a federal prosecutor has closed an investigation into manufacturing practices at the drugmaker's plants in Puerto Rico and will not pursue any legal action.

Schering-Plough's manufacturing has been under a cloud since February 2001, when the company revealed quality-control lapses at plants in Puerto Rico and New Jersey.

The U.S. Food and Drug Administration (news - web sites) last year fined the company $500 million in connection with the problems.

The U.S. Attorney's Office in New Jersey, along with the criminal investigative unit of the FDA, had been further investigating the matter.

Schering-Plough products made in Puerto Rico include ribavirin, a hepatitis C treatment.

New Chief Executive Fred Hassan was hired earlier this year in part to resolve problems such as the manu-facturing woes.

But to satisfy investors, he also must boost earnings, a difficult task with the company's two major product lines, allergy and hepatitis treatments, facing major competition.

Shares of Schering-Plough rose to $15.74 in pre-market electronic trading on Wednesday, up from a closing price of $15.24 on the New York Stock
Exchange

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October 2nd, 2003

Obesity tied to cirrhosis in non-drinkers

Researchers say they've found obesity raises the likelihood of death from cirrhosis in non-drinkers but doesn't increase the death risk among drinkers.

The study, appearing in the October issue of Gastroenterology, the journal of the American Gastroenterological Association, involved 11,465 patients studied by researchers at the University of Washington in Seattle.

Lead author, Dr. Jason Dominitz, an associate professor at the university, said the findings, however, do not necessarily imply weight reduction would lead to a reduction in cirrhosis-related complications.

He said further studies must evaluate the role of weight reduction in decreasing the risk of cirrhosis and cirrhosis-related complications among patients with non-alcoholic fatty liver disease and other chronic liver diseases.

Cirrhosis develops when chronic diseases cause the liver to become permanently injured and scarred. The scar tissue harms the structure of the liver, blocking blood flow through the organ.

Cirrhosis is one of the leading causes of death in the United States, although half of the cirrhosis-related deaths are associated with alcohol. Other causes of cirrhosis include chronic viral hepatitis, drugs, toxins and infections.

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Spontaneous Elimination of HCV Documented in a Japanese Population
By Megan Rauscher

Some chronic hepatitis C virus (HCV) carriers may spontaneously eliminate the virus, suggest findings from a long-term population-based cohort study conducted in Japan.

"The natural course of HCV infection has not been fully elucidated," Dr. Takafumi Saito from Yamagata University School of Medicine and colleagues note in the September issue of the Journal of Medical Virology (J Med Virol 2003;71:56-61.).

"No one has clarified how many infected individuals spontaneously withdraw from a carrier status and thus have a reduced risk of progressive liver disease," Dr. Saito further explained in comments to Reuters Health.
To investigate, Dr. Saito and colleagues followed for an average of seven years 435 chronic HCV carriers living in an area endemic for the disease. Spontaneous elimination of serum HCV RNA was documented in 16, or 3.7%, during follow up. Thus, "the incidence of spontaneous HCV elimination in the infected general population is 0.5% per year," Dr. Saito reported.

In multivariate analysis, a low zinc sulfate turbidity test (ZTT < 11 Kunkel units) and the absence of chronic liver disease on ultrasound were significantly associated with spontaneous viral elimination in chronically HCV-infected individuals.

Three of 16 spontaneous HCV eliminators had biochemical evidence of chronic hepatitis. The neutralization of binding (NOB) antibody was detected in all three, and was associated with natural resolution of the disease.

Dr. Saito emphasized that the results are not generally applicable to other populations, "since all the subjects were Japanese living in a small local area, the routes of HCV infection were obscure, and the age distribution of HCV-infected individuals in this area was different from that in other countries."

"The most important point to be learned from this study," he said, "is that there are rare populations in which the virus is eliminated spontaneously in a self-limiting manner during the course of chronic HCV infection."

"This does not mean that hesitation in starting antiviral therapy for chronic hepatitis C patients is justified," he continued, "but it seems worthwhile to further clarify the genetic characteristics of such a population."

If there are indeed differences at the gene level between carriers who can clear the virus spontaneously and those who cannot, "this would provide valuable information for future strategies aimed at the control of HCV infection through translational studies of target genes associated with viral clearance," Dr. Saito said. "We are now focusing on such genome analysis," he added.

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October 3rd, 2003

Fisher's SPS is Acquired by Medmark, Inc., a Subsidiary of Highmark, Inc.

Medmark, Inc., a subsidiary recently formed by Highmark, Inc., reported today that it completed the acquisition of Fisher's Specialized Pharmacy Services, a specialty pharmacy serving individuals with special or chronic medication needs such as hepatitis C, multiple sclerosis, growth hormone deficiency, infertility, and cancer. Fisher's SPS has served over 35,000 patients nationally and employs about 50 professionals at its Pittsburgh facility. The Company will operate as a wholly owned subsidiary of Medmark with co-founders Jeff Fisher and Betty Rich staying on in senior management positions.

