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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 distinguishes patients with chronic HBV infection from those with inactive infection. However, this level is not always applicable, because some patients with active liver disease have lower HBV DNA levels, particularly those who lack HBeAg, in whom HBV DNA levels are commonly under 105 copies/mL.

Antiviral Therapy
Patients with a persistently normal ALT level generally undergo periodic laboratory tests even if active viral replication is present; they are not treated with any antiviral agent because response rates are low. However, the potential benefit of viral suppression in such patients, particularly those with cirrhosis, is of increasing interest since the advent of new oral agents with a low frequency of resistance. Other patients may receive interferon alfa-2b (recombinant) (Intron A), lamivudine (Epivir), or adefovir dipivoxil (Hepsera).

Intron A (interferon alfa-2b)
Interferon has been used for the treatment of hepatitis B for more than two decades. It has antiviral, immunomodulatory, and antiproliferative properties, although its exact mechanisms of action are not clearly defined. In a meta-analysis of 15 trials, 837 patients observed for 6 to 12 months after therapy showed a statistically significant response to interferon; in the studies, most patients were given interferon in a dosage of 5 MU daily or 10 MU three times weekly for 16 weeks. HBeAg loss was noted in 33% of patients; 37% of patients had no detectable virus in their bloodstream (in most cases, measured with older hybridization technology). Histologic improvement occurred concomitant with virologic response.

Subsequent studies have demonstrated a durable treatment response to interferon: 80% to 90% of successfully treated patients observed for up to 8 years remained HBeAg-negative. Indeed, in some patients, HBsAg clearance occurs years after clearance of HBeAg in response to a course of interferon. Although clearance of the virus is the immediate goal of hepatitis B therapy, preventing further complications from liver disease is the ultimate objective. Data show that advanced liver disease is less likely to occur in responders to interferon therapy than in nonresponders.

Patients who do not have HBeAg are more refractory to interferon therapy. Sustained response rates of only 15% to 18% have been seen (defined as persistently undetectable HBV DNA as measured with hybridization techniques). Viral suppression after the initiation of therapy is common, but relapse is more common than with wild-type HBV infection. Increasing the duration of therapy to 12 or 24 months raises response rates in these patients, but compliance is a challenge because of significant adverse effects. Patients with sustained response to therapy have lower HBV DNA levels at the end of treatment than patients who respond but then relapse.

Adverse effects: Adverse effects of interferon are numerous and include flulike symptoms (eg, fever, headache, fatigue), myalgias, hair loss, diarrhea, difficulty concentrating, depression, peripheral neuropathy, nausea, rash, injection site reactions, neutropenia, thrombocytopenia, and thyroid dysfunction. Serious adverse effects are uncommon but can include exacerbation of bronchospasm, cardiac ischemia or arrhythmias in predisposed patients, seizures, and retinopathy. The drug must be self-injected. Dose reductions or even discontinuation may be necessary.

Nonresponse and delayed response: In addition to infection with the precore mutant strain of HBV, other factors have been shown to predict nonresponse to interferon therapy. These factors include low ALT levels, very high serum HBV DNA levels, immunosuppression, and coexisting hepatitis D virus infection.

Many patients who ultimately respond to interferon have a disease flare during therapy that features a sharp rise in ALT and aspartate transaminase. Although this flare is a favorable indication of subsequent response, it can result in decompensation in patients with preexisting cirrhosis. Interferon should be used with caution in patients with cirrhosis and generally should be avoided in patients with borderline or decompensated liver function.

Epivir-HBV (Lamivudine)
In 1998, lamivudine became the first oral agent to be approved by the FDA for the treatment of chronic HBV infection. It is a synthetic nucleoside analogue that results in premature DNA chain termination when its phosphorylated form is incorporated into viral DNA. Lamivudine, which is a strong inhibitor of both HIV reverse transcriptase and HBV reverse transcriptase, has been a mainstay of HIV therapy. The drug offers several advantages over interferon, including availability as an oral agent and a favorable side effect profile. The recommended dose for the treatment of chronic hepatitis B is 100 mg per day in contrast to 150 mg twice daily for HIV patients.

Two controlled trials in treatment-naive patients established the role of lamivudine in the treatment of HBeAg-positive patients with chronic HBV infection. In a US study conducted by Dienstag and colleagues, 137 treatment-naive patients were randomly assigned to receive either lamivudine, 100 mg once daily, or placebo for 52 weeks. Lai and associates randomly assigned 358 treatment-naive patients to receive lamivudine, 25 or 100 mg once daily, or placebo for 52 weeks.

Overall, lamivudine demonstrated significant improvement at a number of end points, including HBeAg clearance, HBeAg seroconversion, HBV DNA suppression, ALT normalization, and histologic improvement, when compared with placebo. However, although lamivudine achieved an initial virologic response in many patients, this response did not appear to be durable. Even though 98% of the US patients had undetectable HBV DNA at least once during therapy, only 44% had sustained viral suppression through week 52. Moreover, 16 weeks after cessation of therapy, median HBV DNA levels rose to 55% of their baseline values.

Response: A key predictor of response to lamivudine is baseline ALT level. Much better results are seen in patients with an ALT level more than twice the upper limit of normal. Important data about long-term therapy emerged from an extension of the trial by Lai and colleagues. Sustained HBV DNA suppression occurred in 52% of patients who received lamivudine, 100 mg daily for 104 weeks, compared with 5% of those who received lamivudine in the first year and placebo in the second year. In a smaller group of patients treated for a third year, the HBeAg seroconversion rate increased to 40%.

Such observations led to the widespread practice of administering long-term (>52 weeks) lamivudine treatment in patients without clearance of HBeAg. This practice is further supported by a recent long-term study demonstrating progressive histologic improvement over 3 years of lamivudine therapy, including reversal of fibrosis in patients with bridging fibrosis or cirrhosis.

Resistant mutations: Unfortunately, the development of lamivudine-resistant HBV mutations (mutations in the tyrosine-methionine-aspartate-aspartate [YMDD] region of the HBV DNA polymerase gene) has been associated with lamivudine and has a direct correlation with the duration of therapy. In the long-term lamivudine trial by Liaw and associates (10), 40% of the 154 patients treated continuously for 104 weeks had evidence of the YMDD mutation versus 14% after 52 weeks of therapy. Resistance increased to 53% after 3 years and to 66% after 4 years.

Another study conducted by Liaw and colleagues explored the clinical implications of the emergence of the YMDD mutation in 32 of 55 patients who received continuous lamivudine therapy for at least 104 weeks. Elevation of ALT levels occurred in 94% of patients, and acute exacerbation of hepatitis B (defined as an abrupt twofold increase of ALT to a level greater than five times the upper limit of normal, or 300 U/L) was seen in 41% at a median of 24 weeks after the development of the YMDD mutation.

Thus, the development of the mutation with long-term lamivudine therapy has important clinical ramifications that limit the drug's overall effectiveness. However, the development of the mutation does not completely preclude the possibility of subsequent HBeAg clearance, a finding that is consistent with the progressive increase in both YMDD mutation appearance and HBeAg clearance in the long-term studies.

Studies examining the treatment of other populations (eg, HBeAg-negative patients, liver transplant recipients, and patients infected with both HBV and HIV) show similar viral-suppressive effects. Initial histologic and virologic responses are seen in HBeAg-negative patients, but these responses may be lost or reversed over time owing to a lack of durability or the development of YMDD mutants. Development of the mutation is associated with increased graft failure after liver transplantation. A high percentage of patients who are infected with both HBV and HIV have lamivudine resistance because they have been on lamivudine therapy for years as part of their HIV treatment.

Hepsera (adefovir dipivoxil)
In September 2002, the FDA approved adefovir, an oral adenosine analogue, for the treatment of chronic HBV infection. In two major double-blind studies published recently, 342 HBeAg-positive patients with chronic HBV infection received either adefovir, 10 mg/day, or placebo for 48 weeks, and 185 HBeAg-negative patients with chronic HBV infection were randomly assigned to receive either adefovir, 10 mg/day, or placebo in a 2:1 ratio.

Both studies demonstrated the histologic, virologic, serologic, and biochemical benefits of adefovir. Recent observations of patients who had been receiving adefovir for 72 weeks revealed significant increases in end points of success, with 44% experiencing HBeAg loss, 23% having seroconversion, and 46% experiencing a reduction of HBV DNA level to fewer than 400 copies/mL. Similar effects were seen in a randomized trial of 184 HBeAg-negative patients , in whom there was a 3.9-log drop in HBV DNA. Among these patients, 66% had fewer than 400 copies/mL at 48 weeks and 80% had fewer than 400 copies/mL at 72 weeks.

Lack of resistant mutations: A major feature of the response to adefovir is the apparent lack of resistant mutations. In the two major phase 3 trials involving nearly 700 patients treated for 48 weeks, HBV polymerase substitutions were seen at several sites in patients given either adefovir or placebo; however, no in vitro resistance or viral rebound during therapy was seen. In a long-term extension study involving 39 patients treated for up to 136 weeks, there was again no evidence of the emergence of resistant mutations.

Adefovir could clearly have an impact on the treatment of patients with lamivudine-resistant hepatitis B mutations. A recent double-blind study explored the effects of adefovir in 59 patients with the YMDD mutation. Patients were randomly assigned to receive either adefovir monotherapy, 10 mg/day; adefovir, 10 mg/day, combined with lamivudine, 100 mg/day; or lamivudine monotherapy, 100 mg/day, for 48 weeks. Serum HBV DNA levels decreased significantly, between 3.5 and 4 logs, in both groups receiving adefovir compared with the lamivudine group. Another study has examined the role of adefovir in the treatment of lamivudine-resistant hepatitis B in patients who also have HIV. Substantial histologic, virologic, and biochemical responses were evident after 96 weeks of therapy.

Another intriguing recent finding is that episomal closed circular covalent HBV DNA sharply decreases within hepatocytes after 48 weeks of therapy with adefovir. The importance of this observation stems from the critical role of closed circular covalent HBV DNA as the template for viral replication and the potential for viral reactivation as long as this episomal form of the HBV genome persists.

New Treatment Options
Currently, several options are available for the treatment of patients with chronic HBV infection who have not previously received antiviral therapy. A number of other agents are being investigated for the treatment of chronic HBV infection. Entecavir, a nucleoside analogue, and tenofovir disoproxil fumarate (Viread), a nucleotide analogue recently approved for the treatment of HIV, have shown particular promise. Trials are also in progress to assess the efficacy of pegylated interferon alfa-2a and alfa-2b in HBV infection.

Some physicians continue to use interferon alfa for patients with predictive factors for favorable outcome, such as HBeAg-positive status, an ALT level greater than twice the normal level, and the absence of cirrhosis. Other experts prefer to start with an oral agent. Lamivudine has the advantage of familiarity and lower cost, and adefovir is attractive because it has not yet been linked to the emergence of resistant mutations.

Discontinuation of oral agents
Deciding when to stop oral agents can be difficult. Some physicians, including the authors of this article, prefer to continue therapy for at least 6 months after HBeAg loss or seroconversion has been achieved; other physicians believe that such protracted therapy has not been rigorously shown to be necessary. In the absence of HBeAg loss, most physicians continue these agents indefinitely on the basis of reports of histologic improvement and the hope that the degree of viral suppression achieved will slow disease progression.

