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

Alan Franciscus
Editor-in-Chief

Early Virologic Response (EVR) to Treatment with PEG-Intron (peginterferon alfa-2b) Plus Rebetol (ribavirin) in Patients with Chronic Hepatitis C
Algorithm for HCV RNA Testing to Identify Patients with Early Virologic Response Treated with Peginterferon Alfa Plus Ribavirin
Finding the Right Combination to Fight Hepatitis C
Vaccination Guide
12-Month Combination Therapy with Intron A Plus Epivir-HBV Is Effective As Initial Treatment of Patients with Chronic Hepatitis B
Kidney Failure a Major Problem in Transplants
High body mass index is a risk factor for nonresponse to treatment in hepatitis C
A Summary Review of Steps in the Management of Chronic Hepatitis C
Oral piercings can lead to gum disease, infections and fractures
Grant targets Southeast Asian health education
Operative morbidity of living liver donors in Japan
Fibromyalgia, Hepatitis C Infection and the Cytokine Connection
Interferon and Ribavirin Safe for Patients with Hepatitis C-Related Renal Insufficiency
Hassan Taps His Buddy List
S.E.C. Penalizes Schering-Plough Over a Fair Disclosure Violation
Hepatitis C virus infection among drug users in Italy
Nigeria bans dangerous relaxant drugs from China
Life-insurance ban is unfair for many with HIV: Study
Prison outreach for the diagnosis and prevention of hepatitis C
Warning of disease risk on body art
Is It Too Late To Save Schering? ; CEO Fred Hassan has a hair-raising task: fixing the drugmaker's problems in the lab, in the plants, and in the market.
Hepatitis C Virus; Early Response to Therapy Allows Accurate Prediction Of Treatment Success
New process prolongs blood platelets' shelf life
North America's first supervised heroin injection site opens
Vancouver Opens Safe-Injection Site for Addicts
Variceal hemorrhage in patients with cirrhosis
Effective Methadone Dose Does Not Harm Newborns
Dude! You Call This Medicine?
Description of Entecavir Resistance-associated Mutations
Hepatic injury in patients taking the herbal weight loss aids
Hep C blood 'went untreated'
Isis Optimistic About Latest Antisense Compounds
Resection of hepatocellular carcinoma in patients eligible for transplantation
VA Seeks Former POWs for Possible Benefits
Cheaper Doesn't Mean Better. Ask a Canadian
Matria Healthcare Signs Strategic Disease Management Agreement with Schering Corporation
Predictive factors for early mortality following liver transplantation
Hepatitis Threatens to Wipe Out Two Amazon Tribes
UNICEF hopes to save two ethnic groups in Peru after hepatitis outbreak
Insurers issue new rules on gays
Molluscs could help fight cancer
Hepatitis A Boosters May Be Unnecessary
'Whitey' from 'Leave It to Beaver' Dies
Sex with Strangers Dogging English Parks
Obesity Predicts Poor Response to Hepatitis C Treatment
Ribavirin ANDAs Still Waiting For FDA; Other Generic Issues Have Priority
Hepatitis virus could be passed on by kissing
State grant provides Broward fire-rescue workers with free hepatitis C tests
Hepatitis C seen as 'the new epidemic'. Virus is four times more common than HIV, experts say
Nucleonics Receives NIH Grant Supporting Research Partnership Aimed at Developing RNAi Approach to Treatment of Hepatitis B Infections
Herbal Web sites not always honest
Obesity as a risk factor for cirrhosis-related death or hospitalization
Transmission of Hepatitis B and C Viruses in Outpatient Settings—New York, Oklahoma, and Nebraska, 2000--2002
Neb. Dr. in Hepatitis Case Loses License
Probe Ends in Schering-Plough Drug Case

September 1st, 2003

Early Virologic Response (EVR) to Treatment with PEG-Intron (peginterferon alfa-2b) Plus Rebetol (ribavirin) in Patients with Chronic Hepatitis C
by hivandhepatitis.com

Hepatitis C virus (HCV) replicates at a rapid rate, producing between 1010 and 1012 viral particles per day that have a half-life of only a few hours. Thus, virus levels decline rapidly when a potent antiviral agent such as interferon inhibits replication.