Fisher's SPS was represented exclusively by Provident Healthcare Partners, LLC. Commenting on the acquisition, "Provident Healthcare Partners was pleased to represent Fisher's in completing this landmark acquisition for the specialty pharmacy industry," said Robert Ciardi, Managing Partner of Provident Healthcare Partners. "Fisher's history of strong revenue and earnings growth, and its superlative record of client service will serve perfectly as a platform for Medmark's entry into the specialty pharmacy industry."

With Highmark spending hundreds of millions of dollars each year on injectable drugs, the formation of Medmark and the acquisition of Fisher's are the first steps being taken to combat the rising costs of prescription drugs. Specialty distribution of pharmaceuticals for chronic-disease patients is estimated to be a $20 billion industry with growth of more than 25 percent a year in the United States. Fisher's SPS's exceptional reputation, coupled with their strategic geographic location and strong management team, will provide Medmark with the essential components of a successful distributor.

Highmark is the investor allowing Medmark to purchase the assets of Fisher's SPS. While there is no telling exactly how much this will save Highmark, their ability to distribute directly to patients, and provide enhanced quality of service and care, will be dramatic in overall spending and undoubtedly add to their bottom line. With a total of 4.2 million healthcare members, Highmark is creating a schedule to transition its line of pharmaceutical purchases exclusively to Medmark. This will allow Highmark to contain costs and provide better care for its members. While the focus on Medmark will be on serving Highmark as a customer, the Company plans on pursuing other insurance companies as well.

Commenting on the acquisition, Dr. Kenneth Melani, Highmark's president and chief executive officer stated, "Through Medmark, we intend to better manage the rising costs of high-cost injectable pharmaceuticals, while at the same time providing patients and providers with improved care and service. Fisher's SPS will serve as a platform for these efforts and brings with it a tremendous reputation for service in both the local and national marketplace. We look forward to continuing to grow the current operations of Fisher's SPS, and, thereby, creating significant new job opportunities in the Pittsburgh region."

About Fisher's, Specialized Pharmacy Services
Fisher's SPS is a full-service pharmacy specializing in dispensing high dollar biological medications such as those used for the treatment of Hepatitis, RSV, multiple sclerosis, cancer, and infertility. The Company's service area targets the populations of Western Pennsylvania, however, ships throughout the United States.

About Medmark, Inc.
Medmark, Inc. was formed in September of 2003 as a specialized pharmacy providing high-cost injectables to patients suffering from chronic disease. The company will operate as an independent for-profit subsidiary of Highmark, Inc.

About Highmark, Inc.
Highmark Inc. is a Pennsylvania-based nonprofit corporation that provides a range of insurance products to its approximately 23 million members in the state and across the nation. They operate as Highmark Blue Cross Blue Shield in Western Pennsylvania and as Highmark Blue Shield in the rest of the state, partnering with Blue Cross of Northeastern Pennsylvania and Independence Blue Cross.

About Provident Healthcare Partners, LLC
Provident Healthcare Partners is a Boston-based investment banking firm specializing in the healthcare industry. The firm is comprised of senior- level healthcare and corporate finance professionals with in-depth knowledge and extensive transaction experience. The firm has successfully completed merger and acquisition transactions with companies operating in all sectors of the healthcare industry.

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Immunization with an Adjuvant Hepatitis B Vaccine After Liver Transplantation for Hepatitis B-related Disease
by hivandhepatitis.com

Patients who undergo transplantation for hepatitis B virus (HBV)-related diseases are treated indefinitely with hepatitis B hyperimmunoglobulin (HBIG) to prevent endogenous HBV reinfection of the graft.
Active immunization with standard hepatitis B vaccines in these patients has recently been reported with conflicting results. Two groups of 10 liver transplant recipients on continuous HBIG substitution who were hepatitis B surface antigen (HBsAg) positive and HBV DNA negative before transplantation were immunized in a phase I study with different concentrations of hepatitis B s antigen formulated with the new adjuvants 3-deacylated monophosphoryl lipid A (MPL) and Quillaja saponaria (QS21).

Participants remained on HBIG prophylaxis and were vaccinated at weeks 0, 2, 4, 16, and 18. They received 3 additional doses of vaccine B at bimonthly intervals if they did not reach an antibody titer against hepatitis B surface antigen (anti-HBs) greater than 500 IU/L.

Sixteen (8 in each group) of 20 patients (80%) responded and discontinued HBIG. They were followed up for a median of 13.5 months (range, 6-22 months).

The vaccine was well tolerated.

"Most patients immunized with the new vaccine can stop HBIG immunoprophylaxis for a substantial, yet to be determined period of time," according to the study authors.

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Nebraska Revokes Medical License of Doctor Linked to Hepatitis C Outbreak

Nebraska officials on Wednesday revoked the medical license of Dr. Tahir Javed, who officials say is responsible for a hepatitis C outbreak in his Freemont, Neb., clinic, the AP/Las Vegas Sun reports. Nearly one hundred people were infected with hepatitis C, which can cause severe liver damage, and one patient has died due to the infection (AP/Las Vegas Sun, 10/1).