However, the emergence of YMDD mutations in patients receiving lamivudine can be associated with a significant flare of disease. Patients can be switched to adefovir if the YMDD mutation emerges during lamivudine therapy. Physicians should be aware that the emergence of this mutation may be foreshadowed by the return of a high HBV DNA level and by a flare of disease, underscoring the importance of periodic monitoring. Studies have not sufficiently addressed whether using both oral agents together confers an advantage to treatment-naive patients.

Combination therapy
Some physicians believe combination therapy with interferon and an oral agent has a role in the treatment of chronic HBV infection. In the largest trial evaluating interferon plus lamivudine versus either drug alone, HBeAg seroconversion occurred in 18% of subjects who received lamivudine, 19% of those treated with interferon, and 29% of those given combination therapy.

These differences were not statistically significant, but patients given combination therapy received only 6 months of lamivudine versus 12 months in the lamivudine monotherapy group. In a study of prior interferon nonresponders who received lamivudine alone versus lamivudine combined with interferon in which the lamivudine was started first, the patients receiving lamivudine alone had better response rates. When interferon and an oral agent are used together, some physicians start the two concomitantly or with a brief course of interferon preceding the oral agent; in both cases, the oral agent is continued for some time after the interferon is stopped.

With the anticipated development of additional oral viral inhibitors, it is likely that in several years combination regimens analogous to those used for HIV will be available. It will be important for the hepatology community to design and conduct appropriate trials to test such combinations. Whether an immunomodulatory drug such as interferon will be needed in addition to viral enzyme inhibitors, and what the role of pegylated interferons will be, must be determined through clinical trials.

Conclusion
More than 1 million people in the United States are chronically infected with HBV. Immunization and greater public awareness have led to fewer new infections, but the treatment of persons already infected is of vast concern. Antiviral therapy does not appear to alter the course of acute HBV infection or affect the risk of being chronically infected. Most chronically infected persons do not even know they are infected until long after chronicity has been established. However, these patients can benefit from antiviral therapy to halt viral replication and stop the progression of chronic liver disease. Three such drugs are FDA-approved for this indication, and more drugs are expected to be approved in the near future.

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Hepatitis C in Recipients Of Living Versus Cadaveric Liver Grafts
By gastrohep.com

The incidence of cholestatic hepatitis is significantly greater in patients with hepatitis C virus undergoing living donor liver transplantation, find researchers in the September issue of Liver Transplantation (Liver Transpl 2003; 9: 1028-35).

Histologic injury caused by recurrent hepatitis C virus (HCV) occurs in up to 90% of HCV-infected patients who receive a cadaveric liver graft.

In comparison, the natural history of HCV after living donor liver transplantation (LDLT) is unclear.

In this study, researchers from the United States performed a retrospective analysis of 68 consecutive HCV-infected adult patients. Of these 45 received cadaveric grafts (CAD) and 23 grafts from living donors.

The team defined recurrence as elevated serum transaminases, positive HCV RNA, and liver biopsy consistent with histologic evidence of HCV.

The research team found that the incidence of HCV recurrence, as well as the time to recurrence, was no different between the CAD and LDLT groups.

They determined that the overall incidence of HCV recurrence—cholestatic hepatitis, grade III to IV inflammation, and/or HCV-induced graft failure—was not different between the groups.

17% of living donor liver transplantation patients developed cholestatic hepatitis C.

However, no CAD patients developed cholestatic hepatitis C, compared with 17% of the LDLT patients.

Dr Paul Gaglio's team concluded, "The timing and incidence of HCV recurrence were not different when comparing CAD versus LDLT".

However, "The incidence of cholestatic hepatitis was significantly greater in patients with HCV who underwent LDLT".

In a related editorial in the same publication, Dr Mitchell Shiffman discusses living donor liver transplantation in patients with chronic hepatitis C.

Dr Mitchell concludes that, "The availability of a living donor may be potentially advantageous for the patient with chronic HCV awaiting LDLT".

"However, this potential will only be realized if the LDLT is timed to occur in conjunction with an organized and aggressive approach to HCV treatment".

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October 9th, 2003

Checkup: Hepatitis C

Overview

The condition:
Hepatitis C causes chronic inflammation of the liver and affects about 4 million people in the U.S., with roughly 30,000 new cases occurring each year.

What's interesting about the condition:
Hepatitis C is caused by a virus that can incubate quietly in the body for years, but may eventually cause liver cancer or failure. A leading cause of liver transplantation, hepatitis C is commonly transmitted via blood or body fluids. There are six major types of hepatitis C virus and at least 50 subtypes, but there is no broadly effective antiviral therapy. A screening test did not exist until 1992. Hepatitis C used to be known as hepatitis non-A and non-B.

What's in the pipeline:
Standard hepatitis C treatment includes antiviral agents interferon and ribavirin, although these drugs have shown side effects such as flu-like symptoms, irritability, depression and anemia. Drugs in development help existing drugs kill viruses, but also enhance the body's immune response to viral infections. And another drug is designed to prevent hepatitis C reinfection following a liver transplant. "I would expect to see a lot of big changes in [hepatitis C] drug therapies in the next two to four years," said Michael Gale Jr., an assistant professor of microbiology at The University of Texas Southwestern Medical Center at Dallas.

Zadaxin/SciClone Pharmaceuticals Inc. (Phase III)

Medical Benefit:
Zadaxin stimulates immune-cell production. The drug, delivered by injection, is designed to supplement interferon. "[Zadaxin] adds efficacy to current therapies without adding side effects," said Dr. Eduardo B. Martins, vice president of medical affairs. Zadaxin has been approved for sale in more than 30 countries as a treatment for hepatitis B and C.

Company Benefit:
Roche provides free Pegasys, an interferon drug, to SciClone for its tests in exchange for full access to SciClone's trial data. But Roche doesn't receive product rights. SciClone last month issued 6 million common shares worth approximately $45 million to help fund its clinical trials. Ronald Opel, a senior analyst at Moors & Cabot, expects Zadaxin to generate $117 million in revenue in 2006.

Timing:
SciClone expects to complete its most recent clinical trial for Zadaxin in the second half of 2005, but could not estimate when the drug may reach market.

Ceplene/Maxim Pharmaceuticals (Phase II)

Medical Benefit:
Ceplene, which is injected, is based on naturally occurring histamine and prevents the premature breakdown of healthy immune cells. It protects vital immune cells called natural-killer cells and T-cells that combat viral invaders, and supplements interferon and ribavirin. Trial data have shown some side effects, including slight headaches, itching of the palms and flushing, but these disappear in about 30 minutes, a Maxim spokesman said.

Company Benefit:
Maxim, a 10-year-old company, has spent about $225 million in development of its drugs, including Ceplene. In its trials, Maxim is using Schering-Plough's drugs Peg-Intron (interferon) and Rebetol (ribavirin) at no cost. "We believe [Ceplene] will bring us to profitability, but not necessarily in its first indication," the spokesman said. "It's a drug that will be used in combination with other drugs." The company could not provide sales estimates.

Timing:
Maxim's most recent study, which finished patient enrollment in August, is expected to last 18 months, and the company aims to begin work on an oral formulation by the end of this year, the spokesman said.

Civacir/Nabi Biopharmaceuticals Inc. (Phase I)

Medical Benefit:
Civacir is designed to prevent hepatitis C reinfection following a liver transplant, and acts as a standalone drug. The drug, delivered intravenously before, during and after transplantation, is derived from human plasma enriched with hepatitis C antibodies collected from screened donors. Nabi wasn't able to discuss side effects yet since Civacir is in its first clinical test.

Company Benefit:
Civacir's first clinical trial was funded entirely by the National Institutes of Health. Nabi could not estimate Civacir's potential sales, but said the world-wide market for such drugs could be worth $150 million to $200 million a year. Nabi spent $5.8 million on research and development for its entire stable of drugs in first-quarter 2003, up from $1.4 million a year earlier.

Timing:
Nabi expects data "sometime this quarter" from Civacir's first clinical test, said Mark A. Soufleris, vice president of investor and public relations. Nabi received orphan drug status, or market exclusivity, for Civacir from the FDA In late 2002.

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In Situ Split-Liver Transplantations
by gastrohep.com

Split-liver transplantation is an effective way of expanding of the cadaver donor pool and reducing dependence on living donation, find researchers in the October issue of Annals of Surgery (Ann Surg 2003; 238(4): 496-507).

Split-liver transplantation allows 2 allografts from a single cadaveric donor liver.

Researchers from Los Angeles, California, identified the predictors of graft and recipient survival for in situ split-liver transplantations. They also compared these outcomes to those from living donor and whole organ transplantations.

The team conducted a retrospective analysis of 100 consecutive in situ split-liver transplantations, which were performed at the University of California between 1991 and 2003.

Each liver yielded a left lateral segment and right trisegment graft, and 190 allografts were available for transplantation. Long-term graft function was excellent.

The transplant recipients included 105 children and 60 adults.

The team compared outcomes and complications with living donor and whole organ recipients who underwent transplantation during the same period.

The doctors found there was no difference in the incidence of biliary and vascular complications in left lateral segment recipients, compared with left lateral segments from living donors. There was also no difference between these patients and children receiving whole-organ grafts from pediatric donors.

The team did not find any differences in left lateral segment graft and recipient survival between split-liver, living donor, and whole-organ recipients.

However, with the right trisegment split-liver grafts there was a 10% incidence of biliary complications and a 7% incidence of vascular complications.

Overall, the researchers determined that long-term graft function was excellent. Patient and graft survival was equal to that of whole-organ
recipients, from donors aged 10 to 40 years.

The team identified several predictors of graft and recipient survival. These included United Network for Organ Sharing status at transplantation, indication, complication occurrence, donor creatinine, and length of donor hospitalization.

Dr Hasan Yersiz's "Split-liver transplantation is n effective mechanism for immediate expansion of the cadaver donor pool that can reduce dependence upon living donation".

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Roche to Kick Off Q3 Season With Improving Sales
by Ben Hirschler and Michael Shields

What a difference a year makes. Roche Holding AG will kick off the reporting season for European drug firms next week having dispelled its image as the sick man of the sector and with sales on a clearly improving trend.

Industry analysts expect the Basel-based pharmaceuticals and diagnostics group to report a gain of around 12 percent in third-quarter sales to some 6.8-7.0 billion Swiss francs ($5.15-5.3 billion) on October 16.

The figure will be distorted by two factors—held back by adverse exchange rates but boosted by the integration of Japanese drugmaker Chugai Pharmaceutical Co Ltd <4519.T>.

The underlying picture, though, is of a company on the mend following the launch of two key new drugs as well as encouraging results in the clinic from several experimental ones.

Genentech Inc <DNA.N>, majority-owned by Roche, on Wednesday set the scene for a promising set of results by reporting a 70 percent jump in quarterly profit, driven by strong demand for cancer treatments MabThera/Rituxan and Herceptin.

The U.S. company's earnings beat expectations, and the 26 percent jump in sales of MabThera/Rituxan—Roche's biggest-selling medicine—also topped forecasts.

PEGASYS A STRENGTH

With the strength of the core oncology business in little doubt, attention next week will focus on Roche's hepatitis C drug Pegasys, which has seen strong growth in prescription numbers this year.

