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

Alan Franciscus
Editor-in-Chief

• HIV-Infected Patients Are Good Candidates for Liver Transplantation
• Hepatitis C Infections May Come From Routine Dentistry
• Bone Loss in Liver Transplant Patients
• Antiviral Therapy Has Long-Term Benefits for Liver Recipients with Recurrent HCV
• Comparison of Fibrosis Progression in Chronic Liver Diseases
• NPS Pharmaceuticals and Enzon Pharmaceuticals Agree to Merger of Equals
• Pegylated Interferon Associated with Eye Disorders
• Final Results of 68-Site Trial of Daily vs Weekly Interferon plus Ribavirin in Treatment-Naïve Patients Co-infected with HIV
• Interferon Therapy after Tumor Ablation Associated With HCV
• Rate of Natural Disease Progression in Patients with Chronic Hepatitis C
• HCV Infection Identified as Risk Factor for Other Infections
• Drug Addicts Would Use Injection Facility: Survey
• Schering-Plough Boosts Litigation Reserves
• Roche Says Pegasys Sales Off To a Strong Start
• Complications Common among Living Adult Partial Liver Donors
• Cost Comparison of Living-Donor and Cadaveric Liver Transplantation
• Lamivudine Can Help Some Chronic Hepatitis B Patients with Hepatic Decompensation
• Roche CEO Sees Advantages for New Hepatitis C Drug
• Inmates Not Entitled To Hepatitis C Treatment
• The New AIDS Fight Don't Forget This Infectious Killer
• Prisoners Not Entitled To Hepatitis Treatment, Court Rules
• Anadys Reports Completion of Phase IA Study of ANA245
• Adefovir Dipivoxil for the Treatment of Chronic Hepatitis B
• Sen. Lindsay Calls for Drug Needle Exchange Program
• Many Infants Born to HBV-Infected Women Fail to Complete Vaccination Series
• Pediatric Hepatitis C Is Mild but Persistent
• Schering-Plough Hits 6-Year Low after New Warning
• Prolonged HAART May Increase Hepatitis C Diversity in HIV-Infected Patients
• Schering PEG-Intron Supply Constraints Resolved; Earnings Forecast Cloudy
• Tattoo and Piercing Still Risky: Hepatitis C, HIV, Infection Risks High in Body Art
• Hepatitis Not HAART Causing Serious Liver Toxicity in HIV Patients
• Does Pegylated Interferon Have a Role in the Treatment of Early Stage HIV?
• Prolonged HAART May Make Treatment of HCV less Effective
• Thrombocytopenia in Patients with HCV-Positive Chronic Hepatitis: Efficacy Of Leucocyte Interferon-Alpha Treatment
• Gilead Sciences' Hepatitis B Drug Hepsera Approved for Marketing in European Union
• H.I.V. Lessons Used In Hepatitis C Treatment
• Cerebral Dysfunction in Chronic Hepatitis C Infection
• Correlation between Ammonia Levels and the Severity of Hepatic Encephalopathy
• Hepatitis C Associated With Atherosclerosis in Patients with Diabetes
• Enanta Earns Milestone Payment in Hepatitis Project
• MedMira Rapid Tests for HIV, Hepatitis 'B' and 'C' Go to the Frontline of Campaign against Disease in Africa
• Severe Hepatotoxicity during Combination Antiretroviral Treatment
• Natural History of Liver Fibrosis in Hepatitis C Virus Infection
• Pegasys (Peginterferon alfa-2a) More Tolerable Treatment for Hepatitis C Patients
• Lamivudine Treatment for Chronic Hepatitis B Infection

February 15th, 2003

HIV-Infected Patients Are Good Candidates for Liver Transplantation
By Peggy Peck

Patients infected with HIV do just as well as uninfected people when they receive cadaver organ transplants, according to Margaret Ragni, MD, professor of medicine at the University of Pittsburgh in Pennsylvania.

Dr. Ragni presented findings here yesterday from a study of HIV-infected liver transplant recipients at the 10th Annual Conference on Retroviruses and Opportunistic Infections. She compared their outcomes to outcomes of historical controls. The study was presented "These findings suggest that HIV infection should no longer be a contraindication to organ liver transplantation," said Dr. Ragni, MD.

Dr. Ragni compared survival of 23 HIV-infected patients with end-stage liver disease with survival of 11,453 patients who were not infected with HIV but who received organ transplants. The uninfected patient figures were provided from a database compiled by the United Network for Organ Sharing (UNOS).

Among HIV patients who received transplants, 12-month survival was 90.3% compared with 87% survival among patients who were not infected with HIV.

At two years, the survival of the HIV-infected patients was 76% compared with 82% for the UNOS patients. The difference did not approach statistical significance. Dr. Ragni said that since 1997 when she began her series of patients, five of the HIV-infected patients have died. Most of the patients required liver transplants because they were coinfected with hepatitis C or hepatitis B.

While HIV-infected patients should be considered candidates for cadaver organ transplant, Dr. Ragni told Medscape that "there are no data on live organ transplant."

"One in four patients with HIV have co-infection with hepatitis C and often times the management of these patients is not successful and the patients go on to have liver failure," David Thomas, MD, from the Johns Hopkins University School of Medicine in Baltimore, Maryland, told Medscape. "Dr. Ragni's presentation is very important because it shows how one can manage patients with transplantation." Dr. Thomas was not involved in the study.

The patients who didn't fare well after transplantation were those who were unable to tolerate their antiretroviral drugs after the operation; who had reduced levels of CD4+ cells, and those who had increased levels of HIV in their blood after transplantation. However, none of those conditions prior to transplant could predict if the patients would have a successful outcome, Dr. Ragni said.

"The study is important," said Scott Holmberg, MD, senior medical epidemiologist for the Centers for Disease Control and Prevention in Atlanta, Georgia, "because it addresses an issue that is larger than just liver transplants. It has to do with surgery for anything."

Dr. Holmberg, who was not involved in the study, told Medscape that in the days before HAART surgeons were reluctant to perform major operations on HIV-infected people. "They figured, 'What's the point? They are not going to live long enough to derive any benefit from it.' But this report is among a host of studies that have been done over many years that shows that, yes, you can operate on these people and yes, they can benefit from these big operations."

Dr. Holmberg said that because HIV infection has become medically manageable, patients should be offered operations such as coronary artery bypass surgery and transplantation procedures.

"HIV is the fifth leading cause of end-stage renal disease and surgeons are reluctant to do kidney transplants," Dr. Holmberg said, "Yet, we know that HIV-infected people will do well on those operations too. There is no particular reason to withhold these surgical options for HIV-infected people."

Hepatitis C Infections May Come From Routine Dentistry
By Kate Foster

Thousands of people infected with the life-threatening hepatitis C virus may have caught it during routine dental treatment.

Health campaigners warned that current practices in dental surgery, including the way tools are sterilized, may not be rigorous enough to remove the risk of transmission of the highly infectious virus between patients.

Although intravenous drug use is the most common method of transmission, health workers say dental practices could be the source of infection for a "substantial number" of the 38 percent of sufferers for whom the source of infection is not known.

In Scotland, 10,000 people are known to be infected with the disease, which can cause liver disease and cancer and is 100 times more infectious than HIV.

But because sufferers can live for 20 years before showing any symptoms, experts believe that a further 25,000 Scots are unknowingly infected.

Jeff Frew, the secretary of Capital C, an Edinburgh-based support group for sufferers, said many people do not know how they became infected and he believes there is a risk of infection from dentists' tools.

His claims have been backed by Nigel Hughes, the chief executive of the British Liver Trust, who said the risk of infection from dental surgeries "could not be ignored".

Mr. Frew said "Many of our hepatitis C positive clients do not fall into any of the risk categories for catching the infection.

"Dental treatment is the only time when members of the public come into contact with blood and there's a huge throughput of patients receiving dental treatment every day. "

He added: "Although dentists sterilize their tool-heads, there is a risk of infection from the actual tools themselves, from the machinery that drives the tools. Blood could gather behind the drive mechanisms of tools, which could lead to transmission.

"In order for there to be no risk of infection, dentists would have to have two or three spare sets of tools in order to ensure all equipment was sterilized properly, and at the moment that is not the case.

"This is a public health concern of immense proportions."

According to figures from the Scottish Center for Infection and Environmental Health, 58 per cent of hepatitis C sufferers are known to have injected drugs. About 7 percent are thought to have picked up the virus during surgery, from blood transfusions, from sex with an infected partner or from receiving tattoos.

For 38 percent of sufferers, no information on the source of infection is available and campaigners believe that some people in this category may have been infected during dental treatment.

Mr. Frew added: "There are people who are infected who were not injecting drug users, who have not had blood transfusions, who do not have tattoos or pierced ears and who have only ever had one sexual partner. They must have got it from somewhere, but at the moment we do not know what the other sources are. I believe that most of them caught it during dental treatment, or at least the potential is there."

Mr. Hughes said: "One problem lies with the mechanical dental handpiece which sucks fluid, including blood and other matter, from the mouth. After treatment, if the dentist adheres to guidelines, it is flushed through very rigorously and left to rest for some time.

"It would be possible to catch hepatitis C in this way if the equipment is not rigorously cleaned and sterilized. There's always a distinct possibility, especially if the dental practice session is very busy."

However, Mr. Frew believes the day-to-day practice of dentists should be reviewed. He said: "It is up to the dental profession to prove that there is no risk and until they do we must assume that there is a risk. We can trust dentists to adhere to guidelines, but how can we keep track of how they carry out their day-to-day surgeries?"

...that cavity ain't so bad now is it?

February 19th, 2003

Bone Loss in Liver Transplant Patients

Decreased bone mineral density following liver transplantation is affected by vitamin D deficiency, cyclosporine use, and the duration of glucocorticoid therapy, find researchers in the February issue of Clinical Transplantation (Clin Transplant 2003; 17(1): 13-9)

Osteoporosis is a major cause of morbidity in liver transplant recipients. It is associated with multiple factors.

In this study, researchers from Israel evaluated bone mineral density (BMD), bone turnover and calcium-regulating hormones in 29 patients. Patients were assessed 2 to 12 years after liver transplantation for non-alcoholic liver disease.

Of the 29 patients, 15 were on immunosuppressive treatment with tacrolimus, and 14 with cyclosporine.

19 of 29 patients had decreased bone mineral density.

Overall, 11 patients were on prednisone, while 18 patients had stopped glucocorticoid treatment 6 months to 11 years prior to the study.

The team found that 19 patients had decreased BMD according to WHO criteria, 17 at the femoral neck and 13 at the lumbar spine.

Furthermore, 19 patients had a subnormal (<15 ng/ml) serum level of 25 (OH) D3. These patients had significantly lower BMD at the femoral neck.

The team determined that femoral neck BMD negatively correlated with serum parathyroid hormone level, length of the post-transplantation period, and duration of glucocorticoid treatment, regardless of its cumulative dose.

They also found that symptomatic fractures were less frequent in tacrolimus treated patients, than in cyclosporine users.