Clinic officials discovered the outbreak in October 2002, and the clinic was officially closed within one month. Health officials speculated that the infections may have occurred when a worker at the clinic, which specializes in chemotherapy and hematology, reused a contaminated needle and syringe to treat several people. Another possibility is that a worker used a contaminated needle to draw medication, thereby polluting the vial. Health officials sent letters to 612 patients who had received treatment between March 2000 and December 2001 advising them to get tested for hepatitis C (Kaiser Daily HIV/AIDS Report, 7/31).

In a state settlement, Javed did not contest allegations that there were unsanitary conditions at the Fremont Cancer Clinic, according to the AP/Sun. There have been at least 81 lawsuits filed against Javed on behalf of his former patients. Javed, who has returned to Pakistan and is now a health minister there, last month told a Pakistani newspaper that the allegations were "anti-Muslim propaganda" stemming from the Sept. 11, 2001 terrorist attacks (AP/Las Vegas Sun, 10/1).

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October 6th, 2003

Transfer of Products From CBER To CDER Completed

After months of bureaucratic shuffling and budget balancing, the Center for Drug Evaluation and Research (CDER) Oct. 1 officially took over responsibility and oversight for a number of biologic therapeutic products from the Center for Biologics Evaluation and Research (CBER).

The move, designed to increase cooperation between the centers and improve the review process for new products, meant the transfer of the following drug classes from CBER to CDER:

A total of 59 previously approved products now will be overseen by CDER instead of CBER, including such popular drugs as Allergan's cosmetic treatment Botox (botulinum toxin), Immunex's arthritis drug Enbrel (etanercept), and the hepatitis-C treatments Peg-Intron (peginterferon alfa-2b) and Pegasys (peginterferon alfa-2a).

CBER retains oversight of vaccines, gene therapies, allergenics, antitoxins and antivenoms, and blood-related products, the agency said. As part of the reorganization, CDER has created two new offices and five divisions within the department, staffed by former CBER employees.

The new Office of Drug Evaluations VI, run by Karen Weiss under the CDER Office of New Drugs, includes the Division of Therapeutic Biological Oncology Products, the Division of Therapeutic Biological Internal Medicine Products and the Division of Review Management and Policy.

The new Office of Biotechnology Products, with Yuan-yuan Chiu as acting director, includes the Division of Monoclonal Antibodies and the Division of Therapeutic Proteins. This office falls under CDER's Office of Pharmaceutical Science.

In addition, a number of researchers and staff reviewers from the Office of Biotechnology were moved into the CDER infrastructure, the FDA said. With the start of the federal fiscal year yesterday, $33 million in salaries and operations from CBER also are now part of CDER's budget.

The FDA worked hard this summer to ease industry concerns about the transfer, and although the agency made the transfer in a step-by-step process throughout much of the year, an industry official told WDL this summer that there still was "a lot of angst" among drugmakers over the transfer (WDL, July 23, Page 6).

CDER's new web page on Biological Therapeutic Products, which includes links to all current labels and reviews affected by the transfer, can be seen at http://www.fda.gov/cder/biologics/default.htm.

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Can Interferon Prolong Life?
by Rafael Esteban, MD
Liver Unit, Department of Medicine, Hospital General Universitario Valle de Hebron, Barcelona, Spain
Hivandhepatitis.com

The following provocative editorial on the potential survival advantage of interferon use for many patients, including for nonresponders, appears in the August 2003 issue of Hepatology:

In the past few years, the prevalence of hepatocellular carcinoma (HCC) has increased in Western countries and currently cirrhosis related to the hepatitis C virus (HCV) is the most common cause of liver transplantation worldwide.

Studies projecting future complications of chronic hepatitis C, using mathematic models, are not optimistic. A substantial number of currently asymptomatic patients infected by HCV will progress to cirrhosis and HCC in the coming years, and it is estimated that the number of liver-related deaths will increase by 180%.

Antiviral therapy for patients with chronic hepatitis C has the final objective of decreasing the mortality of infected patients by preventing HCC and decompensation of cirrhosis. Given the difficulties of putting these objectives into practice, we use the sustained virologic response (SVR) as a parameter to measure these goals.

SVR is defined as the clearance of virus, which means HCV RNA undetectable by sensitive methods 6 months after discontinuation of therapy. This parameter has proved to be an excellent surrogate marker of the resolution of infection.

Follow-up studies have shown that response is durable in the majority of patients and the progression of liver lesions is stopped. It has been shown that liver fibrosis diminishes when the inflammatory activity disappears; this probably is due to the antifibrogenic effect of interferon.

It is important to note that even in patients without a sustained virologic response, liver histology may improve by stopping the progression of fibrosis.

In this setting, there are some difficult questions: Can antiviral therapy prevent the development of HCC? Does antiviral therapy prolong the survival of treated patients? Might therapy be beneficial in nonresponders?