Paul Diggle of Panmure expects Pegasys sales to reach 275 million Swiss francs in the quarter, keeping the product on track to become a major driver of Roche sales and profits in the years ahead.

Sales of novel HIV drug Fuzeon for patients grown resistant to other therapies have made a slow start, however, and initial sales are likely to be modest.

Expectations for Fuzeon were dampened when development partner Trimeris Inc last month gave disappointing third-quarter sales growth estimates for the product.

Andrew Fellows of Pictet & Cie expects diagnostics to show a partial recovery after a weak first half, although the business is still likely to have underperformed due to weak biotechnology investment.

Overall, analysts are confident Roche will be able to reiterate its robust outlook for full-year 2003 underlying sales and operating profit to rise by double-digit percentage rates.

For investors, though, much of the recovery story may already be in the price.

Roche certificates have rallied 50 percent since their mid-March lows earlier this year, and the stock now trades at 21.5 times forecast 2004 earnings based on Reuters Research data, against 16.5 times for bigger cross-town rival Novartis AG.

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October 10th, 2003

Prospective Analysis of Risk Factors for Hepatocellular Carcinoma in Patients with Liver Cirrhosis
by hivandhepatitis.com

Better knowledge of the risk factors associated with the appearance of hepatocellular carcinoma (HCC) could improve the efficacy of surveillance programs.

A total of 463 patients aged 40 to 65 years with liver cirrhosis in Child-Pugh class A or B were included in a program of early diagnosis. The predictive value of different risk factors was evaluated using the Kaplan-Meier method and Cox regression model.

Thirty-eight patients developed HCC. In the multivariate analysis, 4 variables showed an independent predictive value for the development of HCC:

*Age 55 years or older;
*Antibody to hepatitis C virus (anti-HCV) positivity; and
*Platelet count less than 75 W 103/mm3.

According to the contribution of each of these factors to the final model, a score ranging between 0 and 4.71 points was constructed to allow the division of patients into 2 different risk groups.

The low-risk group included those with a score of 2.33 points or less (n = 270; 4 with HCC; cumulative incidence of HCC at 4 years, 2.3%), and the high-risk group included those with a score greater than 2.33 (n = 193; 34 with HCC; cumulative incidence of HCC at 4 years, 30.1%) (P = .0001).

In conclusion, a simple score made up of 4 clinical and biological variables allowed the investigators to distinguish 2 groups of cirrhotic patients at high and low risk for the development of HCC. They believe this score can be useful in establishing a subset of cirrhotic patients in whom a surveillance program for early detection of HCC could be unjustified.

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Current Therapy for the Treatment of Chronic Hepatitis B
by hivandhepatitis.com

The virological profile of infection with the hepatitis B virus (HBV) is changing in many parts of the world from the classical hepatitis B e antigen (HBeAg)-positive serological pattern to a HBeAg-negative pattern, linked to the replacement of wild-type HBV by HBV variants with mutations in the core-promoter and in the precore region that prevent the secretion of HBeAg.

The wild-type HBV disease is characterized by steady levels of alanine aminotransferase (ALT) and high HBV-DNA levels, responding relatively well to IFN treatment (3 - 5 MU/day or 10 MU every other day for 16 weeks), which induces anti-HBe seroconversion and normalizes ALT levels in approximately 30% of the adults, with a minimal risk of relapse.

Pegylated interferon (IFN) appears to have superior efficacy over conventional IFN-alfa. Mutant-type disease (anti-HBe-positive/HBeAg-negative) is less responsive to IFN given for 6 - 12 months. This has led to the use of novel nucleoside analogues, of which the prototype is Epivir-HBV (lamivudine).

The response to lamivudine therapy shares with IFN a rapid decline in ALT accompanied by an improvement in histology; at variance with IFN, in HBeAg-positive chronic hepatitis B (CHB) there is delayed seroconversion to anti-HBe which accumulates over time, the switch to anti-HBs is more rare and in the long-term, the activity of the drug is abolished by the emergence of viral mutations (YMDD-motif mutants) that may rekindle the disease.
The combination of IFN plus lamivudine may be more efficacious than IFN or lamivudine monotherapy. Lamivudine therapy needs to be prolonged in HBeAg-negative CHB. Short-term lamivudine-therapy is highly efficacious in preventing HBV reinfection in liver transplants. Recent data suggest that long-term IFN therapy (24 months) may achieve a response in 30% of HBeAg-negative patients.

The advent of Hepsera (adefovir dipivoxil), an analogue of adenosine monophosphate, may provide a safer alternative to lamivudine in the control of HBV disease; the drug is well tolerated and treatment raises drug-resistant mutants in < 2% of the patients over 2 years of therapy. Adefovir provides rescue therapy against YMDD mutants raised by lamivudine therapy.

Department of Gastroenterology, University of Torino, Torino, Italy.

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Long-term Interleukin 10 (IL-10) Therapy in HCV Patients Has a Proviral and Anti-inflammatory Effect
by hivandhepatitis.com

An imbalance in Th1 and Th2 cytokine production is implicated in disease progression of HCV. The aim of this study was to determine the effect of interfeukin 10 (IL-10) administration in patients with HCV-related liver disease.

Thirty patients with advanced fibrosis who had failed antiviral therapy were enrolled in a 12-month treatment regimen with SQ IL-10 given daily or thrice weekly. Liver biopsies were performed before and after therapy. Serum and PBMC were collected for HCV RNA, ALT, and functional T-cell analysis.

IL-10 led to significant improvement in serum ALT (mean ALT: day 0 = 142 1 17 vs. month 12 = 75 1 10; P < .05). Hepatic inflammation score decreased by at least 2 in 13 of 28 patients and 11 of 28 showed a reduction in fibrosis score.

Serum HCV RNA levels increased by 0.5 log during therapy and returned to baseline at the end of follow-up. Five patients developed viral loads of greater than 120 Meq/mL and two of these developed an acute flare in serum ALT.
IL-10 caused a decrease in the number of HCV-specific CD4+ and CD8+ IFN- secreting T cells and alterations in PBMC cytokine production towards a Th2 dominant profile. These changes parallel the improvement in ALT and rise in HCV RNA.

In conclusion, long-term rIL-10 therapy appears to decrease disease activity, but also leads to increased HCV viral burden via alterations in immunologic viral surveillance.

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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
by hivandhepatitis.com

In patients with chronic HCV genotypes 1 and 4, 48 weeks or more of therapy with peginterferon (PEG-IFN) + ribavirin are required to achieve a sustained virologic response (SVR), and this outcome occurs only in about half of these patients.

In contrast, recent studies document that treatment of patients with chronic hepatitis C genotypes 2 and 3 with peginterferon alfa + ribavirin produces an SVR following only 24 weeks of therapy in the vast majority of these patients (>80%).

In the current, prospective study, German researchers confirm this outcome. It has been shown that a 24-week three times weekly (tiw) treatment period with standard interferon alfa and ribavirin is sufficient to achieve SVR for genotype 2 and 3 patients.

However, the recent multicenter studies investigating the effect of pegylated interferons and ribavirin used a 48-week schedule for all patients irrespective of the HCV genotype. Thus, the German investigators prospectively investigated the efficacy of a 24-week treatment period with pegylated interferon alfa-2b (1.0-1.5 microgram/kg once weekly) and ribavirin (1-1.2 g daily) in 54 patients with HCV genotype 2 and 3 at two different sites.

29 patients were included in Herne, Germany (private practice) and 25 patients were treated in Hannover, Germany (Medical School).
After the end of follow-up 46 (85%) patients showed a virological sustained response in the intent to treat analysis. Only four patients demonstrated a virological treatment failure (3 relapse, 1 breakthrough), two patients were non-compliant, and at each center, therapy was stopped in one patient due to adverse events.
There was no difference regarding treatment response between both sites, even though the patients in Herne were treated only with 1,0 microgram/kg PEG-IFN alfa-2b, while patients in Hannover received 1,5 microgram/kg PEG-IFN alfa-2b.

The authors conclude, "The response rates of this study do not differ from the results of the 48-week treatment period of the recently published multicentre trials. Thus, we suggest treating all patients with HCV genotype 2 and 3 for only 24 weeks when PEG-IFN alfa-2b is used in combination with ribavirin."

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October 11th, 2003

CEO Fred Hassan Is Building A Solid Foundation For Long-Term Growth And A Productive Future For Schering-Plough
by Demian Faunt

As the new CEO, Fred Hassan is making big changes in the way Schering-Plough Corp. does business, and he is bringing in trusted executives from his previous company, Pharmacia Corp., to help. Since taking the leadership position in April 2003, Mr. Hassan has initiated several steps as part of his plan to revitalize Schering-Plough and build the company for long-term growth. "Through changes in strategy, structure, people, and processes, we are establishing the foundation for a top-tier, cohesive business organization designed to operate with greater shared accountability and transparency while delivering excellence in execution," Mr. Hassan says.

In spring 2003, Schering-Plough's board of directors asked Mr. Hassan to make a 360-degree review of the company. Almost immediately, Mr. Hassan began an in-depth analysis of the company's processes and business structure and began restructuring its management (see box on page 144).

"My review of the situation we inherited confirmed the need for aggressive measures, including aggressive cost containment and cost cutting in order to stabilize the company and to create a realistic base on which to build a turnaround," Mr. Hassan says. "My review also confirmed that we have a commitment to make significant strategic investments in Zetia and the Zetia/simvastatin combination product in order to achieve their market potential. My review additionally concluded that we must make major investments to build value in some exciting research projects." These research projects will be featured at the company's analyst meeting scheduled for November.

Due to the downward slopes in sales and market share of key profit-generating products that the new Schering-Plough management team is addressing, earnings per share in the second half of 2003 are likely to be lower than those recorded in the first half. Earnings per share in 2004 are likely to be lower than earnings per share for 2003.

In line with his review, Mr. Hassan announced several actions. The key cost-cutting actions being implemented include elimination of bonuses for 2003 under the company's standard plans.

Although Mr. Hassan could have earned an incentive as high as $2 million for achieving his personal objectives to implement the company's agenda, he voluntarily gave up this opportunity.

There will be a zero payout of the targeted 15% profit sharing for all employees. This marks the first time in 47 years that profit sharing has not been paid by the company.

All routine employee-merit increases are frozen through 2004, with exceptions only where local contracts or practices prevent this action, for customer-contact employees, for employees dedicated to fulfillment of the company's consent-decree obligations, and other business-critical employees. Schering-Plough launched a voluntary early-retirement program in the United States in August. Based on an eligible population of 2,900 U.S.-based employees, the company anticipates a headcount reduction of 1,000 or more. A pretax charge of about $150 million is anticipated in the fourth quarter of 2003 for this program. This is the first phase of a global work force reduction in all areas of the company, excluding customer-contact employees, employees dedicated to the fulfillment of the company's consent-decree obligations, and other business-critical employees. Other phases will follow on a global basis.

Global procurement programs will replace fragmented site and business unit-based purchasing, and there will be tight controls globally on new hires and major cutbacks in travel costs, meeting costs, and general expenses. Among these actions will be the sale of the company's Gulfstream G-IV airplane. To set the right tone at the top, there will be an elimination of executive privileges, including the closing of executive dining rooms, cutbacks in executive travel options, and elimination of nonstandard executive health plans.