Viral kinetic studies have shown that the first phase of viral decay occurs within 24 to 48 hours after a dose, is rapid, and results in HCV RNA level reductions of up to 4 logs. However, this early initial decline in HCV RNA levels correlates poorly with the eventual response to interferon-based therapy.

Rather, treatment response correlates best with the subsequent slow, prolonged, and more variable period of viral decline referred to as phase 2 decay. The rate of phase 2 decay correlates closely with sustained virologic response (SVR) to interferon-based treatment regimens. Thus, it might be anticipated that changes in virus level over the first several weeks of therapy might correlate closely with the likelihood of ultimate eradication of HCV.

The aim of this study was to investigate whether early changes in HCV RNA levels during treatment with pegylated interferon and ribavirin could be used to accurately predict treatment response. Because early discontinuation of treatment in nonresponders could avoid the expense and inconvenience of continuing unnecessary treatment, the researchers also examined the potential cost savings of strategies that would use early virologic response (EVR) to develop early stopping rules for such patients.

Data from the recent international clinical trial reported by Manns et al. comparing pegylated interferon alfa-2b (PEG-Intron; Schering Corp., Kenilworth, NJ) plus oral ribavirin (Rebetol; Schering Corp.) with standard interferon (Intron A; Schering Corp.) and ribavirin was evaluated retrospectively to determine whether EVR could predict treatment outcome.

The investigators most closely evaluated treatment responses in the 511 subjects who were randomized to pegylated interferon alfa-2b at a dose of 1.5 microgram/kg each week and 800 mg/d of oral ribavirin (PEG/R) because this regimen was licensed by the Food and Drug Administration.

However, they also examined the subgroup of patients (n = 174) from the above group who received pegylated interferon alfa-2b at a dose of 1.5 microgram/kg each week and a dose of ribavirin that was at least 10.6 mg/kg/d (PEG/R >10.6), the so-called weight-based dosing regimen, because this is the approved standard of care outside the United States and may represent a more optimal dosing regimen.

Finally, the researchers also looked for comparison at the 505 subjects randomized to standard interferon at a dose of 3 million units 3 times per week plus 1,000 to 1,200 mg/d of ribavirin (1,000 mg/d for a pretreatment weight <75 kg and 1,200 mg for weight >75 kg) (I/R).

All subjects were treated for 48 weeks and provided informed consent for the study, and the ethics committee at each clinical site approved the study. The databases for the study were created and maintained by the study sponsor.

The researchers examined the accuracy of different degrees of viral inhibition during the early weeks of treatment (early virologic response [EVR]) with pegylated interferon alfa-2b and ribavirin (PEG/R) in identifying patients who would not respond to therapy.

The best definition of EVR was a reduction in hepatitis C virus (HCV) RNA by at least 2 logs after the first 12 weeks of treatment compared with baseline. Between 69% and 76% of patients achieved this threshold, depending on the treatment regimen, and sustained virologic response (SVR) occurred in 67% to 80% of these patients. Patients who did not reach EVR did not respond to further therapy.

If treatment had been stopped in patients without EVR, drug costs would have been reduced by more than 20% [Emphasis added-Ed].

In conclusion, the authors state, "Early confirmation of viral reduction following initiation of antiviral therapy for chronic hepatitis C is worthwhile. It provides a goal to motivate adherence during the first months of therapy and a milepost at which to reassess the need for continued treatment. Most patients who are able to complete the first 12 weeks of therapy achieve EVR and have a high probability of SVR."

"Patients who fail to achieve EVR will not clear virus even if additional months of therapy is received. Therapy can be confidently discontinued in those cases."

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Algorithm for HCV RNA Testing to Identify Patients with Early Virologic Response Treated with Peginterferon Alfa Plus Ribavirin
by hivandhepatitis.com

Following is a new algorithm for HCV RNA testing designed to identify peginterferon plus ribavirin-treated patients with an early viral response (EVR) to therapy. These patients have a high probability of achieving a sustained viral response (SVR). The algorithm also will identify those treated patients without EVR in whom treatment justifiably may be discontinued.