In 1995, a randomized study with a small number of patients was published showing a decrease in the number of HCC cases in patients with cirrhosis caused by HCV treated with interferon versus untreated controls. However, the high rate of HCC in the control group made the results doubtful. Since then, numerous studies have been published on this topic. In 1994, a retrospective surveillance study in Japan was started called Inhibition of Hepatocarcinogenesis by Interferon Therapy, which focused on the appearance of new cases of HCC.

The study included chronic hepatitis C patients who underwent liver biopsies and periodic imaging during follow-up for the diagnosis of HCC. In 1998, data from 2,890 patients, 2,400 treated with interferon and 490 untreated, were evaluated.

The results showed a significant beneficial effect of interferon by reducing the incidence of HCC in treated patients. This effect was greater in patients who achieved a SVR and also in those who normalized alanine aminotransferase levels.

In untreated patients, an increase in the incidence of HCC was observed in parallel with the degree of fibrosis, from an annual rate of 0.5% for patients with F0 to F1 to 7.9% in those with F4. Interestingly, the effect of interferon in preventing HCC was more beneficial in patients with F2 or F3 than in patients with F4 (cirrhosis). The incidence of HCC in sustained virologic responders was 0.49%, whereas in nonresponders it was 5.32%.

Also in Japan, in 1999, Ikeda et. al. published similar results from 1,643 patients of whom 1,191 had received interferon therapy. The incidence of HCC in treated patients was 7.6% after 10 years of follow-up evaluation, compared with 12.4% in untreated patients. Again, patients who normalized alanine aminotransferase levels had a lower incidence of HCC despite the lack of virologic response.

At the same time these studies were performed in Japan, 2 European studies failed to show that interferon had a beneficial effect either on the development of HCC or on the survival of treated patients.

In a randomized study with 99 patients followed-up for 3 years, Valla et al.observed no difference between controls and treated patients with interferon. In a retrospective study with 384 patients with cirrhosis caused by HCV, Fattovich et al. also found no differences during follow-up. In contrast, in a retrospective study of 103 patients with HCV cirrhosis, Serfaty et al. observed a beneficial effect of interferon on the development of HCC and on survival during a follow-up of 3.5 years.

There are various explanations for the differences in the results of these studies. First, in Japan, the sustained virologic response rate is higher than that observed in Europe and the United States. Almost 30% of patients achieved a SVR after interferon monotherapy. In Western countries, the rate of SVR in patients with advanced fibrosis is lower, only 5%.

Second, the incidence of HCC is much higher in Japan. Both factors make it easier to show a preventive effect of therapy. There also are important methodological questions. The majority of the studies are retrospective and nonrandomized, introducing a bias in the selection of patients for therapy. In fact, in the large studies, the baseline clinical characteristics of treated and control patients are different.

Factors associated with a higher incidence of HCC and cirrhotic decompensation such as higher age, lower albumin levels, lower platelet counts, and more advanced fibrosis are more frequent in the untreated control group. Although the majority of studies introduce stratified subgroups to statistically balance the difference, this can be erroneous. In addition, the type, duration, and doses of interferon and follow-up are different between the studies, which further complicates the comparison of the results.

Camm` et al. performed a meta-analysis that included 3 randomized and 11 nonrandomized studies with a total of 3,109 patients and 356 cases of HCC. In 13 of the 14 studies, interferon reduced the incidence of HCC with a statistical significance in 10 studies.

Overall, the differential risk was 12.8 (confidence interval, 8.3 to 17.2; P < .00001) for patients treated with interferon. The effect of treatment was more beneficial in patients who achieved a sustained biochemical response and also in those who showed no cirrhosis in the liver biopsy.

In the current issue, Imazeki et al. present a follow-up study of 459 patients with chronic hepatitis C over 8.2 years to examine the survival rate relative to interferon treatment. The investigators describe the variables associated with mortality: age, sex, degree of fibrosis, interferon treatment, and response to treatment.

Cirrhotic patients with a SVR showed a reduction in mortality, differential risk, 0.219 (confidence interval, 0.068-0.710). Only one patient with a SVR developed HCC during the follow-up in contrast to 11 cases in the untreated group and 14 cases in nonresponders.

In relation to liver-related mortality, patients who received interferon showed a significant reduction, even nonresponders. This beneficial effect continued after adjusting the data for age and sex. The survival in the overall cohort of hepatitis C patients was reduced compared with the general population (standardized mortality rate, 1.6). The standardized mortality rate for patients with HCC was 12.6 and for those with cirrhosis was 5.9.

Once again, because the study was retrospective and nonrandomized, the interpretation of the results is difficult. Untreated patients were older, with lower levels of serum albumin and high viral load.
However, there was no difference in the degree of fibrosis, in genotype distribution, or duration of the infection. The benefits of treatment were maintained after performing a regression analysis, which included 15 variables with statistical significance in the univariate analysis.

One notable aspect of this study is that the mortality rate of infected patients was higher than that of the general population, not only in patients with cirrhosis but also in patients with stages F2 and F3, the stages at which therapy can have a stronger preventive effect.