"We will all be making sacrifices as a result of these actions," Mr. Hassan says. "We remain confident that, by taking these actions, we will set a strong foundation for long-term growth."
The cutbacks come after other actions Mr. Hassan took when he became CEO. One of Mr. Hassan's first actions was the creation of a single Global Pharmaceutical Business unit. The move consolidated several previously autonomous prescription pharmaceutical business units into a unified, globally integrated operation under the leadership of former Pharmacia executive Carrie Cox as executive VP and president.

The new business structure consists of seven units organized by geographies, customers, and products. The heads of the seven units will report directly to Ms. Cox. The guiding principles for the new organization include a flat organizational design, global roles for the senior team, profit-and-loss accountability with a focus on key products and countries, and deep functional expertise. Mr. Hassan's intent is to sharpen the company's focus on its key products in major markets around the world, while providing enhanced support to drive performance in all countries.

Schering-Plough's international pharmaceutical business will be separated into two regions: Japan, Latin America, and Far East; and Europe, Canada, Middle East, and Africa. Tom Lauda, who has been the acting head of the international pharmaceutical business, now heads the Japan, Latin America, and Far East region. Apet Iskenderian has taken over as the new head of the Europe, Canada, Middle East, and Africa region.

Schering-Plough (sgp.com) has consolidated and streamlined key support functions in the Global Business Operations unit, which has the responsibility for U.S. sales operations and distribution, global training, global planning and financial forecasting, new product development, global market research, pricing and contracting, finance, and information technology. The business unit is headed by Bruce Reid, who joins Schering-Plough as senior VP, Global Business Operations.The Global Business Operations unit will provide functional support in these areas to all regions, products, and customers. In addition, Global Business Operations is responsible for Warrick Pharmaceuticals, Schering-Plough's generic business based in Reno, Nev.

Mr. Hassan believed that one of the steps needed to mend Schering-Plough was to shed former CEO Richard Kogan's culture of secrecy. He believes that a customer-facing philosophy is core to the design of the new organization. To that end, the company brought in Ken Banta, who is responsible for strategic communications. Mr. Banta is working closely with Mr. Hassan and the other members of the company's executive management team on improving internal and external communications.

Mr. Hassan is making significant changes in Schering-Plough's U.S. and global marketing organizations that he hopes will accelerate the turnaround and drive the performance of the company's brands worldwide. The company's goals have been reoriented around customers and products and organized into global brand groups.

The new organization has fewer layers and brings senior management closer to the customer interface. The global marketing department has been eliminated and its people will be folded into the customer groups. These customer groups will contain U.S. sales and marketing and regional marketing, which will work with the country operations.

The Primary Care Customer Group is composed of products, U.S. sales, and consumer communications. Chuck Ziakas has been appointed as VP of primary care sales and is responsible for U.S. sales training, reporting to the head of the Primary Care Customer Group.
The Specialty Customer Group will encompass four global product groups organized around key specialty growth drivers. These products include the Peg-Intron hepatitis C franchise, Remicade, Integrilin, and oncology products, which include Temodar. Global brand teams for these product groups will report to the respective customer group head.

Mr. Hassan's organizational changes have extended to the consumer market with the appointment of Stanley F. Barshay as chairman of the newly organized Consumer Health Care group. Schering-Plough sells over-the-counter medicines such as Drixoral, Gyne-Lotrimin, Coppertone, and Dr. Scholl's.

One of the key points in Mr. Hassan's plan is to revitalize Schering-Plough's drug pipeline. Schering-Plough Research Institute is experiencing organizational changes designed to fully integrate all drug-discovery functions. Catherine Strader, Ph.D., executive VP, discovery research, heads up Schering-Plough Research Institute, which is based in Kenilworth, N.J. Ms. Strader is responsible for directing the activities of the Schering-Plough Research Institute discovery-research organization, which includes biological research, chemical research and technology acquisition, and external collaboration.

John Curnutte, M.D., CEO of Dnax Research Inc. (dnaxresearch.com), has assumed responsibility for drug-discovery activities in Schering-Plough Research Institute laboratories in California, including research activities at San Diego-based Canji Inc. These organizational changes streamline the research programs in biologics and are expected to improve the flow of new product discoveries.

Mr. Hassan formed the Global Scientific Research & Health Outcomes Group to further develop scientific knowledge and data about the company's products for the benefit of physicians and patients. The company will set and enforce high standards for postmarketing research to ensure compliance, business integrity, and scientific rigor. Uli Goldmann, M.D., will serve as acting head of the newly expanded area. The Global Scientific Research & Health Outcomes Group will report to Ms. Cox with a dotted-line relationship to Schering-Plough Research Institute.

Analysts at global investment-research company Morningstar Inc. believe that Mr. Hassan has the ability to turn the company around. "New leadership is key, and new CEO Fred Hassan understands this," says Todd Lebor, analyst for Morningstar (morningstar.com). "He's set in motion the necessary changes for a turnaround. He replaced senior management with executives who believe in his plan and with whom he has worked before. He's putting the company through a head-to-toe review, looking for cost savings and efficiencies. He's redeploying assets behind top products like Zetia, Remicade, and Peg-Intron. He's changing the company's culture. These changes will take several years and cost tens of millions, but they should put Schering-Plough back on track to earn the lofty margins of a global pharmaceutical company."

Mr. Hassan is faced with the daunting challenge of addressing the company's dire business situation while reenergizing a stagnant product pipeline. Analysts at Merrill Lynch & Co., an industry-research company, believe that Mr. Hassan's management changes and turnaround efforts will pay off over the long term. Many analysts have written 2003 off as a rebound year for Schering-Plough. Merrill Lynch (ml.com) projects full-year earnings for Schering-Plough's in 2003 would represent a 68% decline compared with its 2002 profit of $1.42 per share.

In 2002, the company generated sales of $10.18 billion, 4.3% more than in 2001, net income of $1.97 billion, an increase of 1.6%, and earnings per share of $1.34, 1.5% more. Sales for the first six months of 2003 were $4.41 billion, down 18% from first-half 2002. Net income fell 71.2% to $355 million. Diluted earnings per share were 24 cents, down 71.4% from the first half of 2002.

Analysts say Schering-Plough is in a vulnerable situation, but the company still has a solid product portfolio, a strong cash position, and positive operating cash flows. The company still has a chance to turn around, but only by protecting its hepatitis C franchise and building Zetia into a megablockbuster.

Analysts say Zetia, a novel cholesterol absorption inhibitor, has the potential to make a huge impact in the marketplace. Mr. Hassan is placing the company's hopes firmly on the shoulders of his new business structure and expects Zetia to drive Schering-Plough's financial engine for the future. Mr. Hassan created a new position to represent Schering-Plough's joint venture with Zetia, which is jointly marketed in most territories around the world with Merck & Co. (merck.com). The role focuses on implementation in the United States, working with the regions, and charting the future for Zetia in Japan, where Schering-Plough retains sole development rights. Mr. Lauda serves as the acting head of the joint venture Merck/Schering-Plough Pharmaceuticals located in North Wales, Pa., as the company conducts a search to fill this important role.

Zetia as a single-entity product has achieved a significant penetration of the $20 billion global cholesterol-management market. The launch of Zetia already has resulted in more than 1.5 million prescriptions filled since the drug's U.S. launch in mid-November 2002. Lehman Brothers Inc. (lehman.com), an industry-research company, estimates that Zetia as monotherapy will achieve $365 million in sales for 2003 and peak sales of $2 billion. Merck/Schering Plough remains on track to file a once-daily combination tablet containing Zetia and Merck's cholesterol-management medicine Zocor, chemically composed of simvastatin, in late 2003. Estimated peak sales of Zetia/Zocor are $5 billion.

Although Mr. Hassan has made significant changes at Schering-Plough, he faces an uphill battle due to continuing competitive pressures on the company's major product franchises. Schering-Plough's prescription allergy franchise, Clarinex antihistamine and Nasonex nasal spray, is experiencing intense competition in the U.S. allergy market. During second-half 2003, the company faces additional private-label competition for its over-the-counter Claritin line of nonsedating antihistamines, as the initial 180-day period of exclusivity expires for the first over-the-counter generic competitor. In August, the Court of Appeals for the Federal Circuit in Washington upheld a lower court decision, which had ruled against certain claims of U.S. Patent No. 4,569,716 in litigation relating to Claritin. Schering-Plough managers will continue to focus its energy on marketing the Claritin line as over-the-counter products.

In 2002, Claritin sales were $1.8 billion, 43% less than in 2001. First-half 2003 sales of prescription Claritin were $221 million, 84.8% less than in first-half 2002. Sales of over-the-counter Claritin in first-half 2003 were $212 million.

First-year sales of Clarinex, the successor to Claritin, were $598 million in 2002. The product was launched in January 2002. First-half 2003 sales of Clarinex were $392 million, 51.9% more than in first-half 2002. Nasonex sales in 2002 were essentially flat at $523 million. In first-half 2003, sales grew 6.7% from first-half 2002 to $254 million.

Besides troubles with its allergy franchise, Schering-Plough's hepatitis C franchise is being negatively impacted by the launch of a competing drug, Pegasys, marketed by Roche (roche.com). The franchise includes the anticancer/antiviral agent Intron A injection as monotherapy and in combination with Rebetol capsule for treating hepatitis C and Peg-Intron powder for injection, a longer-acting form of Intron A, as monotherapy and in combination with Rebetol for treating hepatitis C. In 2002, Intron franchise sales rose 89.1% to $2.74 billion. Generic rivals to Rebetol could arrive in third-quarter 2003, slowing sales growth to 12% in the period from about 40% in the second quarter. In first-half 2003, sales were $1.08 billion, 10.9% less than in first-half 2002. Although the patent for ribavirin, the active substance in Rebetol, expires soon, Peg-Intron has patent life until 2014.

One of Schering-Plough's brightest spots in its portfolio is the anti-inflammatory drug Remicade. The company markets Remicade in all countries outside of the United States, except in Japan and parts of the Far East where it is marketed by Tanabe Seiyaku Co. (tanabe.co.jp). Johnson & Johnson subsidiary Centocor Inc. (centocor.com) has exclusive marketing rights to the product in the United States. In 2002, Remicade brought in international sales of $337 million, more than double the sales generated in 2001. In the first half of 2003, Remicade sales were $240 million, 75.2% more than in the same period in the previous year. Sales are being driven by increased patient use.

Schering-Plough's troubles have some analysts questioning whether the company can generate meaningful cash flow. Standard & Poor's Ratings Services lowered its corporate credit rating on Schering-Plough to "A+" from "AA-". In addition, Standard & Poor"s lowered its short-term corporate credit and commercial paper ratings on the company to A-" from A-1+. The rating actions result from greater-than-expected sales erosion of Peg-Intron. The still-strong investment grade ratings on Schering-Plough does reflect the continued diversity of its product portfolio, the promise of Zetia, and the solid financial profile, partially offset by weakened business prospects and an expected steep earnings and cash-flow decline.