Dr Elena Segala's team concluded, "Decreased BMD is frequent following liver transplantation and is affected by vitamin D deficiency, cyclosporine use, and the duration of glucocorticoid therapy, but not by its cumulative dose".

"Achievement and maintenance of optimal vitamin D status and shortening of glucocorticoid treatment period may have a favorable effect on bone preservation."

February 20th, 2003

Antiviral Therapy Has Long-Term Benefits for Liver Recipients with Recurrent HCV

Combination therapy with interferon and ribavirin provides persistent suppression of hepatitis C virus (HCV) in selected patients after liver transplantation, French investigators have found. An absence of detectable HCV RNA in the graft at the end of antiviral therapy is a favorable prognostic indicator.

Dr. Thierry Bizollon, of Hotel-Dieu in Lyon, and colleagues reviewed the records of 54 patients who underwent liver transplantation for HCV cirrhosis. Serum HCV RNA, intrahepatic HCV RNA, and elevated serum alanine aminotransferase (ALT) levels were measured at least 6 months later. The patients received interferon plus ribavirin induction therapy for 6 months, then 12 months of ribavirin.

Ten men and four women had a sustained response to antiviral therapy, the group reports in the February issue of Gut (Gut 2003;52:283-287). A sustained response was defined as normal serum ALT levels each month for the first 6 months after therapy ended, as well as no serum HCV RNA at 6 months.

The research team followed these 14 patients for 3 years after withdrawal of antiviral combination therapy. In 13 of the 14 patients, no serum HCV RNA and no HCV RNA on the graft was detected at any time. The mean Knodell score for fibrosis remained relatively stable, and five patients had normal or near-normal scores.

These findings "very likely indicated eradication of the chronic HCV infection and subsequent interruption of the disease progression, with a low risk of further relapse of development of cirrhosis on the graft," Dr. Bizollon's group infers.

The patient who relapsed developed serum HCV RNA 7 months after the end of antiviral therapy and exhibited an increased serum ALT level at 22 months. He was the only patient of the 14 who exhibited positivity for HCV RNA on the graft at study entry.

"This case may suggest that the treatment does not completely suppress viral replication and very low replication rates remain in the compartment of replication-competent cells (mainly hepatocytes)," the investigators write.

They note that the patient had serum and graft HCV RNA, but no hepatitis, for 15 months. "This observation of late relapse raises the question of the cytopathogenicity of HCV for hepatocytes and suggests that mechanisms other than direct cytotoxicity may be implicated in HCV-induced graft damage."

Comparison of Fibrosis Progression in Chronic Liver Diseases

Rates of fibrosis progression differ markedly between the predominant causes of chronic liver disease, find researchers in the March issue of the Journal of Hepatology (J Hepatology 2003; 38 (3): 257-65, 357-60).

. Liver fibrosis progression rates and risk factors in chronic liver diseases have not been compared. This would enable better organization of screening strategies.

In this study, an international team of researchers retrospectively studied

4852 patients. Of these, 2313 had chronic hepatitis C (HCV), 180 HIV-HCV co-infection, 777 hepatitis B (HBV), 701 alcoholic liver disease (ALD), 406 primary biliary cirrhosis (PBC), 383 genetic hemochromatosis (GH), 57 auto-immune hepatitis (AIH), and 35 delta hepatitis.

The research team estimated fibrosis progression rates from birth and from the date of exposure, when known, to the first biopsy.

Highly significant differences were found in the rates of fibrosis progression.

The team found highly significant differences in the rates of fibrosis progression.

The most rapid was in patients with HIV-HCV co-infection, and the slowest in patients with PBC.

The team found that fibrosis progression accelerated with aging.

Furthermore, fibrosis progression was slower in females, compared with males for HCV, HBV, GH, and PBC.

In contrast, in ALD, the fibrosis progression was more rapid in females.

Dr Thierry Poynard's team concluded, "Rates of fibrosis progression differ markedly between the predominant causes of chronic liver disease, and according to age and gender".

"Patients with HIV-HCV co-infection are at particularly high risk of fibrosis progression."

In a related editorial in the same publication, Dr William Rosenberg discusses the rating of fibrosis progression in liver disease.

He discusses the difficulty of accurately measuring fibrosis progression.

Dr Rosenberg concludes by stressing the need for "reliable, reproducible, non-invasive surrogate indicators," possibly serum markers.

NPS Pharmaceuticals and Enzon Pharmaceuticals Agree to Merger of Equals

NPS Pharmaceuticals, Inc. and Enzon Pharmaceuticals, Inc. announced today that they have signed a definitive agreement to a merger of equals in a stock-for-stock transaction with a value of approximately $1.6 billion. Under terms of the agreement, each Enzon shareholder will receive 0.7264 shares of the new company's common stock for each Enzon share owned. Each NPS shareholder will receive 1.00 share for each NPS share owned. The combination will create a powerful, integrated biotechnology company featuring demonstrated research capabilities, extensive drug development and manufacturing expertise, an innovative product pipeline, established commercial infrastructure, and a strong and growing revenue base.

NPS and Enzon will combine management and scientific talent to create a new biotechnology leader. The new company will have one of the industry'sdeepest and most innovative drug discovery and development pipelines addressing opportunities in areas of unmet therapeutic need, combined with a number of powerful revenue generators and over $300 million of cash. The company will be headquartered in Bridgewater, New Jersey, and will maintain major research, development and manufacturing facilities in Salt Lake City, Utah; Toronto, Canada; Indianapolis, Indiana, and additional locations in New Jersey. Dr. Hunter Jackson, currently the Chairman, President and CEO of NPS, will serve as Executive Chairman of the new company, and Arthur J. Higgins, Enzon's Chairman, President and CEO, will serve as the new company's Chief Executive Officer. Teams from both companies have begun planning the post-merger integration process, which will include introducing a new name.

"Combining NPS's tremendous research and development capabilities with Enzon's commercial and operating expertise will empower us to create a truly integrated team addressing all aspects of operations. Our combined strength will enable us to maximize success across a broad range of opportunities," said Dr. Jackson. Mr. Higgins added, "Our new entity will possess all of the necessary elements to emerge as a new biotechnology leader. With a high-potential product pipeline, a growing revenue base, and a commitment to disciplined execution, we are positioned for sustainable growth and expect to reach profitability in 2006 or before."

Marketed Products

Building on its established commercial organization, including a hospital-based sales force and a focused specialty oncology sales team, the newly formed company will immediately benefit from estimated revenues of approximately $200 million for the year ending December 31, 2003. Company revenues will be driven by four internally marketed products, as well as free cash flow due to royalties on PEG-INTRON(R). The line-up of marketed products includes:

* PEG-INTRON: a longer-acting form of INTRON(R) A (interferon alfa-2b, recombinant) is used in the treatment of chronic hepatitis C. This product uses proprietary PEG technology developed by Enzon and is marketed by Schering-Plough. * ABELCET(R): an antifungal used in hospitals to treat patients with invasive fungal infections related to cancer, organ transplantation and other conditions. * ONCASPAR(R): a PEG-enhanced version of a naturally occurring enzyme called L-asparaginase used in conjunction with other chemotherapeutics to treat patients with acute lymphoblastic leukemia. * DEPOCYT(R): an injectable chemotherapeutic for the treatment of patients with lymphomatous meningitis. * ADAGEN(R): a PEG-enhanced enzyme replacement therapy that is used for the treatment of severe combined immunodeficiency disease, or SCID, also known as the "Bubble Boy Disease."

Its revenue stream, in combination with a strong cash position, will create the unusual but invaluable flexibility to selectively choose how it commercializes its late stage pipeline, and optimizes the value of its product development opportunities.

Pipeline Highlights

A distinguishing characteristic of the company is its combined pipeline addressing significant unmet medical needs, including:

Two Phase III programs: PREOS(TM) for the treatment of osteoporosis, and cinacalcet HCl, which is being developed by Amgen for the treatment of secondary hyperparathyroidism. * Three Phase II programs: PROTHECAN(R) for various solid tumors; ALX-0600 for Short Bowel Syndrome and other gastrointestinal disorders; and cinacalcet HCl for primary hyperparathyroidism. * Over 10 specific early stage programs addressing unmet medical needs in endocrinology, immunology, oncology, neurology, and gastroenterology. Upon completion of the merger, the candidate portfolio will be reviewed and resources will be focused on the most promising programs.

February 21st, 2003

Pegylated Interferon Associated with Eye Disorders
By Brian Boyle, MD - hivandhepatitis.com

Ophthalmologic (eye) disorders have been recognized as potential side effects of interferon-alpha (IFN). These disorders include reports of retinal vascular occlusions, retinal hemorrhages, and cotton wool spots (CWS) and, uncommonly, potentially sight threatening optic neuropathy.

In an open-label prospective trial conducted at the National Institutes of Health (NIH), HIV/HCV co-infected patients were treated with PEG-Intron (Pegylated-IFN alfa-2ß) and Rebetol (ribavirin) 48 weeks. These patients had ophthalmologic evaluations at baseline and at least every 3 months, which included visual acuity, threshold visual field testing, color vision exam, and indirect ophthalmoscopy.

The investigators found that 7 of the 16 patients enrolled in the study (44%) developed ophthalmologic pathology. Six (6) developed cotton wool spots (CWS) on their 12 week follow-up funduscopic examination, which "waxed and waned" while PEG-Intron therapy was continued.

In addition to CWS, 1 of these patients was found to have bilateral cataracts at 12 weeks, while another patient subsequently developed a unilateral cataract. Finally, 1 patient developed a 50% decrease in color vision requiring cessation of PEG-Intron therapy. This patient's color vision improved over the 4 weeks following PEG-Intron discontinuation, but did not return fully to normal.

The authors conclude, "The incidence of serious ocular pathology associated with treatment with anti-HCV therapy may be very high and is likely associated with peg-IFN. While HIV, hypertension, and diabetes mellitus are associated with these ocular lesions, incident cases of CWS and cataracts occurred in pts with high CD4+ T-cell counts and developed soon after beginning peg-IFN therapy.

"As with patients treated with ethambutol, medications toxic to retinal ganglion cells can cause lesions such as optic neuropathy and result in color blindness or loss of vision.

"Our findings suggest a need for increased vigilance in monitoring pts treated with peg-IFN for visual changes. Color vision testing should be a routine component of the standard examination, as loss of color vision may be a harbinger of serious optic neuropathy."

Final Results of 68-Site Trial of Daily vs Weekly Interferon plus Ribavirin in Treatment-Naïve Patients Co-infected with HIV
From hivandhepatitis.com

Hepatitis C virus (HCV) infection may cause substantial morbidity and mortality in individuals with HIV infection. Few studies have evaluated the safety and efficacy of combination interferon (IFN)/ribavirin (RBV) in HIV-HCV co-infected patients.

In this multicenter (68 sites), randomized, controlled trial, researchers assessed the efficacy and safety of RBV in combination with daily (QD) or 3 times weekly (TIW) IFN for chronic HCV in HIV co-infected patients. The final (48 week) results were presented at the 10th CROI in Boston.