Perhaps the conclusion of this study, with similar results to those published by Yoshida et al., is that treated patients who achieve SVR have a higher survival due to the decrease of incidence of HCC and cirrhosis complications and this should be the aim of therapy. Luckily, with the combination of pegylated interferon and ribavirin, the overall SVR is higher than 50%, particularly in patients with cirrhosis, in whom it is much more efficacious that the old standard interferon monotherapy.

The still unanswered question is whether interferon therapy can be beneficial in nonresponders. Different studies show that patients who achieve a biochemical response with normalization of alanine aminotransferase levels but without a virologic response seem to have a lower incidence of HCC during follow-up evaluation and this could be related to the suppression of fibrosis progression by interferon.

If this assumption is correct, the current rule of discontinuation of therapy in nonresponders at week 12 should be revised to benefit a higher number of patients. Whether long-term maintenance therapy with pegylated interferon could be of additional benefit in clinical terms, due to its antifibrogenic effect, still needs to be clarified.

The answer will probably be found when the 3 ongoing studies (HALT, COPILOT, and EPIC) with interferon maintenance are completed.

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Cryosurgery: How It Helps Treat Liver Cancer
by John C. Martin, hepatitisneighborhood.com

Patients diagnosed with hepatocellular carcinoma, the most common form of liver cancer, face varied treatment options. It primarily depends on whether the cancer found is resectable, or able to be removed by surgery, or unresectable, which generally means that it has progressed to the advanced stage.(1)

Some of the available treatment options include surgery. The conventional form of surgery includes a liver transplant combined with a hepatectomy, chemotherapy, or radiation therapy.(2)

Yet one fairly new form of surgery for nonresectable liver cancer tumors is known as cryosurgery, in which extreme cold produced by liquid nitrogen is used to destroy abnormal tissue.

How Cyrosurgery Works
The procedure is used to treat primary liver cancer that has not spread, and is primarily chosen when conventional surgery to remove liver tumors is not possible. The treatment is also used to treat cancer that has spread to the liver from another part of the body, known as metastasis.

It is important to note that cryosurgery can also cause damage to the bile ducts and/or major blood vessels in the liver, which can lead to hemorrhage or infection.

Once cryosurgery is decided upon, however, surgeons circulate the liquid nitrogen through a hollow instrument called a cryoprobe, which is placed in contact with the tumor. The doctor then uses ultrasound or magnetic resonance imaging (MRI) to guide the cryoprobe, and monitor liver cell freezing, which limits damage to surrounding healthy tissue.

A ball of ice crystals subsequently forms around the probe, freezing nearby cells. Sometimes, more than one probe is used to deliver the liquid nitrogen to various parts of the tumor. The cyroprobes are either placed in the tumor during surgery, or are directed through the skin. Afterwards, the frozen tissue thaws and is naturally absorbed by the body.

Cryosurgery does have side effects, though they may be less severe than those linked to surgery or radiation therapy. The effects also depend on the location of the tumor, but more studies are needed to determine the long-term outcome of this procedure. Cryosurgery may also interact negatively with certain types of chemotherapy.

Why Cryosurgery?
Why is cryosurgery performed over other methods of cancer treatment? Because it offers advantages, such as limited invasiveness, lower cost, and the use of local anesthesia in some cases, experts point out. The procedure involves only a small incision or insertion of the cryoprobe through the skin, meaning that the complications of surgery are minimized. It also is less expensive, and requires a shorter recovery period and hospital stay. Sometimes, cryosurgery can be performed on an outpatient basis.

Because physicians focus cryosurgical treatment on a limited area, they can avoid the destruction of nearby healthy tissue. It can also be repeated, and can be used in conjunction with standard surgery, chemotherapy, hormone therapy and radiation when circumstances call for those procedures.

Other advantages of cryosurgery include the ability to operate on cancers considered inoperable, or which dont respond to standard therapy. It can also be offered to patients who, otherwise, would not be good candidates for surgery because of their age or other medical conditions.

The one disadvantage of this procedure, experts contend, is that there is still much uncertainty about its long-term effectiveness. While it can treat tumors that surgeons can visualize, it may miss the spread of microscopic cancer. And because this procedure is still considered somewhat experimental, insurance coverage may not be available.

More Questions to Answer
But once studies comparing cryosurgery to other standard treatments like surgery, chemotherapy and radiation can be carried out, physicians will have a better understanding of its effectiveness, especially over the long-term. It may also provide a benefit for liver cancer in combination with other treatments, a question that still needs to be answered, experts say.

One study of 57 patients with liver cancer found that cryosurgery was "effective and safe" with "low risk of complications", but did not necessarily improve survival.(4)

Another positive study found only a 30 to 40 percent chance of surviving 3 to 5 years after cryosurgery, but the German researchers wrote that the survival rates "appear comparable to the results of liver resection."

Thus, they argued that "it seems justified to conduct a prospective, randomized trial comparing liver resection and cryotherapy for respectable tumors."(5)

1. American Cancer Society.
2. National Cancer Institute. Adult Primary Liver Cancer
3. National Cancer Insitute. Cancer Facts.
4. Sheen AJ et al. Cryotherapeutic ablation of liver tumors. Br J Surg 2002 Nov;89(11):1396-401.
5. Siefert JK et al. [Cryotherapy for primary and secondary liver tumors.] Zentralbl Chir 2002 Apr;276(4):275-81.