Schering-Plough's profitability measures are expected to remain strong and consistent with the high investment ratings. The company continues to maintain a conservative financial profile, characterized by a net cash position. Industry analysts believe that margins and returns will likely continue to decline in the intermediate term, as lower-margin foreign sales make up a greater portion of overall sales. Operating margins have declined to 25% from 34% in 2000 because of increased research and development spending, promotional spending to launch Clarinex and OTC Claritin, and the loss of high-margin prescription Claritin sales. Return on capital declined during the same period to 25% from nearly 55%.

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October 12th, 2003

AAFP: Hepatitis C Offers Unique Challenges for Physicians
by Mike Fillon

The goal in treating patients with hepatitis C virus (HCV) is to prevent the patient from progressing to cirrhosis, according to a course on hepatitis C held here October 2nd at the 55th Annual Scientific Assembly of the American Academy of Family Physicians.

Hepatitis C is a leading cause of cirrhosis in the United States, resulting in 10,000 to 20,000 deaths per year. It is also associated with an increased risk of liver cancer, and is the most common reason for liver transplants.

William Cassidy, MD, associate professor of medicine, Louisiana State University Health Science Center, Baton Rouge, United States, noted that the infection is especially challenging for family physicians to diagnose and manage.

HCV is a progressive, fibrotic liver disease with a linear-progression profile. It is a ribonucleic acid (RNA) flavavirus that mutates every time the immune system attacks it. As a result, it often becomes a chronic infection. The infection is transmitted through blood-to-blood contact and drug users account for 60% of those who become infected. It is uncommon for HCV to be transmitted sexually. It is estimated that about 4% of Americans have chronic HCV, with as many as 15% of 20- to 45-year-olds developing the disease.

There are six major genotypes of HCV, but more than 75% of those with the diseases have genotype 1, subtype a or b. "The genotype dictates the length of therapy and predicts the patient's therapeutic response," said Dr. Cassidy. "Patients with genotype 1 require longer therapy and usually respond slower to therapy."

Dr. Cassidy said one of the toughest challenges is diagnosis, since symptoms develop in only 20% of patients and about 25% of those have nonspecific symptoms. Lab tests can offer some clues. HCV-RNA can be detected in blood within one to three weeks after exposure to the virus. Typically, elevations in alanine aminotransferase are present within 4 to 12 weeks. The average time from exposure to seroconversion is 8 to 9 weeks, and the average time from exposure to symptom development is 6 to 7 weeks.

Dr. Cassidy said current treatment options are either interferon given twice weekly with ribavirin or pegylated interferon alfa taken once weekly with ribavirin. Patients should respond to drug therapy within 12 weeks of therapy. Dr. Cassidy said patients need to be told to avoid non-steroidal anti-inflammatory drugs and Aspirin, to lose weight and to avoid alcohol. [Study title: Hepatitis C In Primary Care. Abstract 543]

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Needle Exchange Programs for IV Drug Users Gets Nixed in California

Legislation to make it easier for California cities and counties to develop needle-exchange programs for intravenous drug users was vetoed Saturday by Gov. Gray Davis.

With more than 200 bills awaiting action this weekend, Davis signed nine measures and vetoed five, including the needle-exchange proposal, AB 946.

The measure would have revised a current requirement allowing local governments to operate needle-exchange programs only during health emergencies.

AB 946 was one of numerous controversial proposals whose fate was left to a governor defeated in last week's recall election but remaining in office until votes officially are certified, a process expected to be completed next month.

Davis has rejected Gov.-elect Arnold Schwarzenegger's request that he not sign any pending bills during his final days in office.

Davis is expected to act on a mountain of legislation today, including bills to allow low-income immigrants to receive a free community college education, to restrict sales of the ephedra diet supplement, and to permit creation of a special taxing district to help finance construction of a professional sports arena in downtown Sacramento.

Aides said Davis tentatively plans to make decisions on all remaining legislation today, though his deadline is not until Monday, after which any bills remaining on the governor's desk would become law without his signature.

The needle-exchange bill, by Assemblywoman Patty Berg, D-Sebastopol, had been approved by the Assembly and Senate largely along party lines, with most Democrats supporting it and most Republicans opposed.

For years, numerous health advocates have argued that needle-exchange programs can save lives by reducing the spread of AIDS, hepatitis and other diseases contracted from sharing dirty needles. But opponents have argued that California should neither sanction illicit drug use nor create programs that enable such activity by exchanging clean needles for dirty ones.

Davis sought a middle ground in 1999, signing legislation that did not technically "legalize" needle exchanges but barred prosecution when local governments created such programs by declaring a health emergency and renewing it every two weeks.

Davis' veto message for AB 946 said Berg's bill infringes on a foundation of the compromise reached in 1999.

"(AB 946) undermines the key element that won my support for that legislation, by eliminating the requirement for a local governing body to make a declaration of a local emergency," Davis said.

More than a dozen needle-exchange programs exist in California and more than 110 nationwide, according to a legislative committee analysis of AB 946.

Two Sacramento County supervisors, Illa Collin and Roger Niello, had differing reactions to Davis' veto of AB 946.

Niello said he was not familiar with details of the bill but opposes the concept of needle-exchange programs.
"We need to help drug users get off drugs, not give them needles to use them safer," Niello said. "I'm just not in favor of needle exchange."
But Collin said she was disappointed by Davis' veto.

"I think most people feel that if you can stop the spread of hepatitis and AIDS, that's good for the whole community and certainly more humane for the people involved," she said.
In a separate action Saturday, Davis signed AB 231, which would allow food stamp recipients to own an automobile valued at more than $4,650 without endangering their eligibility.

Assemblyman Darrell Steinberg, the Sacramento Democrat who proposed AB 231, said the $4,650 limit makes it difficult for food stamp recipients to have a reliable vehicle for finding and commuting to a job.

AB 231 also supports allowing alternatives to face-to-face interviews in determining eligibility for food stamps.

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October 13th, 2003

Schering-Plough Announces FDA Approval of PEG-Intron Redipen for the Treatment of Chronic Hepatitis C

Schering-Plough Corporation today announced that the U.S. Food and Drug Administration (FDA) has granted marketing approval to PEG-INTRON REDIPEN(TM), a pre-filled pen for administering PEG-INTRON(R) (peginterferon alfa-2b) Powder for Injection, the most-prescribed interferon treatment for patients with chronic hepatitis C.

PEG-INTRON REDIPEN is the first and only pen delivery system approved for administering pegylated interferon therapy. Pegylated interferon in combination with ribavirin is the standard of care in treating chronic hepatitis C. The REDIPEN is designed to be simpler to use than a traditional vial and syringe, thus enhancing patient confidence with dosing of their PEG- INTRON regimen.

"Individualized, weight-based dosing of PEG-INTRON used in combination with REBETOL Capsules has proven effective in patients with chronic hepatitis C," said Fred Poordad, M.D., associate director of hepatology and liver transplantation, Cedars-Sinai Medical Center, Los Angeles. "The simplicity of the PEG-INTRON REDIPEN may enhance patients' confidence in dosing and make treatment administration easier for some patients."

The PEG-INTRON REDIPEN is a disposable, single-dose delivery system that allows patients to administer PEG-INTRON in three easy steps: Mix, Dial and Deliver. Mixing occurs by simply pushing down on the pen to combine the PEG- INTRON powder with sterile water, both of which are stored in the pen; Dialing allows the patient to accurately select their predetermined individualized dose; and Delivery allows the patient to inject their individualized dose of the medication. The REDIPEN will be available in four different strengths: 50, 80, 120 and 150 mcg, each indicated by a color-coded label and dosing button. An instructional videotape and brochure for use by patients and healthcare professionals will also be available.

"The REDIPEN is a high-tech pen delivery system for injecting peginterferon therapy and offers an easy-to-use alternative for people who may be put off by using a traditional vial and syringe," said Alan P. Brownstein, president and chief executive officer of the American Liver Foundation.

"Development of the PEG-INTRON REDIPEN is consistent with Schering- Plough's continuing role as an industry leader in providing innovative products and patient services to people with chronic hepatitis C," said Robert J. Spiegel, M.D., senior vice president of medical affairs and chief medical officer, Schering-Plough Research Institute. "We are very pleased to bring forward this latest advance in meeting the needs of the hepatitis C patient community," he said.

The PEG-INTRON REDIPEN is expected to be available in the United States in early 2004. It is currently available in the European Union (EU) and several other international markets.

Commitment to Hepatitis C Patients As the leading innovator of interferon-based treatments for hepatitis C, Schering-Plough on Sept. 23, 2003, announced plans to initiate the IDEAL trial, a major clinical study involving 2,880 patients that for the first time will directly compare the two approved forms of pegylated interferon therapy for chronic hepatitis C: PEG-INTRON versus PEGASYS (peginterferon alfa- 2a/Hoffmann-La Roche, Inc.), both used in combination with ribavirin. Schering-Plough Research Institute, in collaboration with leading medical centers, will conduct the comparative study in response to requests by the hepatitis C medical and patient communities, and to clear up misperceptions in the marketplace about these two treatments.

In addition to its ongoing commitment to research and development, Schering-Plough is committed to supporting hepatitis C patients with education and service programs as well as to help locate financial assistance for patients in need. The company's programs for patients in the United States are among the most comprehensive in the industry, providing support and guidance to patients, and ensuring that all eligible patients have access to the company's hepatitis C products.

Schering-Plough's Be In Charge hepatitis C patient-support program has enrolled more than 55,000 U.S. patients to date, with more than 25,000 patients enrolling in 2002 alone. This U.S. program is designed to support patients treated with Schering-Plough hepatitis C products through the use of educational materials and telephone contact with personal nurse counselors skilled in the management of hepatitis C.

Twenty-five percent of all U.S. patients currently treated with PEG-INTRON and REBETOL(R) (ribavirin, USP) combination therapy are enrolled in the company's Commitment to Care program, which provides medication and/or reimbursement assistance to eligible patients. The market value of assistance and treatment provided to hepatitis C patients through this program exceeded $100 million in 2002.

PEG-INTRON and REBETOL combination therapy is indicated for the treatment of chronic hepatitis C in patients with compensated liver disease who have not been previously treated with interferon alpha and are at least 18 years of age.

PEG-INTRON is a long-acting, pegylated form of INTRON(R) A (interferon alfa-2b, recombinant) Injection that is taken once weekly for 48 weeks in an individualized dosing regimen based on a patient's body weight. PEG-INTRON (1.5 ug/kg/week) in combination with REBETOL (800 mg/day) is the market- leading hepatitis C therapy in the United States. More than 300,000 hepatitis C patients worldwide, including 175,000 U.S. patients, have received this combination therapy since its introduction in 2001.

PEG-INTRON, the only interferon product for hepatitis C approved for dosing according to body weight, uses proprietary PEG technology developed by Enzon, Inc. (Nasdaq: ENZN) of Bridgewater, N.J. PEG-INTRON, recombinant interferon alfa-2b linked to a 12,000 dalton polyethylene glycol (PEG) molecule, is a once-weekly therapy that is designed to achieve an effective balance between antiviral activity and elimination half-life. Schering-Plough holds an exclusive worldwide license to PEG-INTRON. REBETOL is an oral formulation of the antiviral agent ribavirin, a synthetic nucleoside analog.

WARNING
-- REBETOL monotherapy is not effective for the treatment of chronic hepatitis C virus infection and should not be used alone for this indication. (See WARNINGS.)