The trial compared compared IFN 3 mIU QD vs TIW + RBV (800 mg/d) for 48 wks in 180 IFN/RBV-naïve, HIV-infected pts with compensated liver disease on stable antiretroviral therapy (ART).

Those with active OIs, active substance abuse, severe psychiatric disease, or CD4 < 100/mm3 were excluded.

Efficacy (HCV RNA) was assessed at treatment (Tx) wks 12, 24, and post-Tx wk 24. Safety assessments included incidence of AEs, rate of dose modification/discontinuation. CD4 count and HIV RNA levels were monitored.

Patient characteristics (QD/TIW) were as follows: mean age, 44/44 yrs; male, 78/74%; Caucasian, 58/44%; genotype 1, 78/80%; ART, 89/82%, mean CD4, 551/533/mm3, mean HIV RNA, 1,531/3,698 c/mL.

A total 162 (79 QD/83 TIW) were eligible for the intent-to-treat (ITT) analysis.

Discontinuation for AEs was similar in both groups; however, more pts taking QD IFN completed 48 wks of Tx (30.0% QD vs 12.0% TIW, p = 0.0003) since 43.4% of pts taking TIW IFN stopped due to virologic failure compared to only 20.2% of those taking QD IFN. The trial participants were administered interferon alfa-2b (Intron A) plus ribavirin (Rebetol) from Schering-Plough.

HCV RNA response (undetectable < 600 IU/mL) was assessed at week 12 (EVR) and wk 24 post-Tx (SVR).

On-treatment results: EVR QD 44.3%/TIW 17.1% (p = 0.004); SVR: QD 42.9%/TIW 28.% (p = 0.03). Intention to treat results: EVR: QD 32.9% /TIW 13.3%; SVR: QD 9.3%/TIW 4.3% (note: missing data = failure).

No significant effect was seen on HIV RNA levels; absolute CD4 fell in both groups (QD > TIW), but no decrease in CD4% was observed. EVR was a strong predictor of SVR (90.9% sensitivity, NPV 93.9%).

Conclusions: Both EVR and SVR were significantly greater in HIV-infected pts taking QD IFN/RBV than in those taking TIW IFN/RBV. The adverse event rate was similar in both groups; however, more pts taking QD IFN completed Tx. However, the attrition rate for both Tx arms was substantial, and the intention-to-treat SVR rates observed were low.

Interferon Therapy after Tumor Ablation Associated With HCV

After tumor ablation by ethanol injection, interferon therapy may enhance patient survival in patients with hepatitis C, find researchers in the latest issue of Annals of Internal Medicine (Ann Intern Med 2003; 138: 299 - 306).

. After the surgical or medical treatment of hepatocellular carcinoma, further tumors frequently develop, leading to poor prognosis.

In this study, researchers from Japan assessed whether combined tumor ablation and interferon therapy can reduce the occurrence of new tumors, thus improving survival.

The team performed a randomized, controlled study.

Rates of second or third recurrence were lower in the interferon group.

They included 74 patients with compensated cirrhosis, 3 or fewer nodules of hepatocellular carcinoma, and low hepatitis C virus RNA loads (<2 x 106 copies/ml) in the study.

Once patients had complete ablation of lesions by percutaneous ethanol injection therapy, 49 patients were assigned to receive 6 million U of interferon 3 times weekly for 48 weeks. A further 25 patients did not receive treatment.

The researchers analyzed abdominal ultrasonography, computed tomography, and determination of blood biochemical measures.

Of the 49 patients treated with interferon, 21 showed a sustained biochemical response, while a further 14 had a sustained virologic response.

The team found that the rate of first recurrence of new foci of hepatocellular carcinoma was similar in both interferon treated and untreated patients.

However, rates of second or third recurrence appeared to be lower in the interferon group, than in the untreated group.

Patients treated with interferon had a survival rate of 68% at 5 years and 53% at 7 years. In comparison, untreated patients had a survival rate of 48% at 5 years and 23% at 7 years.

Dr Yasushi Shiratori's team concluded, "After tumor ablation by ethanol injection, interferon therapy may enhance patient survival in selected patients with chronic hepatitis."

Rate of Natural Disease Progression in Patients with Chronic Hepatitis C

Researchers from France and the United States find that an interval of 4 to 5 years is needed between liver biopsies to measure change in patients with mild liver disease.

The interval at which liver biopsy should be repeated in untreated patients with chronic hepatitis C is not defined.

In this study, researchers examined fibrosis change by METAVIR scoring in patients who had 2 or more liver biopsies.

The team's findings are published in the March issue of the Journal of Hepatology (J Hepatology 2003; 38(3): 307-14)

. The research team studied 180 patients with histologically proven chronic hepatitis C.

They found that the mean interval between biopsies was 3.67 years. This interval was 3.08 years in the 16 patients who had had 3 biopsies.

The team performed univariate and multivariate analyses to determine factors associated with liver fibrosis progression.

The mean interval between biopsies was 3.67 years.

They found that the median rate of fibrosis progression per year was 0.04 to first biopsy, 0 between first and second biopsy, and 0.17 between second and third biopsy.

Multivariate analysis determined that age at first biopsy >40 years (OR=5), and alcohol consumption of 1 to 50 g per day (OR=4), and more than 50 g per day (OR=8) were the only factors associated with severe fibrosis.

The team found that the number of patients who increased in fibrosis stage was significantly higher after 4 years.

Dr Jean-Pierre Zarski's team concluded, "An interval of at least 4 to 5 years is needed between liver biopsies to measure change in patients with mild liver disease."

February 24th, 2003

HCV Infection Identified as Risk Factor for Other Infections

Compared with subjects not infected with hepatitis C virus (HCV), infected patients are at increased risk for infection with a variety of pathogens, including TB, according to a recent report.

The findings are based on a study of 34,204 HCV-infected patients and 136,816 control subjects who were hospitalized at Veterans Affairs' medical center between 1992 and 1999.

HCV-infected patients were more likely than controls to be infected with HIV and with hepatitis B virus, Dr. Hashem B. El-Serag, from the Houston VA Medical Center, and colleagues note in the January issue of the American Journal of Gastroenterology (Am J Gastroenterol 2003;98:167-174.). HCV-infected patients were at increased risk for several immunodeficiency-related infections, including cytomegalovirus (CMV) infection, toxoplasmosis, cryptococcosis, and tuberculosis.

In terms of sexually transmitted diseases (STDs), HCV-infected patients were at increased risk for gonococcal infection, chlamydia, syphilis, and genital herpes, the researchers note. Compared with control subjects, HCV-infected patients were also at increased risk for a variety of bacterial infections, including peritonitis, endocarditis, sepsis, cellulitis, and carbuncles.

After excluding patients with possible immunodeficiencies, the authors found that CMV infection, cryptococcus, tuberculosis, and STDs were still significantly associated with HCV infection.

"Most health care providers are aware of the risk of peritonitis and sepsis in those with chronic liver disease but are not generally aware of the association between HCV and STDs, tuberculosis, and several immunodeficiency-related infections," the investigators note. "We recommend that extra care be taken in examining and testing, where appropriate, HCV-infected patients for these infections."

February 25th, 2003

Drug Addicts Would Use Injection Facility: Survey

More than a third of injection drug users say they would make use of medically supervised safer injecting facilities (SIFs) if such centers were available, according to a survey conducted in Canada.

"It seems clear from our study in the North American context that safe injection sites will reach precisely those people who need it most, namely those at highest risk of HIV and hepatitis C exposure," Dr. Martin T. Schechter of the University of British Columbia, Vancouver, told Reuters Health. Schechter and colleagues note that SIFs, which now operate in 26 European cities and in Australia, have been credited with improving health and reducing overdose deaths and the risk of HIV. Such facilities do not provide drugs, but do give addicts clean injecting equipment, overdose treatment and access to health care and other services. In the survey of 587 injection drug users from the Vancouver area, 37% said they would attend an SIF, 14% were unsure and 49% said that they would not attend. Drug users who were more willing to attend also tended to have difficulty obtaining sterile syringes, required help injecting and were likely to inject in public. In fact, 52% of public injectors said that they would be willing to use a SIF, according to the report in the Journal of Acquired Immune Deficiency Syndromes. "These data indicate a high potential for immediate community and public health benefits if SIFs were presently available," the authors conclude.

Schering-Plough Boosts Litigation Reserves

Schering-Plough Corp. (SGP) reduced its reported fourth-quarter and year earnings by $115 million, or 8 cents a share after boosting its litigation reserves by $150 million.

In a press release Tuesday, the pharmaceutical concern said it restated fourth-quarter earnings as $313 million, or 21 cents a share, citing an adjustment to its estimate of minimum liability related to federal investigations into the company's marketing, sales and clinical trial practices. The company reported previously fourth-quarter earnings of $428 million, or 29 cents a share.

Schering-Plough also reduced its reported earnings for 2002 to $1.97 billion, or $1.34 a share, from $2.09 billion, or $1.42 a share.

Schering-Plough said it boosted the reserves "as a result of "additional information" and ongoing review of the litigation, which it reported in filings with the Securities and Exchange Commission Tuesday and in November.

In the filings, the company said it was served with two additional grand jury subpoenas by the U.S. Attorney for Massachusetts in November. The office had been investigating the company's sales, marketing and clinical trial practices for its hepatitis C treatments Intron A and Rebetron and brain tumor treatment Temodar.

The company was also named in a probe by the U.S. Attorney's office for the Eastern District of Pennsylvania that has been ongoing since 1999. That investigation focuses on whether drug makers provided pharmaceuticals at a deep discount or for free to managed care plans to ensure its drugs were on the health management organizations' formulary, a list of drugs the HMO will reimburse for.

Schering-Plough noted that its total litigation reserve is just an estimate and any final resolution of the investigations may be less than or materially exceed the reserves, and could hurt the company's results of operations or financial condition.

A Schering-Plough spokeswoman declined to comment on the "additional information" beyond the company's filings with the SEC.

The company's New York Stock Exchange-listed shares traded recently at $17.38, down 47 cents, or 2.7%, on composite volume of 3.1 million shares. Average daily volume is 5.6 million shares.

February 26th, 2003

Roche Says Pegasys Sales Off To a Strong Start

Roche Holding AG (ROCZg.VX) said on Wednesday its key new hepatitis C drug Pegasys had got off to a strong start, taking more than 50 percent of the market in Germany and Britain five months after launch.

In its home market of Switzerland, together with Brazil and Mexico, where the product has been on sale for six months, the market share was around 70 percent, Roche's head of pharmaceuticals William Burns told analysts.

In the United States, the world's biggest market, the company had taken a market share of 23 percent of new prescriptions in just two months, he added.

Burns also increased his guidance for peak sales of the company's top cancer drug Mabthera to 3.5 billion Swiss francs ($2.57 billion). Mabthera sales rose 48 percent in local currencies to 2.3 billion francs in 2002.

February 27th, 2003

Complications Common among Living Adult Partial Liver Donors
By Will Boggs, MD

Although mortality among adult liver donors is low, complications are relatively common, according to a report in the February 27th issue of The New England Journal of Medicine (N Engl J Med 2003;348:818-825).