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October 7th, 2003

Those with Hepatitis C Still Face Long Odds
By Jane E. Brody

For once, there is some good news to report about a bloodborne virus that has infected 4 million Americans and 170 million people worldwide.

The disease, hepatitis C, will eventually debilitate the livers of many of its sufferers, but new cases of it have declined 80 percent since the virus was identified in 1988 and blood banks started screening for contaminated donations four years later.

But—and this is no small but—the annual death toll from the long-term consequences of this infection is 10,000 a year in the United States, and scientists expect deaths to triple by 2010 before that statistic begins to decline, unless new treatments are developed to eliminate the virus or at least keep its complications at bay indefinitely.

Several such treatments are being studied, and experts hope they will work as well as those that have radically improved the control of H.I.V. infections. If their early promise holds up in clinical trials, most hepatitis C infections may be cured or at least rendered virtually harmless. Current therapies are lengthy, expensive and can cause devastating side effects. Further, they work in only slightly more than half the patients.

Experts have learned enough about the virus and how it is transmitted to alert those at risk of the need to be tested, to take steps that can forestall complications and to prevent transmission to others.

Sources and Symptoms
Unlike H.I.V., the hepatitis C virus is rarely transmitted through sexual contact. Its primary route to a new bloodstream has been through contaminated needles shared by drug users and by blood transfusions. People with hemophilia and others who received blood products before the testing for the virus began may also be infected.

Low rates of transmission affect health care workers exposed to contaminated blood through needle-stick accidents, men who have sex with men and babies born to infected women.

Fatal cases have resulted from organs inadvertently transplanted from a contaminated donor.

Household contacts and sexual partners in monogamous relationships are rarely affected. But people who engage in high-risk sexual behavior with multiple partners and people who have sexually transmitted diseases face increased risk.

Although those receiving tattoos and body piercings in other countries can be at risk, there is as yet no evidence for transmission by those routes in the United States.
A blood test for the virus relies on the presence of antibodies to it, but antibodies may not appear for weeks after the infection. A more sensitive genetic test can detect the presence of the virus itself.

Testing is recommended for people who have had blood transfusions or organ transplants before July 1992 or were treated for clotting problems with blood products made before 1987, those who have been on long-term kidney dialysis and those who have injected street drugs, even once many years ago.

Not everyone infected becomes ill. Some people seem to eliminate the virus, and a chronic infection never develops.

Others who remain chronically infected may be free of symptoms indefinitely.

In most cases, however, as with H.I.V., the virus can linger in the body for a long time -- even decades -- before symptoms of liver damage appear.

The most serious consequences are severe cirrhosis, a scarring of the liver, liver failure and liver cancer, which have made hepatitis C the leading reason for liver transplants.

Symptoms, when they appear, are usually mild, intermittent and easily attributed to other causes.

The symptoms may include fatigue, nausea, poor appetite, muscle and joint pains and mild discomfort or tenderness in the right upper abdomen.

Those who develop cirrhosis or severe liver disease may, in addition to complaining about those symptoms, experience weight loss, itching, dark urine, fluid retention and abdominal swelling.

Search for Treatment
No vaccine against the virus has been developed, and prospects for one are not promising because there are at least six major genetic types and more than 50 subtypes of the virus. And, it changes rapidly. The possibility of a vaccine depends on finding an exposed part of the virus that remains stable even as its protein coat mutates.

The main goal of treatment is to eradicate the virus to prevent progressive liver disease. Existing therapies are most effective in patients with Genotypes 2 and 3, which represent about 25 percent of patients in the United States. The most common ones, Genotypes 1a and 1b, affect about 75 percent of patients and are the most difficult to treat.

Two main therapies have been developed. One involves injections of interferon, usually long-acting pegylated interferon, which is injected weekly, and the other an oral antiviral drug called ribavirin.

Therapy is most successful when the treatments are used simultaneously. But each can cause serious problems in certain patients. Interferon should not be prescribed for people with serious psychiatric illness, unstable heart disease or poorly controlled diabetes. People with anemias, heart disease, stroke and kidney disease should avoid ribavirin, as should pregnant women.

Patients with the Type 1 virus are treated for 48 weeks; those with Types 2 and 3 do well with 24 weeks. The combination therapy is effective in slightly more than half the cases, in 42 percent of those with Type 1 and 80 percent for those with Types 2 or 3.

The side effects can be quite miserable, at least at the outset. But they subside with time and disappear when the treatment ends. Patients report that the drugs commonly cause flulike symptoms. They can seriously disrupt sleep and create havoc with sexual response and personality.

People tend to become irritable, forgetful and seriously depressed, and they may lose considerable weight. Even when treatment seems to have eliminated the virus, it can sometimes rebound, requiring a second round of therapy.