-- The primary toxicity of ribavirin is hemolytic anemia. The anemia associated with REBETOL therapy may result in worsening of cardiac disease that has led to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with REBETOL. (See WARNINGS, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION.)

-- Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. In addition, ribavirin has a multiple-dose half-life of 12 days, and so it may persist in nonplasma compartments for as long as 6 months. Therefore, REBETOL therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of treatment in both female patients and in female partners of male patients who are taking REBETOL therapy. At least two reliable forms of effective contraception must be utilized during treatment and during the 6-month post-treatment follow-up period. (See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS-Information for Patients and Pregnancy Category X.)

-- Alpha interferons, including PEG-INTRON and INTRON A, may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Patients with persistently severe or worsening signs or symptoms of these conditions should be withdrawn from therapy. In many but not all cases these disorders resolve after stopping therapy with PEG-INTRON or INTRON A. (See WARNINGS, ADVERSE REACTIONS.)
PEG-INTRON There are no new adverse events specific to PEG-INTRON as compared to INTRON A, however, the incidence of some (e.g., injection site reactions, fever, rigors, nausea) were higher. The most common adverse events associated with PEG-INTRON were "flu-like" symptoms, occurring in approximately 50% of patients, which may decrease in severity as treatment continues. Application site disorders were common (47%), but all were mild (44%) or moderate (4%) and no patient discontinued, and included injection site inflammation and reaction (i.e., bruise, itchiness, irritation). Injection site pain was reported in 2% of patients receiving PEG-INTRON. Alopecia (thinning of the hair) is also often associated with alpha interferons including PEG-INTRON.

Psychiatric adverse events, which include insomnia, were common (57%) with PEG-INTRON, but similar to INTRON A (58%). Depression was most common at 29%. Suicidal behavior including ideation, suicidal attempts, and completed suicides occurred in 1% of patients during or shortly after completing treatment with PEG-INTRON. PEG-INTRON is contraindicated in patients with autoimmune hepatitis and decompensated liver disease.
The following serious or clinically significant adverse events have been reported at a frequency 1% with PEG-INTRON or interferon alpha: Severe decreases in neutrophil or platelet counts, hypothyroidism, hyperglycemia, hypotension, arrhythmia, ulcerative and hemorrhagic colitis, development or exacerbation of autoimmune disorders including thyroiditis, RA, systemic lupus erythematosus, psoriasis, pulmonary disorders (dyspnea, pulmonary infiltrates, pneumonitis and pneumonia, some resulting in patient deaths), urticaria, angioedema, bronchoconstriction, anaphylaxis, retinal hemorrhages and cotton wool spots.

Renal failure patients should be closely monitored for signs and symptoms of interferon toxicity and PEG-INTRON should be used with caution in patients with creatinine clearance 50 mL/min. Patients on PEG-INTRON therapy should have hematology and blood chemistry testing before the start of treatment and then periodically thereafter.

INTRON A All patients receiving INTRON A therapy experienced mild-to-moderate side effects. Some patients experienced more severe side effects, including neutropenia, fatigue, myalgia, headache, fever, chills and increased SGOT. Other frequently occurring side effects were nausea, vomiting, depression, alopecia, diarrhea and thrombocytopenia. DEPRESSION AND SUICIDAL BEHAVIOR, INCLUDING SUICIDAL IDEATION, SUICIDAL ATTEMPTS, AND COMPLETED SUICIDES, HAVE BEEN REPORTED IN ASSOCIATION WITH TREATMENT WITH ALFA INTERFERONS, INCLUDING INTRON A THERAPY.

DISCLOSURE NOTICE: The information in this press release includes certain "forward-looking" statements concerning, among other things, the future prospects of the company and its products, which the reader of this release should understand are subject to substantial risks and uncertainties. The company's business prospects and the prospects of its products may be adversely affected by general market and economic factors, competitive product development, product availability, current and future branded, generic and OTC competition, market acceptance of new products, federal and state regulations and legislation, the regulatory review process in the United States and foreign countries for new products and indications, existing manufacturing issues and new manufacturing issues that may arise, timing of trade buying, patent positions, litigation and investigations, and instability or destruction in a geographic area important to the company due to reasons such as war or SARS. For further details and a discussion of these and other risks and uncertainties, see the company's Securities and Exchange Commission filings, including the company's 8-K filed Aug. 22, 2003.

Schering-Plough Research Institute is the pharmaceutical research and development arm of Schering-Plough Corporation, a research-based company engaged in the discovery, development, manufacturing and marketing of pharmaceutical products worldwide.

For more information about Schering-Plough, visit the company's website at www.schering-plough.com .

For information about hepatitis and for full prescribing information regarding PEG-INTRON and REBETOL, visit www.hepatitisinnovations.com.

PEGASYS is a trademark of Hoffmann-La Roche Inc. See the PEGASYS product insert for information on this product.

SOURCE: Schering-Plough Corporation

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Fibromyalgia Syndrome in Patients with Hepatitis C Infection
by hivandhepatitis.com

Fibromyalgia syndrome (FS) is characterized by widespread pain and tenderness at specific anatomic sites. Different theories have been proposed in the etiopathogenesis of this syndrome, and besides genetic, neuroendocrine, psychologic, and traumatic causes, infections have also been reported.

The aim of the present study was to evaluate the presence of FS in patients with hepatitis C virus (HCV) infection.

Ninety-five patients with chronic HCV infection and 95 healthy controls were enrolled in the study. The 1990 American College of Rheumatology classification criteria were used for the diagnosis of FS. Tender point count, pain intensity, sleep disturbance, stiffness, headache, paresthesia, fatigue, irritable bowel syndrome (IBS), and sicca- and Raynaud-like symptoms were assessed.

Study Results
Fibromyalgia was found in 18.9% of patients and 5.3% of healthy controls. Mean tender point count, pain intensity scored on a visual analog scale (VAS), sleep disturbance, stiffness, paresthesia, and fatigue were higher in the HCV group. No significant relationship was observed between the two groups regarding headache, IBS, and sicca- and Raynaud-like symptoms.

In addition, mean tender point count and pain intensity scores were also significantly higher in HCV patients with FS than in control subjects with FS. All of the symptoms except stiffness were not statistically significant between the HCV and control groups with FS.

The authors conclude, "These results demonstrate a tendency toward higher prevalence of FS in patients with HCV infection. Besides various extrahepatic features, musculoskeletal disorders including fibromyalgia might be expected in the progression of HCV infection."

"Detailed examination of the patients helps to differentiate FS from other musculoskeletal complications of HCV infection. This will provide appropriate management approaches and better quality of life for them."

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Pre-treatment Laparoscopic Appearance of the Liver Can Predict Response to Combination Therapy with Interferon Alfa and Ribavirin
by hivandhepatitis.com

The aim of this study was to determine whether the pretreatment laparoscopic appearance of the liver is an additional predictor of response to combination therapy with interferon and ribavirin in patients with hepatitis C.

A retrospective review was performed of 112 patients (61 men, 51 women [ratio 1.3:1]; mean age 50 [10] years, range 15-73 years) with untreated hepatitis C, without other causes of liver disease, who underwent diagnostic laparoscopy * before combination therapy with interferon and ribavirin for at least 24 weeks with a 24-week post-treatment follow-up.

Fifty-nine were white, 37 Hispanic, and 16 African American. Patients were divided into responders and non-responders based on viral clearance. Demographics, genotype, pre-therapy hepatitis C virus RNA, histopathologic, and laparoscopic appearances were analyzed.

Study Results
Ninety-three patients (83%) had genotype 1 with a mean pretreatment hepatitis C virus RNA of 3.2 (2.8) million copies/mL. Thirty-seven (37%) had laparoscopic evidence of cirrhosis, whereas, only 30 (26.4%) had cirrhosis by histopathologic criteria. Patients were treated with interferon and ribavirin (mean dose 10.6 [2.5] mg/kg) for a mean duration of 37.7 (11.4) weeks, depending on response and genotype.

A sustained response was observed in 26 (23%) patients; in 12 (11%), there was only a biochemical response (biochemical responder), while 59 (53%) and 15 (13%) were classified, respectively, as non-responders and relapsers.
Logistic regression analysis revealed that pretreatment laparoscopic appearance (p = 0.034) and genotype (p = 0.002) were significant predictive factors; that is, a lesser extent of fibrosis at laparoscopy and genotypes other than 1 were predictive of a sustained response to combination therapy.

The authors conclude, "Pretreatment laparoscopic appearance alone and genotype are significant predictors of a sustained response to combination therapy in patients with hepatitis C. Laparoscopy and biopsy are complementary for the diagnosis of cirrhosis in hepatitis C."

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Liver Transplantation with Allografts from Hepatitis B Core Antibody-positive Donors
by hivandhepatitis.com

The enduring shortfall of organ donors has inspired the widespread utilization of hepatic allografts from donors with hepatitis B core antibodies in spite of the potential risk of transmitting hepatitis B virus (HBV) infection to the recipient.

The current paper reports on a protocol of naive recipients receiving livers from hepatitis B core antibody-positive donors. From November, 1999 to March, 2002, 77 liver transplantations were performed in 73 patients at the Gastroenterology and Hepatology Unit, University Hospital Marques de Valdeour, Santander, Spain.

Seven patients received livers from hepatitis B core antibody-positive donors. All recipients received 10,000 U/d of intravenous HBIg for 7 days and 100 mg/d of lamivudine until we could obtain the HBV-DNA from the donor samples (serum and liver tissue).

If the results of the HBV-DNA from the donor samples were positive, the patient would continue with prophylaxis and if they were negative the investigators would finish the combined prophylaxis.

After transplantation, HBV serologic markers and HBV-DNA by polymerase chain reaction (PCR) in serum and lymphocytes were tested in the recipients on the seventh, fifteenth, thirtieth, and ninetieth days as well as every 3 months after transplantation.

All seven donor organs were negative for HBV-DNA in serum and liver tissue. Thus, the researchers stopped the combined prophylaxis in all recipients (range, 7 to 10 days). None of the 7 patients developed de novo HBV infection over the 3-year study period (range, 9 to 36 months).

The authors conclude, "Our approach is reasonably safe, and it appears to be very effective in the prevention of de novo HBV infection after liver transplantation."

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Peripheral Neuropathy in Patients with Liver Cirrhosis
by hivandhepatitis.com

Neuropathy in association with chronic liver disease, including cirrhosis, is well recognized. However, there are differences in the incidence and type of neuropathy reported.

The causal relationship of liver disease to neuropathy has been questioned. This study was designed to evaluate the incidence and character of peripheral neuropathy in patients with liver cirrhosis. The effect of alcohol consumption, severity of liver disease and encephalopathy on the incidence and severity of neuropathy were also studied.

Patients having an identifiable cause of peripheral neuropathy, except alcohol, were excluded from the study. Patients with evidence of vitamin B12 deficiency or diabetes were also excluded.

33 patients with liver cirrhosis were evaluated clinically and electrophysiologically to detect any evidence of peripheral neuropathy. Nerve conduction studies were performed in the upper and lower limbs using surface electrodes. These patients also underwent a detailed clinical examination.

Study Results
Clinical signs of peripheral neuropathy were found in seven (21%) patients. Nerve conduction studies were abnormal in 24 (73%) patients. The pattern of involvement was predominantly of an axonal sensory motor polyneuropathy.