Quantitative HCV RNA testing is recommended at baseline and at week 12 of therapy in patients with genotype 1. EVR (decrease in HCV RNA > 2 logs compared with baseline or undetectable by PCR at week 12 of therapy) is associated with a high chance of response and justifies continuation of treatment.

Those who have at least a 2-log decrease in HCV RNA but remain HCV RNA positive by PCR should have HCV RNA retested by PCR at 24 weeks.

Because no patient without at least a 2-log decrease in HCV RNA at 12 weeks subsequently achieved SVR, the lack of EVR usually justifies discontinuation of therapy.

Patients with genotypes 2 or 3 have a high chance of achieving EVR and SVR. Retesting of HCV RNA during treatment is not cost-effective in these cases.

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Finding the Right Combination to Fight Hepatitis C
by Linda Marsa

Just half of the millions of Americans infected with hepatitis C respond to treatment, while others who are infected live with the constant threat that their health could suddenly, and fatally, deteriorate. But a new drug could help improve these odds.

When used with the antiviral drug interferon, the drug Zadaxin could help thousands of patients better fight HCV. "This medication looks promising for people who don't respond to other drugs," said Dr. Sammy Saab, liver specialist at UCLA's David Geffen School of Medicine. "It may also be used as part of a combination drug cocktail for all hepatitis C sufferers, since it seems to work by a different mechanism of action than other medications," added Saab.

Current HCV treatment - a combination of interferon and Ribarvirin - helps only half of those with active infections and less than a third who are infected with the more prevalent and more dangerous form of hepatitis C known as genotype 1.

Zadaxin is a synthetic version of thymosin alpha 1, a naturally occurring protein that stimulates the production of certain immune system cells. The drug, which has no apparent side effects, is approved for sale in 30 countries as an antiviral drug to treat hepatitis B but only in a few countries to fight hepatitis C.

However, results of a US study using Zadaxin to treat HCV were encouraging. The test involved 31 patients with high levels of genotype 1 who had not responded to standard therapy. Zadaxin, used in combination with interferon, greatly reduced levels of HCV in up to 36 percent of the patients.

The findings were particularly significant because patients who do not respond to the initial round of treatment rarely benefit from subsequent therapy. "We purposely chose the most difficult of the most-difficult-to-treat patients," said researcher Di Bisceglie. Zadaxin is in the final phase of US trials.

Around 4 million Americans are infected with HCV, and about 2.7 million of those have an active infection in which the liver is inflamed. Hepatitis C, which kills 10,000 people a year, is the leading cause for liver transplants in the United States.

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September 2nd, 2003

Vaccination Guide

If you're wondering which diseases you should be immunized against, the University of Southern California offers these recommendations:
* Tetanus: Everyone should get a booster shot every 10 years.
* Rubella (German Measles): For health care workers and women of childbearing age.
* Hepatitis A: For people at high risk, including intravenous drug users, homosexuals, institutionalized people and people traveling to or living in areas where it is endemic.
* Hepatitis B and C: High-risk adults such as dialysis patients and health care workers should get the hepatitis B vaccination and should get tested for hepatitis C, because symptoms often don't show up for years. There isn't a vaccination for hepatitis C.
* Pneumonia: For people over 65, plus diabetics and people who have had their spleens removed or suffer chronic heart, lung or liver disease.
* Influenza: Annual flu shots are recommended for the same group of people who should get pneumonia shots.
* Travelers: If you're planning to visit another country, you should contact its nearest consulate to ask whether specific vaccinations are recommended or required.

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September 3rd, 2003

12-Month Combination Therapy with Intron A Plus Epivir-HBV Is Effective As Initial Treatment of Patients with Chronic Hepatitis B
by hivandhepatitis.com

Researchers in Turkey studied the use of prolonged synchronous combination therapy with Intron A (interferon (IFN)-alfa 2b) and Epivir-HBV (lamivudine) with the use of IFN alfa-2b monotherapy in patients with untreated hepatitis B e antigen (HBeAg) positive chronic hepatitis B virus (HBV) infection.