While some experts recommend that everyone who has chronic hepatitis C infection be treated, others suggest that each patient, in consultation with physicians, carefully weigh the likelihood that the disease will progress and the benefits and risks of therapy, as well as its considerable cost.

In a recent article in The Journal of the American Medical Association, Dr. Joshua A. Salomon and colleagues at the Harvard Center for Population and Development Studies noted that ''30 percent to 70 percent of infected individuals may never progress to cirrhosis before dying from other causes.''

The authors further pointed out that progression of the infection was highly variable and unpredictable. The probability of developing cirrhosis over 30 years ranges from 13 to 46 percent for men and 1 to 29 percent for women, they stated. Also, the progression of the infection to serious liver disease is less common among patients who are infected when they are young. They seem better able to fend off the virus or keep it under wraps.

With or without treatment, people infected with the virus should take steps to protect their livers from further damage. The steps include avoiding alcohol, getting vaccinated for hepatitis A and consulting physicians before taking any new medicines, including over-the-counter and herbal remedies.

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Poor Survival after Liver Retransplantation
By gastrohep.com

Survival after liver retransplantation is inferior to that for primary transplantation, but appears to have improved in recent years, find doctors in the September issue of Liver Transplantation (Liver Transpl 2003; 9: 1019-24).

The prevalence of hepatitis C virus (HCV) infection in repeated orthotopic liver transplantation (re-OLT) is increasing. Patient survival may be worse.

In this study, doctors from the United States assessed the prevalence of HCV in re-OLT. They also compared survival between primary OLT and re-OLT for HCV versus non-HCV diseases, and evaluated Model for End-Stage Liver Disease (MELD) scores in re-OLT.

The team analyzed data from the United Network for Organ Sharing database.

Patients with malignancy or those who underwent re-OLT within 30 days of primary OLT were excluded.

During the study period a total of 22,120 primary OLTs and 2129 re-OLTs were performed.

Survival after retransplantation was no different for patients with HCV.

The team found that HCV occurred in 43% of primary OLTs and 42% re-OLTs.

They determined that the overall 1-, 3-, and 5-year patient survival rates were 86%, 79%, and 73%, respectively, for primary OLT. However, these rates fell to 67%, 56%, and 52% for re-OLT.

They also determined that the survival rates of patients with HCV at 1, 3, and 5 years were 86%, 76%, and 68%, respectively, for primary OLT. These rates dropped for re-OLT to 61%, 50%, and 45%.

The researchers confirmed that re- OLT survival for patients with HCV was less than for those with autoimmune hepatitis and hepatitis B.

However, survival after re-OLT was no different for those with HCV than for those with all other causes.

The team also found that MELD scores between 11 and 20 were the most common for re-OLT.

A marked decreased in survival was noted in all patients who underwent re-OLT with MELD scores greater than 25.

Dr Kymberly Watt's team concluded, "HCV prevalence in OLT has reached a plateau in recent years".

"Survival after re-OLT is inferior to that for primary OLT, but re-OLT survival appears to have improved".

"Survival after re-OLT is lower in patients with HCV compared with those with autoimmune hepatitis and hepatitis B, but no different than for those with most other liver diseases".

"Survival appeared worse in patients who underwent re-OLT with a MELD score greater than 25".

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October 8th, 2003

Idun Pharmaceuticals Initiates Phase 2 Clinical Trial In Liver Transplantation

Idun Pharmaceuticals, Inc. today announced that it has initiated a Phase 2 clinical trial of IDN-6556 in patients undergoing liver transplantation. IDN-6556 is designed to protect liver cells from excessive programmed cell death, also known as apoptosis. The study will evaluate if IDN-6556 can decrease the cellular liver damage that can occur during the transport and transplant periods. In the study, the drug will be administered to the donor liver during transport to the transplant center, as well as to the liver recipient. The study was initiated at Mayo Clinic in Rochester, MN, which is the first of twelve leading transplant hospitals that are expected to participate in the approximately 100 patient clinical trial.

"While there are approximately 5,000 liver transplants performed each year in the United States, there are over 17,000 patients on the waiting list for a transplant," according to Gregory Gores, M.D., Professor of Medicine at the Mayo Clinic and Research Foundation and a principal investigator in the study. "There is an enormous need for additional therapies that may allow an increased number of organs to be transplanted. I have conducted several pre-clinical studies in models of liver transplantation with IDN-6556 and it has exhibited very beneficial effects. We hope to see the same sort of benefits in this patient group."

"We are excited to initiate this very important study," said David Shapiro, M.D., Idun's Chief Medical Officer. "We believe that the drug has considerable potential in treating several hepatic diseases and feel that liver transplantation offers the fastest route to clinical proof of efficacy and ultimately, regulatory approval."

IDN-6556, given orally, is currently being studied in a Phase 2 human clinical trial in several groups of patients, initially those with hepatitis C virus who have failed to respond to existing drugs. Idun recently announced that the Food and Drug Administration granted orphan drug designation for the use of the drug in liver and other solid organ transplant patients.