Neuropathy was found both in patients with alcohol-related and non-alcohol-related cirrhosis.

The presence of encephalopathy did not have a significant bearing on the incidence and severity of neuropathy. The neuropathy was also not significantly related to the severity of liver disease.

The present study reveals that a significant number of patients with liver cirrhosis show evidence of peripheral neuropathy, which is present regardless of the etiology of cirrhosis, and is subclinical in a majority of these patients.

The authors conclude, "The cause of neuropathy was probably the liver disease itself, as the incidence and severity of neuropathy in the alcohol-related cirrhosis, although higher, was not significantly different from the neuropathy in patients with non-alcohol-related cirrhosis."

Postgraduate Institute of Medical Education and Research, Chandigarh, India.

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Risk of HCV-Infected Allografts "Serious Public Health Threat"
by Peggy Peck

Limitations in donor screening combined with outmoded donor tissue sterilization procedures suggest that about 300 hepatitis C virus (HCV)-infected musculoskeletal tissue specimens are distributed by U.S. tissue procurement centers each year, according to the results of a study presented here at the 41st annual meeting of the Infectious Diseases Society of America.

Lennox Archibald, MD, medical director of Regeneration Technologies in Alachua, Florida, said that the Food and Drug Administration (FDA) currently "has no approved test for postmortem presence of HCV in donor tissues. Our research suggests that there could be up to 300 infected tissue specimens distributed each year in the U.S. The multiple infections this could cause in the recipient population—and those who have contact with them—presents a serious public health threat." Dr. Archibald supervised investigations of allograft infection outbreaks while serving as a medical epidemiologist with the Hospital Infections Program at the Centers for Disease Control and Prevention from 1995 to 2002.

He noted that about 18,000 cadaveric donors provide 650,000 allografts for transplantation —often cartilage for joint surgeries—each year. Thus, tissue from a single infected donor could be distributed among dozens of recipients.

Serological tests used to screen tissue donors for HIV antibody and hepatitis B virus (HBV) surface antibody are very sensitive, but serology for HCV is not as sensitive (97%), Dr. Archibald said. This is clinically worrisome because data from first-time blood donors suggest that the seroprevalence of HCV is markedly higher, 0.4%, than seroprevalence of HIV (0.02%) or HBV (0.2%). Thus, he theorized that HCV prevalence among tissue donors would also be higher. He said an analysis of data from tissue procurement agencies suggests that HCV is actually more common—almost three times more common—among tissue donors than among first-time blood donors.

In the study, Dr. Archibald and colleagues obtained seroprevalence data collected from July 1996 to June 2001 from 39 U.S. tissue procurement agencies. HIV, HBV, and HCV tests were performed on postmortem blood after standard donor screening, which included medical/social history, physical examination, and review of medical records. Positive HIV Ab was confirmed by Western Blot, HBsAg by neutralization, and HCV by recombinant immuno-blot assay.

Dr. Archibald used published anti-HCV sensitivity data for clinical samples to estimate the annual number of HCV-infected tissue donors that might not be detected on initial screening.

The 39 agencies performed initial serology on a total of 19,300 cadaveric tissue donors. That sample represents about 21% of the tissue donors in the U.S. during the same period. Seroprevalence rate for HCV Ab was 1.06% compared with 0.03% for HIV and 0.29% for HBsAg, he said.

Thus, about five HCV-infected tissue donors would be missed and 180 HCV-infected allografts distributed. But that estimate does not include the number of tissue donors that may be in the "window period" during which serology would not detect infection. So a more accurate estimate, he said, "is about 300 to 350 infected allografts each year."

A sterilization procedure that included viral inactivation would reduce this risk, but Dr. Archibald noted that the FDA does not currently require that tissue processors use such procedures.

"The significance of this study is that, clearly, ongoing testing of cadaveric tissue does not exist and this unique investigation has determined a significant rate of hepatitis C infection among donors," Christopher Woods, MD, director of the microbiology laboratory at the Durham Veterans Administration Medical Center in North Carolina, told Medscape. Dr. Woods was not involved in the study.

He added, "We can't underestimate the importance of making sure that tissues that are being transplanted into our desperately ill patients are, in fact, healthy tissues. [This study] is a very important study."

IDSA 41st Annual Meeting: Poster 372. Presented Oct. 10, 2003.
Reviewed by Gary D. Vogin, MD

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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) (group I/vaccine A: 20 microg HBsAg, 50 microg MPL, 50 microg QS21; group II/vaccine B: 100 microg HBsAg, 100 microg MPL, 100 microg 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 (group I: median, 7,293 IU/L; range, 721-45,811 IU/L anti-HBs; group II: median, 44,549 IU/L; range, 900-83,121 IU/L anti-HBs) and discontinued HBIG. They were followed up for a median of 13.5 months (range, 6-22 months).

The vaccine was well tolerated.

In conclusion, most patients immunized with the new vaccine can stop HBIG immunoprophylaxis for a substantial, yet to be determined period of time.

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October 14th, 2003

Peg-Intron Redipen Approved In the US

Schering-Plough's Peg-Intron Redipen, a pre-filled pen device for delivering its pegylated interferon alfa-2b therapy for hepatitis C, has been approved by the US FDA. It will be available in early 2004.

The Redipen product is already available in around 15 countries worldwide, including some European markets (it is approved throughout the EU). It is designed to be simpler to use than the currently available vial and syringe presentation. Unlike its rival, Roche's Pegasys (peginterferon alfa-2a), dosing of Peg-Intron is weight-based and the product consists of a powder and diluent which patients make up according to their requirements.

The Redipen will be available in four different strengths - 50, 80, 120 and 150 micro g, which are equivalent to the four different vial sizes already available, and will be comparably priced, Schering-Plough says.

Meanwhile, Schering-Plough's plans for a head-to-head study with Pegasys have drawn criticism from one hepatitis C patient advocate. In an open letter to the company, Brian Klein from Hepatitis C Action and Advocacy Coalition points out that in the IDEAL study - announced by the firm last month (Scrip No 2888, p 17) - neither of the drugs nor the dosing strategy will be controlled. "As described so far, this study sounds like clever marketing, but poor science," he told the company.

The trial is designed to compare standard dosing of Pegasys and weight-based dosing of Peg-Intron as these are the approved strategies for each product, he writes. "Therefore any safety and/or efficacy differences that might be detected in the study arms will be confounded and will never be able to show whether that difference is due to the drugs themselves, the dosing strategies or both."

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Across The Nation | Nebraska Insurance Department Malpractice Fund Could Be Depleted Due to Hepatitis C Outbreak Lawsuits

The Nebraska Department of Insurance has asked a Lancaster County district judge to require malpractice insurer Medical Protective of Fort Wayne, Ind., to defend the more than 80 lawsuits filed against Dr. Tahir Javed, who state officials say is responsible for a "massive" hepatitis C outbreak at a Freemont, Neb., clinic, the AP/Omaha World-Herald reports (AP/Omaha World-Herald, 10/9). State officials earlier this month revoked Javed's medical license after nearly 100 people were infected with hepatitis C, which can cause severe liver damage. One patient has died due to the infection. 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, 10/3).

Lawsuit Details
If Medical Protective -- Javed's malpractice insurer -- does not settle all 81 of the lawsuits collectively, state officials have expressed concern that the state's $55 million medical malpractice fund, which doctors in the state pay into each year to reduce malpractice insurance costs, could be depleted. According to court papers, Javed's malpractice insurance policy set a $200,000 limit on individual claims and a $600,000 annual aggregate; however, the state says that the policy contains a provision that would increase to $7 million the total amount the insurer could be required to pay. Medical Protective officials declined to comment on the case, according to the AP/World-Herald. Excluding the Javed claims, the state expects to pay approximately $46 million from its $55 million malpractice insurance fund to settle pending claims. According to Tim Wagner, head of the Department of Insurance, if the Javed case depletes the state's malpractice fund, the 3,100 doctors who currently pay into the fund will be required to pay the remaining claims, which could total tens of millions of dollars, according to the AP/World-Herald (AP/Omaha World-Herald, 10/9).

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Politics and Policy | California Gov. Davis Signs Two HIV/AIDS-Related Bills, Vetoes Two Needle Access Bills

California Gov. Gray Davis (D) on Saturday signed two HIV/AIDS-related bills and vetoed two bills aimed at preventing the spread of HIV, the AP/Contra Costa Times reports. The moves came despite Gov.-elect Arnold Schwarzenegger's (R) request that Davis not act on any of the nearly 300 bills awaiting action after Davis was recalled last week. However, because of provisions in the state Constitution, five of the bills Davis vetoed would have automatically become law if he had not acted (Thompson, AP/Contra Costa Times, 10/11). The following are summaries of the AIDS-related bills.

* AB 879: Introduced by California Assembly member Paul Koretz (D), the new law requires the state Department of Health Services to form a task force that will be charged with creating treatment guidelines for cases of inadvertent sexual or needle exposure to HIV. The state currently only has post-exposure treatment guidelines for health care workers and sexual assault survivors who are exposed to the virus (Kaiser Daily HIV/AIDS Report, 3/11). Researchers have found that people who may have been exposed to HIV can avoid infection if they take a regimen of antiretroviral drugs within 72 hours of exposure and continue a course of treatment for several weeks (AP/Contra Costa Times, 10/11).

* AB 1676: The bill, introduced by Assembly member John Dutra (D), requires physicians to ask pregnant women to undergo HIV testing along with a routine battery of tests and to provide counseling for women who find out that they are HIV-positive. The law allows women to choose not to be tested. In addition, the law requires the state Department of Health Services in conjunction with the Office of AIDS and other organizations to develop by the end of next year culturally sensitive informational material on HIV testing. Last year, Davis vetoed a similar bill, saying that women might perceive the test as mandatory and refuse to obtain prenatal care as a result (Hymon, Los Angeles Times, 10/11).

* AB 946: Davis vetoed the bill, which would have increased cities' and counties' freedom to establish clean needle and syringe-exchange programs to help prevent the spread of HIV/AIDS and hepatitis. In his veto message, Davis said he is committed to helping prevent the spread of HIV and hepatitis but added that he was concerned that the bill would "create more law enforcement problems" than the existing law (AP/Contra Costa Times, 10/11). Currently, state law protects from prosecution any public entity for distributing hypodermic needles or syringes to participants in needle-exchange programs (AB 946 text, 2/20).

* SB 774: Davis vetoed the bill, which would have allowed pharmacies to sell up to 30 hypodermic syringes to an adult without a prescription, according to the Associated Press (Coleman, Associated Press, 10/14). The measure, sponsored by Sen. John Vasconcellos (D), aimed to reduce the incidence of needle sharing among drug users, which contributes to the spread of HIV, hepatitis C and other bloodborne diseases. California law currently requires a prescription to purchase syringes, except when used to inject adrenaline or insulin (Kaiser Daily HIV/AIDS Report, 9/5). In his veto message, Davis said that the bill would "undermine" one-for-one needle-exchange programs already in place, according to the Associated Press (Associated Press, 10/14). Davis added that the measure would "weake[n] county oversight and accountability" and require the state to reimburse local health officials, according to the San Jose Mercury News.