The shortage of cadaveric livers for adult transplantation has prompted the use of living donors for adult liver transplant recipients, the authors explain. The larger right lobe can be safely removed from the donor, and living donation now accounts for approximately 5% of liver transplantations performed in adults. However, information about the morbidity and mortality of donors and recipients is lacking.

Dr. Robert S. Brown, Jr. from Columbia University College of Physicians and Surgeons in New York and colleagues surveyed US programs registered with the United Network for Organ Sharing (UNOS) that perform adult-to-adult liver transplantation from living donors.

The 84 responding centers performed 449 adult-to-adult liver transplants from living donors between 1997 and 2000, the results indicate, with the number of such transplants rising from 1 in 1997 to 266 in 2000.

In only half of the programs did potential donors see a physician who was not a part of the transplant team, the authors report, and only 17% of programs had potential donors evaluated by an ethicist.

Most living donors (74.4%) were genetically related to the recipient, the report indicates, the rest being friends (13.4%), spouses (10.9%), or "good samaritans."

Although only one death had been reported at the time of the survey (for a 0.2% death rate), 65 of the 449 donors (14.5%) experienced one or more complications of donation, the investigators note, including bile leak (in 27 donors), the need for blood transfusion, and the need for reoperation.

Partial liver donation was associated with a median length of stay for donors of 0.25 days in the intensive care unit and 6 days in the hospital, the results indicate.

"Living donor procedures are growing in frequency and are safe, with low mortality but significant morbidity," Dr. Brown told Reuters Health. "There is a need for a registry and outcomes study to define the long-term outcomes and risks of the procedure, as currently there is no standardization."

Living donation "is here to stay and saves lives," Dr. Brown concluded. "More effort is needed to improve cadaveric donor rates and to prevent liver disease, [thereby diminishing] the need for living donor surgeries."

Cost Comparison of Living-Donor and Cadaveric Liver Transplantation

The total comprehensive cost of living-donor liver transplant is slightly higher than for cadaveric transplantation, finds a research team in the latest issue of Transplantation (Transplantation 2003; 75(4): 473-76).

A long-term consideration for living-donor liver transplantation (LDLT) is the expense, compared with cadaveric-liver transplantation.

LDLT is a more complex procedure than cadaveric transplantation. The cost of donor evaluation, surgery, and postoperative care must be included in a cost analysis for LDLT.

Total cost of transplantation:
- Living-donor = 162.7 cost units
- Cadaveric = 134.5 cost units

In this study, researchers from the United States compare the comprehensive cost of LDLT with that of cadaveric-liver transplantation.

The research team evaluated all costs for medical services provided at their institution for 24 LDLT and 43 cadaveric recipients. Patients had greater than 1 year follow-up, and were transplanted between 1997 and 2000.

Donor costs included donors evaluated and rejected or accepted, donor right hepatectomy costs, and donor follow-up costs.

In addition, LDLT and cadaveric recipient costs included medical care 90 days pre-LDLT, recipient transplant costs, and follow-up costs, including retransplantation.

The team expressed cost as an arbitrary cost unit (CU), valued between $500 and $1,500.

Total LDLT costs equaled 162.7 CU.

In comparison, total cadaveric transplant costs equaled 134.5 CU

Dr James Trotter's team concluded, "The total comprehensive cost of LDLT is 21% higher than cadaveric transplantation, although this difference is not significant."

February 28th, 2003

Lamivudine Can Help Some Chronic Hepatitis B Patients with Hepatic Decompensation
By Harvey McConnell

Lamivudine therapy can be effective in treating chronic hepatitis B patients with hepatic decompensation, but effectiveness depends on patient bilirubin levels.

This has been found by clinicians at Chang Gung University, Taipei, Taiwan, who investigate the effect of lamivudine therapy in hepatic decompensation during severe acute exacerbation (AE) of chronic hepatitis B (CHB). The conditions can lead to hepatic decompensation and death. The data is published in the Journal of Hepatology 2003 Mar;38(3):322-7.

Over a 10 month period, the clinicians enrolled 60 consecutive AE patients with jaundice, with prolonged prothrombin time over 3s, who were treated with lamivudine at 150 mg daily. Controls were 31 CHB patients with AE which had resulted in their being hospitalised because of hepatic decompensation in the preceding six months.

Both groups of patients had comparable clinical and biochemical features. After a median treatment period six weeks (range 1 to 48 weeks), all of the 25 patients in the treatment group with bilirubin level before therapy of <20mg/dl survived. Five (25%) of 20 patients in the control group died. At the same time, the mortality rate was similar among patients with bilirubin level before therapy >/=20mg/dl in both groups.

The clinicians said their results suggest that lamivudine may prevent fatality in CHB patients with hepatic decompensation if therapy starts early enough or before serum bilirubin level rise over 20mg/dl. But such therapy will be of little use if serum level already risen over that level.

Roche CEO Sees Advantages for New Hepatitis C Drug
By Jed Seltzer

Roche Holding AG's top official said Friday he expects the Swiss drugmaker to capture half of the global market for Hepatitis C drugs with its new treatment for the disease.

The therapy, called Pegasys, is one of two highly anticipated drugs being rolled out by Roche, along with Fuzeon for HIV and AIDS.

Roche said it has already captured 50 percent of the market in Germany and Britain just five months after launch, and more than that in Switzerland, Brazil and Mexico. In the United States, the world's most lucrative drug market, Pegasys has 23 percent of new prescriptions two months after launch.

Schering-Plough Corp. makes the major competing product, called Peg-Intron, and Roche has priced its treatment lower to undercut Schering-Plough. But the big hurdle for both companies is reaching previously untreated patients, which comprise a majority of the potential hepatitis C market.

"Our first goal is to achieve 50 percent of the current market and then we start expanding the market,'' said Chairman and Chief Executive Franz Humer.

He noted that in the United States, for example, only about 80,000 to 100,000 patients sought treatment for Hepatitis C last year out of a total of 2.5 million afflicted with the liver disorder.

The hepatitis C virus is one of the largest causes of chronic liver disease, which in its most serious forms can lead to infections and deadly liver cirrhosis.

Pegasys could garner annual sales of $1.8 billion by 2006, according to SG Cowen. Schering-Plough's line of hepatitis products generated $2.7 billion in sales last year. Both Pegasys and Peg-Intron are combination therapies.

MARKET EXPANSION

Arrival of a second product in the Peg-interferon class -- in which both therapies last longer in the body than previous therapies, necessitating fewer injections -- should expand the market by allowing re-treatment of patients who have failed initial treatment.

So patients who don't respond to Peg-Intron can try Pegasys and those who fail on Pegasys can start on Peg-Intron.

Humer said Pegasys boasts advantages over Peg-Intron that could help draw in previously untreated patients. The company will simultaneously market a device to discern whether Pegasys has been effective after 12 weeks of therapy - an improvement over the 24 weeks it generally takes to tell whether Peg-Intron has worked.

"One of the advantages we have is the combination of the Peg with the therapy and the predictability of the efficacy of the therapy after 12 weeks rather than 24 weeks,'' Humer said. ''And people feel more at ease with our therapy in terms of side effects and injection-site reactions.''

Analysts say ability to ascertain early which patients respond to Pegasys could be a key economic advantage.

But published data shows that some patients do not show a significant reaction to therapy until after the 12-week period, meaning that it is worth keeping them on the treatment for a longer period of time to see if it works.

Pegasys is a prime example of Roche's strategy to further integrate the use of its diagnostic tools with medicines.

The second-largest Swiss drugmaker, which owns about 58 percent of U.S. biotechnology company Genentech Inc., sells a diagnostic system to determine in what cases Genentech's Herceptin drug would aid breast cancer patients.

Roche on Wednesday reported a net loss for 2002 but estimated 2003 sales would rise by a percentage in the double digits, boosted by Pegasys and Fuzeon and its diagnostics business.

March 1st, 2003

Inmates Not Entitled To Hepatitis C Treatment
By Eric Newhouse

A split Montana Supreme Court has refused immediate help for the state's 900 prison inmates who aren't being treated for hepatitis C.

Inmate Keith A. Brown filed the petition seeking treatment of hepatitis C, one of the leading causes of liver disease in the United States. "We recognize the seriousness of the medical issue that Brown has raised, but are unable to grant relief given the state of the proceeding before us," said a four-judge majority led by Chief Justice Karla Gray.

Justices Terry Trieweiler, James Nelson and William Leaphart dissented from Tuesday's majority opinion.

"We ignore the state's statutory obligation to provide treatment; we enable the violation of Brown's fundamental constitutional rights; and we demean the notion that we live in a 'civilized' society," wrote Nelson and Leaphart.

About 4 million Americans have been exposed to hepatitis C, or about 1.8 percent of the population. That jumps to between 14 and 40 percent of the nation's prisoners, Dr. Anne Spaulding of the Centers for Disease Control in Atlanta said in a telephone interview Friday.

"We tend to house a lot of people with high risk-factor histories in our prisons," explained Dr. Rob Lyerla, one of the authors of a recent CDC report on preventing hepatitis in prisons. The CDC said 25,000 to 40,000 new cases of hepatitis occur annually, and that 60 percent of them are caused by injection drug use.

In Montana, about 30 percent of the state's 2,750 inmates have hepatitis, said Dr. Liz Rantz, chief medical officer for the Department of Corrections. There's no treatment provided for most of those 900 inmates, she said. That's because there's no effective vaccine for hepatitis C. It can be treated with interferon, she said, but there's only about a 40 percent success rate, the side effects can be awful, and a full year's treatment can cost close to $20,000 an inmate.

"There's no way we could go to the Legislature and say we want to treat every inmate with hepatitis C," said Rantz.

She said she currently is developing procedures to identify long-term inmates who might be susceptible to treatment. "We couldn't treat every inmate who just happened to be passing through the system for a year or two," she said.

In his petition, Brown charged that he is dying a slow, painful death at the regional prison in Missoula and asked the high court to either impose an immediate death sentence, grant him a medical parole or order medical treatment in prison.

"The factual uncertainty of this matter, including the nature of Brown's diagnosis, his susceptibility to treatment, and the availability of treatment, require factual resolution," said the majority.

"It is clear that this proceeding does not establish the necessary factual basis for these issues," it added.

But Spaulding said the success rates have been better for a treatment that combines pegylated interferon and ribavirin.

And she said some prison systems have gone to bulk buying, which can reduce the cost.

But cost should not be a factor, said the Supreme Court. "This court will not countenance the failure to provide appropriate treatment for an infected inmate on the basis that the department has insufficient resources to do so," said the majority opinion.

Justice Trieweiler dissented on the grounds that the majority didn't offer any help since Brown is a prisoner, not a lawyer.

"To acknowledge that there are issues in this case which require litigation and resolution by a trial court is to acknowledge that Brown has no remedy at law," wrote Trieweiler. "It's to condemn him to death for the nonviolent offense for which he was imprisoned.

"Worse than that, the court's order puts at risk one-third of the prison population whose only hope now is that they can serve their sentence before they die from a disease which, if untreated, gradually destroys their livers."