Idun Pharmaceuticals, Inc. is a biopharmaceutical company located in San Diego, CA, creating innovative human therapeutics with a primary focus on controlling apoptosis, or programmed cell death. Apoptosis is a normally occurring biological process mediated by a cascade of intra-cellular enzymes. Too much or too little apoptosis is believed to play a role in many important human diseases. Idun believes that its drugs will have utility in treating liver disease, inflammation, cancer, and cardiovascular disease. Idun has an extensive patent portfolio covering the fundamental and core technologies involved in the regulation of cell death.

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Slowing the Progression of Chronic Hepatitis B with Early Antiviral Therapy
by hivandhepatitis.com

About 350 million people worldwide have chronic hepatitis B virus (HBV) infection. Up to 40% of persons infected with the virus may go on to have complications related to cirrhosis or hepatocellular carcinoma.

Antiviral therapy can suppress viral replication and halt the progression of liver disease in persons with chronic infection. Following is an excellent overview article on the modes of HBV transmission, the characteristics of chronic HBV infection, and a review of the drugs now available to treat it.

Introduction
Chronic HBV infection is prevalent in Southeast Asia, China, and Africa, where over 10% of the population may be infected. In western Europe and North America, the disease affects less than 1% of the population (1), but more than 1 million people in the United States have chronic infection. Immunization and greater public awareness have significantly decreased the incidence of new HBV infection, but the treatment of persons already infected remains an important international health concern.

Transmission and Chronicity
Perinatal spread and intrafamilial transmission are the major modes of HBV transmission in high-prevalence areas. In areas of low prevalence, HBV is usually transmitted by sexual contact or injecting drug use. The risk of chronic infection is related to age at time of exposure. Newborns of actively infected mothers become long-term carriers in over 90% of cases. Immunocompetent adults have a risk of chronicity of 5%. Older infants and children have intermediate rates of chronic infection. Nearly all infants and most adults who progress to chronic infection have no symptoms during the acute phase.

Antiviral therapy has not been shown to alter the course or affect the risk of chronicity in patients with clinically recognized acute HBV infection. However, in patients with chronic HBV infection, antiviral therapy to suppress viral replication and halt the progression of chronic liver disease has been the focus of intense interest for more than two decades. The US Food and Drug Administration (FDA) has approved three drugs for this disease, and approval of additional drugs is anticipated in the near future.

Characteristics
The cardinal feature of chronic HBV infection is the long-term presence of hepatitis B surface antigen (HBsAg) in the blood. In contrast, persons who are no longer infected have hepatitis B surface and core antibodies. Most patients receive the diagnosis of chronic HBV infection long after chronicity is established.

When approaching chronic HBV infection, it is important to recognize that chronic HBV infection can exist in either an active replicative phase or an inactive replicative phase and that virologic, serologic, and biochemical tests can help distinguish between the two. Early detection is important because ongoing active viral replication results in progressive liver damage. Assays to assess the replicative state of HBV and its pathogenicity measure levels of the hepatitis B e antigen (HBeAg) and antibody (anti-HBe), HBV DNA, and liver enzymes (especially alanine aminotransferase [ALT]).

Historically, the presence of HBeAg and high levels of HBV DNA have been used to identify patients with active HBV replication. HBeAg is derived from the core portion of the HBV genome. Many patients with these markers have active necroinflammatory liver disease and elevated ALT levels. In cohorts of such patients, roughly 10% per year have spontaneous clearance of HBeAg, usually with the appearance of anti-HBe, concomitant clearance or reduction of HBV DNA, and normalization of the ALT level. Seroconversion from HBeAg to anti-HBe or the loss of HBeAg alone has been the major end point in most trials of antiviral therapy.

Some patients with high HBV DNA levels and active liver disease lack HBeAg and often are positive for anti-HBe. Although such patients may have been infected with the wild-type virus initially, they generally have a preponderance of an HBV strain that has a mutation in the precore region of the HBV genome (an extension of the region that codes for hepatitis B core antigen). This precore mutation results in a failure to translate HBeAg despite ongoing active viral replication and production of intact core antigen. This mutant strain is most common in Asia and the Mediterranean, but its prevalence is also significant in northern Europe and North America.

Infection with the precore mutant strain may result in the same adverse outcomes as infection with the wild-type strain, and several reports have suggested the possibility of even greater pathogenicity. HBeAg seroconversion cannot be used as a marker in HBeAg-negative patients, whose levels of viral replication are monitored to detect a response to therapy.

Measurement of HBV DNA levels
This measurement is a critical aspect of patient evaluation and assessment of response to therapy. As technology has improved, more sensitive HBV DNA assays have emerged. The initial quantitative HBV DNA assays incorporated hybridization techniques with lower sensitivity (lower limit, 105 to 106 genome copies/mL). Recently, more sensitive HBV DNA assays, including polymerase chain reaction (PCR), have enabled detection of levels as low as 2 X 102 copies/mL.

At a recent National Institutes of Health conference, an HBV DNA level of 105 was proposed as the marker that distinguish