Reaction
Vasconcellos was "fuming" on Monday about Davis' veto of the pharmacy needle bill, according to the Mercury News. He called the veto "a real tragedy," adding, "People will die and the people who die can thank Gray Davis" (Marimow, San Jose Mercury News, 10/14). The San Francisco AIDS Foundation expressed "deep disappointment" over the veto, according to a SFAF release. "We thank Governor Davis for [a] strong overall record on HIV/AIDS issues," Dana Van Gorder, SFAF director of state and local affairs, said, adding, "However, he has been overly responsive to unfounded opposition to expanded syringe access despite the fact that similar laws in other states have resulted in neither increased drug use or crime" (SFAF release, 10/13). AIDS Project Los Angeles "commended" Davis for signing the bill that requires physicians in the state to offer HIV testing to all pregnant women, according to an APLA release. "With this bill, it's possible that California could almost completely prevent mother-to-child [HIV] transmission," APLA Executive Director Craig Thompson said, adding, "And because testing will be offered to all pregnant mothers, women will not feel they are being stigmatized or admitting to risky behaviors if they take the prenatal HIV test" (APLA release, 10/13). However, the Los Angeles-based AIDS Healthcare Foundation said that the bill does not go far enough because HIV testing is still voluntary under the law, whereas tests for other sexually transmitted diseases, such as syphilis and hepatitis, are required but allow women to opt-out of testing. "If we think that saving babies from getting infected with HIV is the most important thing, we should have had a bill that made it the same as testing the woman for syphilis. And this bill is not that," AHF President Michael Weinstein said (Los Angeles Times, 10/11).

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Acute Hepatitis C in the HIV Negative Patient
by hivandhepatitis.com

The Hepatitis Controversies Symposium at the 41st IDSA brought together six presenters that addressed many of the difficult questions related to the management of hepatitis B and C infection in patients with and without HIV.
How to manage a health care worker with acute hepatitis C exposure from a needlestick? Dr. David Oldach from University of Maryland presented two studies in the printed literature that attempt to answer this question (Gerlach et al in Gastroenterology 2003 and Jaeckel et al NEJM 2001).

Gerlach enrolled 60 patients. 52% of symptomatic patients cleared hepatitis viral load. What were the predictors of spontaneous clearance? The initial HCV RNA did not predict clearance. Nobody who was viremic beyond 16 weeks developed spontaneous clearance.
HCV specific CD4 responses are necessary but not always sufficient for spontaneous clearance. This has been shown both in hepatitis B and C. There are CD4 responses that wane over time. This leads to the question of when to treat, since some patients will spontaneously clear hepatitis C. Female patients were also more likely to clear spontaneously.

Jaeckel and colleagues treated young female patients. They found the clinically silent window was about 2 months. 43/44 patients cleared their infection. How early is too early and how late is too late to treat?
If you treat too early, won't have immune response to help your outcome. Too early is about 2—4 months. If you treat too late, you won't have the immune responses to help your outcome. Too late is waiting more than 6 months. The optimal time for treatment appears to be 4—6 months following exposure.

Acute asymptomatic infection is more likely to develop into chronic disease. Alberti et al reviewed this topic in Hepatology 2002. Use of standard interferon (IFN) 3 times weekly generated 32% response rate. Other IFN monotherapy studies show that higher levels of 3 times/wk pegylated interferon improved results. Ribavirin did not make that much difference in acute infection (and certainly causes anemia). For most patients with acute hepatitis C, 24 weeks of treatment is adequate to produce a sustained virologic response.
10/14/03

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Future Hepatitis C Treatments
by hivandhepatitis.com

Dr. Ira Jacobson discussed future treatments for HCV infection. There are clearly limitations with current therapy—low responses, difficult to tolerate, expensive, and of long duration.
On the horizon are genome sequenced-based approaches, viral enzyme inhibitors, and others, including improvements of ribavirin, immunomodulators, and therapeutic vaccines. Anti-sense therapy involves a short oligonucleotide chain. ISIS 14803, a 20 base oligonucleotide has completed early trials. RNA interference is a cellular process of gene silencing. Hepatitis C virus is susceptible to these types of technology.

HCV creates first a polyprotein that s broken down into a protease, a helicase and a RNA polymerase. BILN 2061 (Boehringer Ingelheim compound) is a hep C protease inhibitor.

In 10 patients with advanced cirrhosis, BILN 2061 produced profound and immediate reductions in HCV RNA. However, no patient cleared HCV RNA.

There are a variety of other PIs in development as well.

There are polymerase inhibitors in early trials. NM107 and NM283 are active in chimps with HCV. There is a clinical trial in a dose escalation design now ongoing. There are nucleoside analogues as well. There are clinical therapeutic vaccines. One is an E1 vaccine that is in trials. Patients with mild disease can be deferred therapy.

Dr. Jacobson cautioned that none of these therapies will be approved within the next 4-5 years, so not everyone should wait.

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Hepatitis B in the HIV Negative Patient
by hivandhepatitis.com

Coverage of the 41st Annual Meeting of the Infectious Diseases Society of America

Dr. Robert Perrillo discussed treatment for hepatitis B virus (HBV) infection. Monotherapy with a nucleoside analogue is probably doomed to failure, he noted.

As time goes on, after 4 years, 2/3 of patients will develop resistance to Epivir-HBV (lamivudine (3TC)). Hepsera (adefovir dipivoxil) is useful for lamivudine resistance and resistance can be seen within 2 years of use (although it is low).

One can add adefovir to lamivudine resistant patients. Combination therapy is probably preferred due to synergism and less resistance. LdT, a new nucleoside in development, is more potent and appears to be as good as LdT and 3TC combined.

Intron A (interferon alfa-2b) therapy still has a role. It is usually used for short courses—16 to 32 weeks. Preliminary data suggest that Pegasys (peginterferon alfa-2a) may be better than standard interferon. It will cause a flare of chemical hepatitis in about 30% of treated patients.

Is liver biopsy necessary? Yes. HIV is probably likely to promote progression, but the data are not clear. There is no clear risk of HIV-HBV co-infected patients developing hepatocellular carcinoma (liver cancer)—they may not have lived long enough.

Treatment is likely to prevent cirrhosis if viral remission is maintained. ALT and HBV DNA levels can guide management.

There is no benefit of treatment for patients with normal ALT.

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October 15th, 2003



Long-term Clinical Outcomes of One-year Treatment of Chronic Hepatitis B with Epivir-HBV

Japanese researchers evaluated the biochemical and virological outcomes of 19 patients with chronic hepatitis B who had been treated with 100 mg per day of Epivir-HBV (lamivudine/LMV) for 1 year from 1995 to 1996.

Fourteen patients were followed for 4.5-5 years since the end of the treatment without any further active antiviral treatment. During the treatment, DNA levels of hepatitis B virus (HBV) were under the detection limit of a hybridization assay in all the 19 patients.

However, YMDD mutants appeared in 5 (26%) patients during the course of treatment and were accompanied in all five by the elevation of serum alanine aminotransferase (ALT). Mutated HBV DNA was not detected at 1 year after the end of treatment in any of the 5 patients.

Of the patients who were followed for 4.5-5 years, the rate of seroconversion to anti-HBe and negativity for HBV DNA fluctuated. Four of 11 patients who initially had been positive for hepatitis B virus e antigen (HBeAg) became positive for anti-HBe and all of them remained positive for HBV DNA by a transcription-mediated amplification test at the end of the follow-up.

Thus, a 1-year treatment with LMV for chronic hepatitis B resulted in the relapse of HBV viremia in most of the patients who had been positive for HBeAg, although the clinical course ameliorated in some patients.

In addition, HBV DNA remained positive and ALT values were elevated at the end of the follow-up in the three patients who had been treated with interferon, with or without LMV, during the follow-up.

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ICN Plans Job Reductions, Plant Sales
Ransdell Pierson

ICN Pharmaceuticals Inc. Wednesday said it plans to cut costs by $150 million to $200 million within the next five years by selling eight manufacturing plants and reducing the number of its manufacturing employees.

Company spokesman Jeff Misakian said ICN hopes to reduce its ''manufacturing head count'' to about 1,300 or 1,400 employees. He told Reuters he was not immediately able to identify the total number of current manufacturing positions, and therefore the number of positions that ICN hopes to pare away.

``Our plan is to sell the facilities and for our employees to go with the facilities. These employees would be part of the sale,'' Misakian said, adding that no lay-offs would be necessary under that scenario.

The Costa Mesa, California-based drugmaker said the steps are part of a plan begun earlier this year to improve its global procurement process and reduce the cost of making goods by 20 percent to 25 percent over a five-year period.

ICN said it expects to keep five manufacturing plants located in Mexico, Puerto Rico, Poland, Switzerland and China, and has set no immediate deadlines to sell its other facilities.

The company last month said it hopes the restructuring will help it double its revenue and nearly triple its earnings within five years, in part by reducing its costs by up to $200 million within that time frame.

ICN aims to focus on acquiring and developing prescription drugs, primarily in North American markets, in the coming years. Over the past few decades, founder Milan Panic had invested in chemicals businesses in Eastern Europe and a chain of pharmacies in Russia, among other ventures.

But Panic retired as chairman and chief executive last year -- amid shareholder complaints about his corporate spending and personal compensation -- and new Chairman and Chief Executive Robert O'Leary is selling some of the scattered units outside of prescription drugs.

ICN in August completed its reacquisition of shares in biotechnology company Ribapharm that it did not already own. That was 16 months after it spun off 20 percent of Ribapharm in an initial public offering.

Ribapharm's only product was ribavirin, a pill that is sold by marketing partner Schering-Plough Corp. as part of a two-drug treatment for hepatitis C.

Schering-Plough pays ICN royalties on ribavirin, but sales of the drug have lagged due to stiff competition from a similar but less-expensive treatment launched early this year by Roche Holding AG .

Shares of ICN were up 13 cents to $19.71 in midday trading on the New York Stock Exchange.

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Pregnancy Can Be Good for Women with Hepatitis C

Pregnancy and subsequent delivery may help women with chronic hepatitis C clear the virus from their blood, new research suggests.

Hepatitis C is a liver disease caused by infection with the hepatis C virus (HCV), which is spread through contact in some way with contaminated blood. In most patients, the virus is never completely cleared from the body and, after many years of infection, serious liver problems, such as scarring and cancer, can occur.

The new findings, which are reported in the Journal of Medical Virology, are based on a study of 22 pregnant and 120 non-pregnant women with chronic hepatitis C.

In the pregnant group, two women permanently cleared HCV from their blood after delivery and one women temporarily cleared the virus, Dr. Masashi Mizokami, from Nagoya City University Graduate School of Medical Sciences in Japan, and colleagues report.

In contrast, in the non-pregnant group, one woman cleared HCV permanently and another cleared it intermittently.

Considering the size of both groups, this means that 14 percent of pregnant women cleared the virus, compared with only 2 percent of non-pregnant women.

"The mechanism by which pregnancy and delivery influence HCV (blood levels) is not well understood," the authors note in their article in the Journal of Medical Virology. However, it may be relate to differences in how the immune system works during pregnancy compared with other times.

Taken together, the findings suggest that "pregnancy and (delivery) may improve the prognosis in women" with chronic hepatitis C, they add.

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