Trieweiler concluded that the majority stance was hypocritical. "Hepatitis C and the state's refusal to treat it is turning Montana's prisons into potential death camps," he wrote. He said this country fought a war to eliminate death camps and then severely criticized the citizens of those societies for not doing more to end their operation.

"It seems to me that as a society, we have too quickly put the lessons from that experience behind us," concluded Trieweiler.

The New AIDS Fight Don't Forget This Infectious Killer
By Ponsiano Ocama and William M. Lee

AIDS deserves our attention. But so, too, does another infectious disease, one that in the developing world is even more widespread than AIDS-hepatitis.

Worldwide, 400 million people have hepatitis B, 10 times the number of AIDS cases, and 170 million have hepatitis C. Both cause chronic liver infection that can be fatal, especially in developing countries where treatment is rare and a liver transplant is beyond almost everyone's means. Hepatitis B and C are implicated in 80 percent of cases of liver cancer, the fourth most common cause of cancer deaths worldwide. Cancer resulting from these viruses appears to be increasing in most developing countries as well as in the United States.

While aggressive testing and prevention programs have slowed H.I.V. transmission rates in some countries, the spread of hepatitis in the developing world continues unabated. In Uganda, for instance, H.I.V. infection rates have diminished greatly because of public health programs that encourage safe-sex practices. The prevalence of H.I.V. there has declined from 30 percent of Ugandans in 1992 to 5 percent in 2002.

Over the same period, however, the rate of hepatitis B remained steady, and is now found in 12 percent to 15 percent of the population, three times the number infected with H.I.V. The true extent of hepatitis C in Uganda and the rest of Africa is still unknown because testing, though common for more than 10 years in the United States, has not yet become readily available in developing countries.

The lack of testing and treatment means that the disease will continue to spread as the infected unwittingly pass it on to their sexual partners, newborns and to hospital patients via blood transfusions. In the case of hepatitis B, the virus can be spread through living with a infected person.

Fortunately, it is possible to treat, and sometimes cure, people with hepatitis B and C. For that to happen in the developing world, however, testing must be made inexpensive, readily available and reliable. Seeing to it that tests are available at blood banks will lead to a reduction in hepatitis C transmission, as has been the case with H.I.V. and hepatitis B. Focusing on infected sex workers and pregnant women would be a cost-effective way to cut down on the transmission rates. Some drugs being used in Africa against H.I.V. can also be used against hepatitis B. Treating H.I.V. without at the same time diagnosing and treating hepatitis B or C co-infection is foolish.

The push for hepatitis B vaccination is beginning in Uganda and elsewhere; the bad news is that there is not yet a vaccine for hepatitis C. Until such vaccines are widely available, hepatitis, as well as AIDS, deserves the world's attention.

Prisoners Not Entitled To Hepatitis Treatment, Court Rules

Montana's Supreme Court has denied a prisoner's petition for hepatitis C medication and returned the case to a lower court.

The divided court said it wanted an official determination of whether inmate Keith A. Brown's diagnosis is correct. The justices also asked for a determination on whether an effective treatment exists for hepatitis C .

"We recognize the seriousness of the medical issue that Brown has raised, but are unable to grant relief given the state of the proceeding before us," said a four-judge majority led by Chief Justice Karla Gray.

The opinion acknowledged authorities have a responsibility to care for wards of the state, and that money should not affect that responsibility. But that wasn't enough for Justice Terry Trieweiler, one of three dissenting members, who wrote that the court is acknowledging the law cannot help Brown.

"It's to condemn him to death for the nonviolent offense for which he was imprisoned," Trieweiler said of the Supreme Court's ruling. "Worse than that, the court's order puts at risk one-third of the prison population whose only hope now is that they can serve their sentence before they die from a disease which, if untreated, gradually destroys their livers."

Justices James Nelson and William Leaphart joined the dissent and said the majority opinion demeans the idea of living in a civilized society.

Brown contends he is dying a slow, painful death in custody and asked justices to impose an immediate death sentence, grant him a medical parole or order medical treatment in prison.

About 30 percent of Montana's 2,750 inmates suffer from a form of hepatitis, the Department of Corrections says. Hepatitis C is one of the leading causes of liver disease in the United States. The Centers for Disease Control estimates between 14 and 40 percent of the nation's prisoners have been exposed to hepatitis C , many of them the result of injection drug use.

Dr. Liz Rantz, chief medical officer for Montana's prison system, says there's no effective vaccine for the disease. It can be treated with interferon, she said, but there's only about a 40 percent success rate. The treatment also has serious side effects and can cost almost $20,000 for each inmate.

"There's no way we could go to the Legislature and say we want to treat every inmate with hepatitis C ," said Rantz.

She said she is developing a way to identify long-term inmates who might be susceptible to treatment.

The CDC's Dr. Anne Spaulding said success rates have been better for a treatment that combines pegylated interferon and ribavirin. Spaulding said some prison systems have gone to bulk buying, which can reduce the cost.

March 3rd, 2003

Anadys Reports Completion of Phase IA Study of ANA245

Anadys Pharmaceuticals, Inc. ("Anadys") announced today that it has successfully completed Phase IA studies in healthy volunteers on its lead compound ANA245 for the treatment of Hepatitis C infection. The announcement was made by Devron Averett, Ph.D., Senior Vice President of Drug Development in a presentation entitled "Oral Interferon-like Compounds," at the AASLD Single-Topic Conference "Hepatitis C New Drug and Clinical Trials Development" held in Chicago, Illinois. Hepatitis C virus (HCV) infection is a disease that affects 4 million people in the United States and an estimated 170 million people worldwide.

Anadys expects to initiate Phase IB studies with ANA245 shortly. The Phase IB study is designed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of ANA245, following intravenous administration to patients chronically infected with hepatitis C virus.

"Completion of this Phase IA study is important for several reasons," said Kleanthis G. Xanthopoulos, Ph.D., President and CEO of Anadys. "It is Anadys' first compound into the clinic, and therefore represents a significant milestone for the company, as Anadys expands its drug development capabilities. Additionally, it is another step toward our goal of having a significant impact in the treatment of Hepatitis C. We look forward to additional successful clinical studies with this compound and the other candidates in our drug development pipeline. We hope that through our efforts, Anadys can eventually provide great benefits for people affected by Hepatitis C."

"Initiation of the ANA245 study was an important achievement for our company," said Dr. Averett. "The successful completion of the study offers early promise that we will one day be able to offer a novel therapeutic approach for the treatment of chronic HCV infection."

Anadys Pharmaceuticals, Inc. (www.anadyspharma.com) is committed to an integrated discovery and development process that generates novel and powerful anti-infective medicines that the Company intends to commercialize to advance patient care. Anadys' integrated approach, utilizing world-class expertise in drug discovery, lead optimization, and medicinal chemistry, is designed to propel a strong and continual pipeline of drug candidates into the clinic. The Company's primary therapeutic focus encompasses the antiviral and antibacterial market, which represents over $31 billion, with a significant opportunity for novel and improved therapeutics. Anadys has the ability to pursue traditional protein targets as well as underexploited targets including RNA and proteins of unknown function.

Adefovir Dipivoxil for the Treatment of Chronic Hepatitis B

Adefovir dipivoxil treatment results in significant histologic, virologic, and biochemical improvement in patients with chronic hepatitis B, find researchers in the latest issue of The New England Journal of Medicine (New Engl J Med 2003; 348(9): 800-7, 808-16) .

Adefovir dipivoxil, a nucleotide analogue, has shown significant antiviral activity in patients with chronic hepatitis B, in phase 1 and 2 clinical trials.

In this double-blind study, a team of international researchers assessed 185 patients with chronic hepatitis B, who were negative for hepatitis B e antigen (HBeAg).

The team randomized patients to receive either 10 mg of adefovir dipivoxil or placebo once daily for 48 weeks.

The team considered that the primary end point to be histologic improvement.

At week 48, 64% of patients who had base-line liver-biopsy specimens available in the adefovir dipivoxil group had improvement in histologic liver abnormalities. This compared with 33% of patients in the placebo group.

The researchers found reductions in serum hepatitis B virus (HBV) DNA levels in the adefovir dipivoxil group. HBV DNA levels fell to less than 400 copies per ml in 51% of patients in the adefovir dipivoxil group, but in none of those in the placebo group.

They determined that the median decrease in log-transformed HBV DNA levels was greater in the adefovir dipivoxil group, than in the placebo (3.91 versus 1.35 log copies per ml).

In addition, the team found that alanine aminotransferase levels had normalized at week 48 in 72% of patients receiving adefovir dipivoxil, compared with 29% those receiving placebo.

No HBV polymerase mutations associated with resistance to adefovir were identified.

Furthermore, the safety profile of adefovir dipivoxil was similar to that of the placebo.

Dr Stephanos Hadziyannis's team concluded, "In patients with HBeAg-negative chronic hepatitis B, 48 weeks of adefovir dipivoxil treatment resulted in significant histologic, virologic, and biochemical improvement, with an adverse-event profile similar to that of placebo".

"There was no evidence of the emergence of adefovir-resistant HBV polymerase mutations."

In a related study in the same publication, a second team of researchers assessed patients with chronic hepatitis B who were positive for hepatitis B e antigen (HBeAg).

In this study, the research team randomly assigned 515 patients to receive 10 mg of adefovir dipivoxil, 30 mg of adefovir dipivoxil, or placebo daily for 48 weeks.

The primary end point of the study was histologic improvement in the 10-mg group.

Patients showing histologic improvement:
- 10 mg adefovir = 53%
- 30 mg adefovir = 59%
- placebo = 25%

After 48 weeks of treatment, more patients who received 10 mg or 30 mg of adefovir dipivoxil, than who received placebo, had histologic improvement (53%, 59%, 25%, respectively).

In addition, patients in the adefovir dipvoxil group had a reduction in serum HBV DNA levels, undetectable levels (fewer than 400 copies per ml of serum HBV DNA, normalization of alanine aminotransferase levels, and HBeAg seroconversion.

Again, no adefovir-associated resistance mutations were identified in the HBV DNA polymerase gene.

The research team determined that the safety profile of the 10-mg dose of adefovir dipivoxil was similar to that of placebo.

However, in the 30mg group there was a higher frequency of adverse events and renal laboratory abnormalities.

Dr Patrick Marcellin's team concluded, "In patients with HBeAg-positive chronic hepatitis B, 48 weeks of 10 mg or 30 mg of adefovir dipivoxil per day resulted in histologic liver improvement, reduced serum HBV DNA and alanine aminotransferase levels, and increased the rates of HBeAg seroconversion".

"The 10-mg dose has a favorable risk-benefit profile for long-term treatment".

"No adefovir-associated resistance mutations were identified in the HBV DNA polymerase gene".

March 4th, 2003

Sen. Lindsay Calls for Drug Needle Exchange Program
By Melissa Drosjack

A Houston lawmaker wants to help prevent the spread of AIDS, hepatitis C and other diseases in Texas by establishing local hypodermic needle exchange programs.

Sen. Jon Lindsay (R-Houston), said locally run needle exchange programs could help the state save money that it might have to spend later on treating people with those diseases. "It's a cheap, preventative health care measure for very serious diseases," Lindsay said.

Under Senate Bill 438, local government clinics would exchange used hypodermic needles and syringes for the same number of clean hypodermic needles and syringes. The exchanges would be anonymous, and the programs would include initiatives on disease prevention and substance abuse treatment services.

Carolyn Parker, executive director and lobbyist for the Texas AIDS Network, said the legislation is important to help prevent the spread of disease. Disease prevention programs would not only provide clean needles and syringes, but also open a dialogue for some substance abusers to get medical care, Parker said. "It should never be considered as a kind of program to reduce the use of drugs, but to reduce the harm of drugs," Parker said. "It helps reduce the potential for spreading disease."

Opponents of the legislation have argued that providing needles would encourage drug use, not curb the spread of disease. Cathie Adams, president of Dallas-based Texas Eagle Forum, a socially conservative organization, said there are economic and moral problems the government faces in providing a needle exchange program. "The role of the government is to create an environment where law-abiding citizens are safe and healthy, certainly not putting them in a position where they have to bankroll illegal behavior," Adams said.

Many Infants Born to HBV-Infected Women Fail to Complete Vaccination Series

Perinatal hepatitis B immunoprophylaxis is highly immunogenic when administered under routine public health settings, new study findings indicate. But many infants born to hepatitis B surface antigen (HBsAg)-positive women are not completing the recommended vaccination series and being serotested.

"Our data show that public health departments can effectively assist the private physician with perinatal hepatitis B case management to ensure infants born to HBsAg-positive women receive proper immunoprophylaxis and on-time post vaccination serotesting," lead investigator Dr. Gary L. Euler of the US Centers for Disease Control and Prevention told Reuters Health.

In the early 1990s, the US government provided funds to conduct perinatal HBV transmission prevention activities and the CDC began monitoring these activities in selected states. In the February issue of The Pediatric Infectious Disease Journal (Pediatr Infect Dis J 2003;22:123-129), Dr. Euler and colleagues report surveillance results obtained in Dallas, Texas for the period 1992 through 1997.

Of 796 infants born to 787 HbsAg-positive pregnant women, 62% completed postexposure immunoprophylaxis and 80% underwent postvaccination serotesting. These rates are higher than the national rates reported for 1999, which were 56% and 40%, respectively. The authors note that these differences may be contributed to a program of centralized case management with home visits conducted in Dallas.

Of 632 infants who completed postexposure prophylaxis, 94.5% had antibodies to HBsAg at or above the protective level of 10 mIU/m. Infants born to white, non-Hispanic young mothers with a household income <$15,000 were less likely to be serotested.

Dr. Euler told Reuters Health that the post-vaccination serotest identifies infected infants who require follow-up care, as well as uninfected infants who are not protected, who require additional doses of hepatitis B vaccine.

"The best time to ensure an accurate measure of immunogenicity is to serotest at 3 to 4 months after receipt of the third dose of hepatitis B vaccine," he added.

March 5th, 2003

Pediatric Hepatitis C Is Mild but Persistent
By Anne MacLennan

Few children with hepatitis C virus (HCV) infection -- especially those who are infected perinatally -- achieve viraemia clearance in the medium-term, suggests a multicenter European study (Clinical Infectious Diseases 2003;36:275-280. "Chronic Hepatitis C Virus Infection in Childhood: Clinical Patterns and Evolution in 224 White Children") .

Dr. Paloma Jara from the Hospital Infantil La Paz, in Madrid, Spain, and colleagues retrospectively examined the characteristics and evolution of HCV infection among HCV RNA seropositive children seen at seven centres in Spain, Italy and Belgium between 1980 and 1998.

The researchers followed 200 white children who were positive for a mean of 6.2 years. At baseline, 87% of all children enrolled were asymptomatic and 48% had alanine aminotransferase (ALT) levels that were at least 2 times the upper limit of normal.

Results showed that 6% of children achieved sustained viremia clearance and normalisation of the ALT level at the end of follow-up. In 92 revised liver biopsy specimen analyses, the mean fibrosis score was 1.5 for children younger than 15 and 2.3 for those who were 15 or older (p<0.01).

The authors conclude that, although pediatric HCV infection is usually mild, few patients, and especially those infected perinatally, clear viremia in the medium-term.

Conversely, the higher rates of fibrosis observed in older patients suggest the possibility of an insidious progression of HCV-associated liver disease, they add.

March 6th, 2003

Schering-Plough Hits 6-Year Low after New Warning

Shares of Schering-Plough Corp. extended their slide on Thursday and fell to a six-year low, after the drugmaker again lowered its 2003 earnings forecast, triggering concerns the company's prospects are worse than previously believed.

Stock of Schering-Plough was down 87 cents, or 5 percent, to $15.73, its lowest point since December 1996. It was the most heavily traded issue in morning trade on the New York Stock Exchange.

Schering-Plough , based in Kenilworth, New Jersey, on Wednesday slashed its 2003 profit forecast by 25 percent, the second earnings warning for that year since October, citing plunging sales of its Claritin allergy pill and new competition for its hepatitis C treatments. The company's shares fell more than 4 percent on Wednesday after the news.

The new forecast of earnings between 75 cents and 85 cents per share represents a decline of 37 to 44 percent from the $1.34 per share the company earned last year.

Adam Greene, a drug analyst for First Albany Corp., on Thursday lowered his rating on Schering-Plough to ''underperform'' from ``neutral.''

"This news confirms our belief that the company's base business is deteriorating faster than expected,'' Greene said. He estimated the fair value of shares at $15, or roughly 18 times the company's likely per share earnings this year.

Sales of Claritin, formerly $3.2 billion annually, are plunging due to the expiration last

December of its U.S. patent and the company's decision to sell it without a prescription for only a third its previous price.

Just as Claritin sales began to fall, Swiss drugmaker Roche Holding AG late last year launched new treatments for hepatitis C that are denting sales of a similar dual therapy sold by Schering-Plough.

The Schering-Plough products, comprised of the injectible interferon Peg-Intron and an antiviral pill called ribavirin, racked up fourth-quarter sales of $800 million.

Deutsche Bank analyst Barbara Ryan said sales of the hepatitis C drugs could fall 25 percent this year due to competition from Roche, weak demand for the products in Japan, and expected brutal generic competition later this year for the ribavirin component of Schering-Plough's dual treatment.

"The possibility of a takeover only increases as Schering-Plough's market cap shrinks,'' Ryan said.

She added that Merck & Co., which co-developed Schering-Plough's new cholesterol fighter Zetia, could afford to pay a significant premium to acquire Schering-Plough without hurting its 2004 earnings.

``The company remains rudderless with no permanent CEO,'' Ryan added, referring to the planned retirement next month of Chief Executive Officer Richard Kogan.

Kogan helped build Claritin into a blockbuster, but he has been roundly criticized in recent years for quality control problems at the company's plants that have delayed approvals of new company drugs.

March 7th, 2003

Prolonged HAART May Increase Hepatitis C Diversity in HIV-Infected Patients
By David Douglas

In patients coinfected with HIV and hepatitis C virus (HCV), extended highly active antiretroviral therapy (HAART) appears to increase the complexity and diversity of HCV, California-based researchers report in the February issue of the Journal of Virology (J Virol 2003;77:1940-1950). This might make treatment of HCV less effective.

Drs. Mark Holodniy and Jennifer M. Babik of Stanford University School of Medicine note that HCV exists in individuals as a population of quasispecies. Dr. Holodniy told Reuters Health that "other studies in HCV-monoinfected patients suggest that...patients with greater diversity of virus may progress faster and not respond as well to interferon."

He and his colleague retrospectively studied three cohorts of HIV/HCV coinfected patients over periods of up to 10 months.

The first of these was antiretrovirally naive at baseline and went on to receive HAART for the remainder of the study. The next received no antiretrovirals at any point and the third was on HAART for the entire study.

In comparison with the other groups, the subjects who had received HAART over the whole study period had significantly higher CD4+ and CD8+ cell counts. They also exhibited a trend towards a higher HCV load and a significantly increased number of HCV clones, entropy and genetic distance.

The researchers thus observe that "with prolonged HAART, immune restoration results in an increase in HCV load and quasispecies diversity."

Dr. Holodniy said, "If HIV treatment with its resulting improvement in immune function also increases HCV diversity in the process, this may impact the treatment effect of interferon on HCV." However, he stressed that this "is speculation, since we did not study the response to HCV treatment in these patients."

March 8th, 2003

Schering PEG-Intron Supply Constraints Resolved; Earnings Forecast Cloudy
THE-PINK-SHEET

Schering-Plough is ending its supply management program for PEG-Intron (peginterferon alfa-2b) based on enhanced production capacity for the hepatitis C agent.

In a Feb. 18 letter to the trade, Schering informed prescribers and distributors that "patients will now be able to take their prescriptions...directly to their pharmacy to be filled."

The company created the "Access Assurance" program in October 2001 in light of supply constraints following a strong launch for PEG-Intron ("The Pink Sheet" Nov. 5, 2001, p. 20). New patients were placed on a wait list for most of 2002; the wait list was cleared in September.

Even in the absence of a wait list, patients have still been required to obtain an "Access Assurance ID number" before filling a prescription.

"Enhancements to our biotechnology production facility in Brinny, Ireland, increased product output and allowed us to eliminate the Access Assurance program," the company explained.

The wait list was cleared at about the time Roche launched its pegylated interferon brand Pegasys ("The Pink Sheet" March 3, p. 10).

Schering is continuing to sponsor the "Be In Charge" hepatitis C support program, which provides nurse counseling and other services free of charge to Intron patients. The company's letter to the trade also notes that its "Commitment to Care" program will continue to provide free therapy to patients who qualify; the company notes that in 2002 it provided therapy valued at over $100 mil. to 25,000 hepatitis C patients.

The shutdown of the PEG-Intron access program should make Schering's promotional efforts simpler, and help to eliminate any lingering concern among prescribers regarding supply.

The launch of Pegasys is one factor Schering cited in a March 5 press release downgrading earnings guidance for 2003 - and retracting prior guidance towards a strong showing in 2004 and 2005.

The company reduced its 2003 earnings forecast by 25%, from $1-$1.15 per share to $0.75-$0.85 per share. The reduction comes after the company twice cut its forecasts for 2002 in October and immediately after the end of the year. The company then restated its results soon after reporting to reflect a $150 mil. increase in litigation reserves ("The Pink Sheet" March 3, p. 4).

Schering noted that it is in a "transition" period marked by the disappearance of prescription revenues from Claritin following the launch of OTC versions of loratadine and by heavy investment in the launch of the cholesterol agent Zetia.

The press release suggests, however, that other factors are driving the latest forecast, including "the intense U.S. competition it is experiencing in the allergy category" and the potential for PEG-Intron sales to fall short of targets.

Schering cited "lower than expected patient demand in Japan for its hepatitis C treatments" and "new competition in the hepatitis C category in major markets."

The company added that it "is anticipating the possibility of generic ribavirin competitors in the U.S. in 2003." Schering markets the ribavirin brand Rebetol for use in conjunction with its interferon products. Three Rivers, Teva and Geneva are challenging the Rebetol patents; Schering has listed 10 separate patents running until 2018 in the "Orange Book."

The March 5 earnings warning also includes a blanket disavowal of any prior forecasts: "with today's announcement, Schering-Plough said it is withdrawing any previous earnings guidance." The company has previously forecast a strong rebound in 2004, with earnings per share growth of at least 20%.

The formal withdrawal of that projection may be the final step in clearing the way for new management at Schering. CEO Richard Kogan is scheduled to step down in April at the latest, and Pharmacia CEO Fred Hassan is viewed as ready to step in upon the closing of Pharmacia's merger into Pfizer.

The reaction to the earnings warning, however, will also mean that Schering's new management will have to be wary of uninvited merger solicitations. As of March 6, the company was trading at a six-year low with a market valuation below $24 bil. -or about one-tenth the combined value of Pfizer and Pharmacia.

March 10th, 2002

Tattoo and Piercing Still Risky: Hepatitis C, HIV, Infection Risks High in Body Art

Tattoo art and body piercing are popular forms of self-expression. But body art carries a downright dangerous risk of serious infection, including hepatitis C and HIV. Kids need to think twice about it. But if they're sold on the idea, at least make sure the shop is using clean needles and instruments.

"Spring break is a time when lots of young people are impulsively getting tattoos and body piercing -- and unfortunately, they're not exercising good common sense in choosing the shop where they get it done," says David Rosen, MD, MPH, a professor of pediatrics in teenage and young adult medicine at the University of Michigan Health System.

In fact, a recent study of 874 tattoo shops, beauty shops, and hairdressers in Australia-all where tattooing and piercing can be done-found that most lack knowledge of some essential infection-control principles and practices, writes Aurmporn Oberdorfer, MD, MSc, a behavioral sciences researcher at the University of Newcastle, Australia. His study appears in the current issue of The American Journal of Health Behavior.

Although HIV and hepatitis B are more likely to be transmitted through unprotected sexual activity, the viruses can be transmitted by nonsterile tattooing and piercing practices.

Indeed, it's a "buyer beware situation" out there, Rosen tells WebMD. "There are some wonderful shop operators who do a terrific job, and ones who don't. I don't think most people have ability to tell what sort of place they find themselves in. We want make sure potential clients had ability to judge for themselves."

Tattoos have other hidden health hazards, beyond hepatitis and HIV risks. Some people find out they are sensitive to dyes. In a few cases, gangrene has developed from an infection. "Also, it hurts to get a tattoo, to be quite honest," Rosen tells WebMD. "And the tattoo won't be very appealing for a period of time. Most people think it will look good right after it's done, but it doesn't."

Infection from a body piercing is fairly common, Rosen adds. Also, some people have an allergic reaction to metal that is used. One in 10 will have a bleeding complication. One in 15 will have a large scar or reaction at the site. There's also the possibility of toxic shock syndrome. If a nerve happens to get pierced, nerve damage can result. Piercing of the tongue has resulted in chipped teeth, he says.

When choosing a piercing or tattoo art studio, Rosen says, choose a place where:

• Sterile supplies are used. You should be able to see the operator opening up sterile needles in front of you and throw them away afterward.
• An autoclave is used to sterilize equipment is between each use. Soaking instruments in alcohol is not enough.
• The operator uses fresh, disposable gloves. Those gloves should be replaced between procedures and after touching non-sterile items like money.
• Inks are never to be reused from person to person.
• Operators follow laws. If the state law prohibits anyone under age 18 from getting a tattoo -- yet the studio is willing to tattoo a 16-year-old -- "who knows what other rules they're breaking," says Rosen.

Hepatitis Not HAART Causing Serious Liver Toxicity in HIV Patients
By Michael Carter

Severe liver inflammation and liver failure in people taking HAART is due to the effects of infection with hepatitis C or B, rather than the toxicities of anti-HIV drugs, according to a study conducted at the University of Brescia and published in the March 2003 edition of the Journal of Acquired Immune Deficiency Syndromes.

Between March 1997 and June 1998, 755 HIV-positive patients who were prescribed anti-HIV therapy at the HIV clinic at the University of Brescia were included in a study to determine the rate of severe hepatotoxicity and outcome of severe hepatotoxicity in patients on HAART.

At baseline, all patients were ask to complete a questionnaire regarding alcohol consumption, under went a physical examination and routine liver tests (ALT, AST, bilirubin, albumin and prothrombin time), had HIV viral load and CD4 cell measured and were checked for markers of infection with hepatitis viruses. HAART was independently prescribed by the patient's physician and follow-up was provided within a month of starting HAART and then every four months when all patients had liver function tests.

The results of liver function tests were categorised using a scale determined by the US AIDS Clinical Trials Group (ACTG): relevant hepatotoxicity; severe hepatotoxicity; and, liver failure.

If severe hepatotoxicity was diagnosed, patients were asked about drug and alcohol consumption, had a liver ultrasound and body scan, and tests to determine blood lactic levels and for hepatitis B, C and D. Patients were also investigated for opportunistic infections which can affect the liver.

Liver biopsies were performed within three months on 16 patients with evidence of severe hepatotoxicity. HAART was stopped in patients with severe hepatotoxicity, but restarted in all patients after a four month "wash-out" if they showed normalisation of liver function.

In total, 105 cases of relevant hepatotoxicity were observed (17 cases per 100 person years). The only variable found to be significantly associated with relevant hepatotoxicity were anti-hepatitis C reactivity and elevated ALT levels.

Twenty-six of the 105 cases of relevant hepatotoxicity met the definition of severe hepatotoxicity (a rate of 4.2 per 100 person years). Seven of these patients went on to develop liver failure (rate 1.1 per 100 person years).

Treatment regimen did not significantly affect the incidence of severe hepatotoxicity (2 NRTIs and a PI: 4 per 100 person years; 6 per 100 person in people treated with two NRTIs; and, no cases in people treated with an NNRTI and two NRTIs). However, as the investogators themselves acknowledge, there were only 62 treatment episodes of NNRTI therapy, amounting to 41 person years of follow-up, compared to 716 PI treatment episodes amounting to 478 person years.

Patients with severe hepatotoxicity were more likely to be male; to have acquired HIV through injecting drug use; be younger; be coinfected with hepatitis B, C or D; and have abnormal liver function markers at baseline.

Evidence of hepatitis C virus was present in 25 of the 26 patients with severe hepatotoxicity and one person also hepatitis B antigens. In all 26 patients, a direct relationship between an increase in ALT levels and increase in CD4 cell count from baseline was observed.

Liver biopsies were performed on 16 patients, with the results suggesting damage caused by immune reaction. In two patients, liver biopsies had been performed before anti-HIV therapy was initiated, with the post-HAART biopsies showing a worsening of inflammation.

The only patients with severe hepatotoxicity to die were the seven with liver failure. In six of these patients the liver failure was irreversible and they were not subsequently treated with HAART, dying of end stage liver failure within three months to one year. In one patient, liver failure was associated with lactic acidosis and pancreatitis and the patient died within three days. However, one patient did show improvement in liver function after HAART was withdrawn, but as his CD4 cell count was below 50 cells/mm3 he developed several opportunistic infections and it was necessary to recommence anti-HIV therapy, the patient dying of liver failure within a further three months.

Information was available on 17 patients with severe hepatotoxicity but not liver failure. HAART was stopped for a four-month "wash-out" period and then restarted. Seven patients (41%) relapsed to severe liver toxicity within two to four weeks of treatments restarting. However, in the remaining patients, no evidence of relapse was observed in 20 - 32 months of treatment.

In the seven patients who did relapse, five, all of whom had HCV, were treated with alpha interferon. One patient showed clearance of HCV and normalised ALTs. The remaining four were treated with HAART during alpha interferon therapy and did not show a relapse to severe hepatotoxicity within 30 months.

The investigators note that the 17% incidence of liver toxicity recorded in their study was similar to that seen in earlier investigations. However, they were concerned primarily with the 4.2% rate of severe liver toxicity and 1.1% rate of liver failure.

They suggest that immune reconstitution reaction against hepatitis virus antigens in the liver played a major role in the occurrence of severe hepatotoxicity. Indeed, severe liver damage could have been related to the "shock caused by immune reconstitution" against hepatitis viruses in people with severely damaged immune systems prior to starting HAART.

The investigators did not, therefore believe that anti-HIV drugs themselves were responsible for the severe liver toxicities seen in the study, noting that 59% of patients who had stopped HAART due to liver problems were able to restart therapy with the same regimens after a "wash out" period.

"Severe hepatotoxicity was related to preexisting chronic viral hepatitis" conclude the investigators, recommending that people starting HAART who are coinfected with hepatitis and have low CD4 cell counts receive careful monitoring. However they add, that according to their data, the risk of liver toxicity resulting in liver failure was low for coinfected patients with a CD4 count between 350 and 200 cells/mm 3. As regards the patients who developed liver failure, they suggest that liver failure would have been best prevented by the early treatment of chronic hepatitis C whilst the immune system was still relatively intact.

Does Pegylated Interferon Have a Role in the Treatment of Early Stage HIV?
By Ronald Baker, PhD

There is now overwhelmingly convincing evidence that the pegylated alfa interferons (Peg-Intron and Pegasys) offer a significantly greater clinical benefit and significant

improvement in the quality of life compared to standard interferon alfa (Intron A and Roferon) for the treatment of patients with chronic hepatitis C.

Early in the AIDS epidemic, researchers experimented with standard interferon alfa for the treatment of HIV infection. This therapeutic approach has largely been abandoned due to the sometimes severe adverse side effects of interferon alfa, especially among patients with chronic and/or late stage HIV infection using Retrovir (zidovudine; AZT). However, standard interferon alfa is FDA-approved for the treatment of Kaposi's sarcoma in AIDS patients with> 200 CD4+ cells/mm3 and for the treatment of genital warts.

Despite its toxicities, interferon alfa is known to have both antiviral and immuno-enhancing effects. To assess the potential for the new pegylated interferons to contribute to current therapy for HIV, researchers in Bochum, Germany conducted a controlled pilot study using pegylated interferon alfa-2b (PEG-Intron) in 10 treatment-naïve patients with asymptomatic HIV infection.

The 10 patients were enrolled in 2 study arms (treatment group = 5 pts; control group = 5 pts). Those in the treatment group received 80 micrograms PEG-Intron subcutaneously once weekly for 24 weeks. This compares to the standard dose of PEG-Intron 1.0 micrograms per kilogram of body weight given weekly in the treatment of chronic hepatitis C, and which is almost always given in combination with ribavirin 800-1200mg daily)

After 24 weeks, no study participants experienced severe side effects, according to the investigators. The mean number of CD4 cells in the treatment group rose from 462 cells/mm3 to 611 cells/mm3 versus a decline of 535 to 450 cells/mm3 in the control group.

Furthermore, the plasma HIV-RNA in the treatment group declined 0.9 log10 versus a plasma HIV-RNA increase of 0.8 log10 in the control group, according to the researchers.

Based on the viral load decrease and the CD4 increase in the low dose treatment group, the German investigators conclude, "pegylated interferon alfa -[2b] allows early control of HIV replication and a rapid decline of the viral reservoir while CD4-cell levels improve...Pegylated interferon alfa monotherapy might be a new therapeutic option in the treatment of early-stage HIV infection."

Commentary

While the results of this small pilot study in Germany are intriguing and somewhat encouraging, larger studies will be needed to validate the results of significantly decreased viral load and significantly increased CD4 cell counts from the use of pegylated interferon monotherapy in asymptomatic HIV patients. In particular, the adverse side effects of pegylated interferon alfa could limit the utility of this therapeutic strategy in many patients.

This study was supported by the German Competence Network HIV/AIDS Ministry of sciences (BMBF).

Prolonged HAART May Make Treatment of HCV less Effective
HIVandHepatitis.com
By David Douglas

In patients coinfected with HIV and hepatitis C virus (HCV), extended highly active antiretroviral therapy (HAART) appears to increase the complexity and diversity of HCV, California-based researchers report in the February issue of the Journal of Virology (J Virol 2003;77:1940-1950). This might make treatment of HCV less effective.

Drs. Mark Holodniy and Jennifer M. Babik of Stanford University School of Medicine note that HCV exists in individuals as a population of quasi-species. Dr. Holodniy told

Reuters Health that "other studies in HCV-monoinfected patients suggest that...patients with greater diversity of virus may progress faster and not respond as well to interferon."

He and his colleague retrospectively studied three cohorts of HIV/HCV coinfected patients over periods of up to 10 months.

The first of these was antiretrovirally naive at baseline and went on to receive HAART for the remainder of the study. The next received no antiretrovirals at any point and the third was on HAART for the entire study.

In comparison with the other groups, the subjects who had received HAART over the whole study period had significantly higher CD4+ and CD8+ cell counts. They also exhibited a trend towards a higher HCV load and a significantly increased number of HCV clones, entropy and genetic distance.

The researchers thus observe that "with prolonged HAART, immune restoration results in an increase in HCV load and quasi-species diversity."

Dr. Holodniy said, "If HIV treatment with its resulting improvement in immune function also increases HCV diversity in the process, this may impact the treatment effect of interferon on HCV." However, he stressed that this "is speculation, since we did not study the response to HCV treatment in these patients."

March 11th, 2003

Thrombocytopenia in Patients with HCV-Positive Chronic Hepatitis: Efficacy Of Leucocyte Interferon-Alpha Treatment
By Anne MacLennan

Leucocyte interferon-alpha is effective treatment for patients with thrombocytopenia linked with hepatitis C virus (HCV) infection, suggest researchers in Italy (Int J Clin Pract 2003 Jan-Feb;57:1:17-9).

Dr A Benci and colleagues from the Department of Haematology, San Donato Hospital, Arezzo, found that the therapy is well-tolerated by these patients.

Moreover, in cases of sustained virological inhibition, leucocyte interferon-alpha is able to increase the platelet count, they report.

The pathogenesis of thrombocytopenia is still unclear, making treatment of HCV patients with it a problem. However, these investigators evaluated both clinical and hematologic response to leucocyte interferon-alpha in 20 such patients.

All of the patients were naive to the treatment and had chronic HCV and thrombocytopenia (platelet count of less than 140 x 10(9)/l for at least six months) without portal hypertension and/or hypersplenism. They were treated with the leucocyte interferon-alpha (3 MU three times per week) for 12 months and followed up for another 12 months, and their biochemical (ALT) and virological (HCV-RNA) responses determined.

Of the 20 patients, two discontinued treatment because of hyperthyroidism.

Of the remaining 18 patients, all of whom completed treatment, 12 (66%) showed a biochemical response and, of these, 10 (55.5%) also showed a virological response.

At the end of the follow-up period, 4 patients (22%) showed a complete (biochemical and virological) response.

During the course of therapy, platelet counts in most patients decreased to less than 10 to 20% of pretreatment values. Of the 4 patients with a complete response, 3 showed a platelet increase during treatment and throughout the follow-up period.

Gilead Sciences' Hepatitis B Drug Hepsera Approved for Marketing in European Union

Gilead Sciences, Inc. today announced that the European Commission granted Marketing Authorisation for Hepsera(TM) (adefovir dipivoxil 10 mg) in all 15 member states of the European Union. Hepsera is indicated in Europe for the treatment of chronic hepatitis B in adults with compensated liver disease with evidence of active viral replication, persistently elevated serum alanine aminotranseferase (ALT) levels and histological evidence of active liver inflammation and fibrosis; or decompensated liver disease. On November 21, 2002, the Committee for Proprietary Medicinal Products (CPMP), the scientific committee of the European Medicines Evaluation Agency (EMEA), issued a positive opinion on Hepsera.

More than 400 million people worldwide have chronic hepatitis B, which is caused by infection with the hepatitis B virus (HBV), and between one quarter and one third of these individuals are expected to develop progressive liver disease, such as cirrhosis and liver cancer. Approximately nine million people are chronically infected with HBV in Europe. An estimated one million people die annually from complications of chronic hepatitis B making it one of the leading causes of death worldwide.

"To date, the limitations of available hepatitis B drugs, such as poor tolerability and rapid development of viral resistance, have made them unsuitable or ineffective for many patients," said Professor Stephanos Hadziyannis, MD, Department of Medicine, Henry Dunant Hospital, Athens, Greece. "In clinical studies, Hepsera significantly reduced disease progression in a wide range of patients. Broad efficacy, good tolerability and a low risk of resistance make Hepsera an important advancement in the treatment of chronic hepatitis B."

Hepsera is administered as a once-daily 10 mg tablet and works by blocking HBV DNA polymerase, an enzyme involved in the replication of the virus in the body. The U.S. Food and Drug Administration (FDA) cleared Hepsera for marketing in the United States on September 20, 2002. Regulatory filings for the drug also have been completed in Australia, Switzerland, Turkey and Canada, and additional regulatory filings are planned in other countries in the coming months.

"The approval of Hepsera by the European Commission comes less than a year after Gilead filed its Marketing Authorisation Application with the European authorities, demonstrating the important unmet medical need Hepsera will address for physicians and their patients with chronic hepatitis B," said John C. Martin, PhD, President and CEO, Gilead Sciences.

Access to Hepsera

In July 2002, Gilead initiated an early access program to provide Hepsera to chronic hepatitis B patients with lamivudine-resistant virus. To date, over 1,600 patients have enrolled in Hepsera early access programs in France, Italy, Greece, Spain, Portugal, Germany, the United Kingdom, Canada and Australia. The Hepsera early access programs will continue until the drug is commercially available to patients in these countries. For more information regarding the Early Access Program for Hepsera in Europe, please call +33 1 44 90 34 75.

Clinical Studies of Hepsera

Two placebo-controlled studies and a number of additional studies have evaluated Hepsera in a wide range of patients. The placebo-controlled studies included patients with compensated liver function and either "e" antigen-positive (HBeAg-positive) or "e" antigen-negative (HBeAg-negative, or precore mutant) chronic hepatitis B. The 48-week results from these two pivotal studies were published in the February 27 edition of the New England Journal of Medicine. Precore mutant hepatitis B infects up to approximately 50 percent of chronic hepatitis B carriers worldwide, and is most prevalent in countries of the Mediterranean and Southeast Asia, where between 30 and 80 percent of chronic hepatitis B patients are estimated to be infected with this strain. Hepsera also has been studied in patients who were treated with and developed resistance to lamivudine, including patients wait-listed for liver transplantation, post-liver transplantation patients and patients co-infected with HIV.

In clinical studies, Hepsera reversed or slowed the progression of liver damage, reduced HBV DNA levels in the blood and increased rates of seroconversion and normalization of ALT levels (an indicator of liver function) significantly more effectively than placebo in treatment-naive patients and in patients with prior interferon treatment.

Tolerability and Safety Profile

The adverse reactions considered at least possibly related to treatment in the first 48 weeks of therapy with Hepsera were asthenia (weakness), headache, abdominal pain, nausea, flatulence, diarrhea and dyspepsia. With extended treatment, mild to moderate, reversible, increases in serum creatinine were observed infrequently in patients with chronic hepatitis B and compensated liver disease treated with Hepsera for a median of 49 weeks and a maximum of 109 weeks. Changes in serum creatinine were observed very commonly in patients with pre- and post-liver transplantation with lamivudine-resistant hepatitis B and multiple risk factors for changes in renal function who were treated with Hepsera for up to 129 weeks, with a median time on treatment of 19 and 56 weeks, respectively. Clinical and laboratory evidence of exacerbations of hepatitis has been observed after discontinuation of treatment with Hepsera. Special warnings and precautions for use are included in the Summary of Product Characteristics regarding monitoring of renal function and post-treatment exacerbations of hepatitis, use in patients with underlying renal impairment or patients co-infected with HIV, and occurrence of nucleoside analogue-associated lactic acidosis and severe hepatomegaly with steatosis.

Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes therapeutics to advance the care of patients suffering from life-threatening diseases worldwide. The company has six marketed products and focuses its research and clinical programs on anti-infectives. Headquartered in Foster City, CA, Gilead has operations in the United States, Europe and Australia.

H.I.V. Lessons Used In Hepatitis C Treatment
By ANDREW POLLACK

Drugs that interfere with H.I.V. have had a major effect in reducing death and disability from AIDS. Now drug companies are beginning to test the first similar drugs for the hepatitis C virus, which can cause fatal liver disease and has infected far more people than H.I.V.

''If they work, they could have the same impact on H.C.V. that the H.I.V. drugs do,'' said Dr. Frank Chisari, a professor of virology at the Scripps Research Institute in San Diego.

Hepatitis C is now treated by the combination of alpha interferon, an immune system protein, and a pill called ribavirin. The newest versions of the combination can virtually eliminate the virus in about half of the patients.

But that leaves the other half at the mercy of the virus. Moreover, the treatment has severe side effects that include anemia, birth defects, flulike symptoms, depression and even an urge to commit suicide.

''There's a huge need for better drugs, less toxic drugs,'' said Dr. Michael G. Katze, a professor of microbiology at the University of Washington.

Neither interferon nor ribavirin was specifically designed to attack hepatitis C. Each appears to give a general boost to the immune system to help it attack the virus, though scientists do not fully understand how they work.

But the new hepatitis C drugs entering clinical trials are designed to interfere with enzymes that the hepatitis C virus needs to replicate, like protease and polymerase. Similarly, the AIDS drugs interfere with two enzymes used by H.I.V. to replicate, protease and reverse transcriptase. Some of the AIDS drugs can also be used for hepatitis B but not for hepatitis C, which operates differently.

It will take years to know if the new drugs will work. But scientists are encouraged by a proof of principle reported by Boehringer Ingelheim, a German drug company, at the American Association for the Study of Liver Diseases conference in Boston in November. The company said its experimental protease inhibitor reduced viral levels by a range of a hundredfold to more than a thousandfold in a small number of patients who took the drug for only two days.

''Sort of a hush went over the audience,'' Dr. Charles M. Rice, director of the Center for the S