Thirty-three patients received therapy with lamivudine (100 mg daily) and IFN alfa-2b (10 million U 3 times per week) for 12 months; 16 patients received IFN alfa-2b alone (10 million U 3 times per week for 12 months).

The primary end point was sustained suppression of HBV DNA and HBeAg seroconversion, which was observed in 15 (45%) of 33 patients treated with combination therapy and in 3 (19%) of 16 patients treated with monotherapy (P = .133). Both therapeutic regimens were well tolerated.

Combination therapy increased the rate of sustained suppression of HBeAg and resulted in significant improvement in Knodell histologic activity index scores, compared with monotherapy. However, there was no significant difference in rates of sustained suppression between the 2 groups at the end of follow-up.

Discussion
Until now, the short-term use of IFN-alfa alone or in combination with lamivudine has not been reported to be effective for treatment of chronic hepatitis B infection. Data on combination therapy are few and are restricted to studies of courses of treatment of 4 6 months' duration. Moreover, the 4 published trials of combination therapy provide little support for the use of the IFN alfa lamivudine combination.

Also, the design of the initial studies of combination therapy may not have been optimal for showing the full effects of combination therapy. On the other hand, in many controlled trials, it has been shown that there was an increased clearance of both HBeAg and HBV DNA after prolonged IFN alfa therapy, compared with treatment for the standard period of 16 weeks.

The current study demonstrates that administration of combination therapy for 12 months to HBeAg-positive patients induces rapid inhibition of viral replication, normalization of liver function, and histologic evidence of improvement in liver disease.

The study found a high rate of HBeAg seroconversion (54% of patients) after 12 months of combination therapy, a finding that is not in accordance with the seroconversion rate of 29% after 16 weeks of combination therapy reported by Schalm et al., nor with the seroconversion rate of 33% after 24 weeks of therapy reported by Barbaro et al.

The enhanced efficacy of prolonged treatment was so pronounced that, in future treatment regimens that include combination therapy, prolongation of therapy for up to 52 weeks should be considered.

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

Histologic evidence of improvement in liver disease is a significant marker of biologic improvement after therapy, especially when the number of patients is low. In the present study, combination therapy significantly reversed necroinflammatory activity, compared with IFN alfa mono-therapy. This large benefit occurred regardless of patients' HBeAg sero- conversion status and treatment response status in the combination therapy group.

The 84% rate of improvement in hepatic inflammation observed in these study patients was higher than the rate of 46% reported by Barbaro et al., the rate of 56% after 1 year of lamivudine therapy reported by Lai et al., and the rate of 54% after a 24-month course of IFN alfa therapy reported by Lampertico et al. Adding a prolonged course of IFN alfa therapy to a course of lamivudine therapy seems to double the substantial beneficial effect of lamivudine on liver disease.

In the present study, both treatment regimens were safe and well tolerated, and the efficacy of concomitant IFN alfa and lamivudine therapy appears to be better than that of IFN alfa monotherapy and the previously studied sequential administration of IFN and lamivudine.
Several factors may possibly explain this difference:

(1) A synchronous combination regimen is superior to a sequential combination regimen;
(2) A prolonged course of combination therapy is more effective than shorter course of combination therapy;
(3) Combination therapy is better than monotherapy; and
(4) Patients enrolled in this study tended to have a higher mean ALT levels, a higher HAI score, and a lower stage of fibrosis.

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

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Kidney Failure a Major Problem in Transplants
by Ed Edelson
HealthDay Reporter

Kidney failure is a disturbingly high risk for all transplant patients, says the largest survey ever done.

Ironically, the major cause of those kidney failures is an unavoidable side effect of the rejection-suppressing drugs that made transplantation possible, experts say.

"The five-year risk of chronic renal [kidney] failure after transplantation of a non-renal organ ranges from 7 to 21 percent, depending on the type of organ transplanted," says a report in the Sept. 4 issue of the New England Journal of Medicine by transplant specialists at the University of Michigan.

Kidney failure in those patients more than quadruples the risk of death, the researchers say.

"The magnitude of the problem is much higher than what one would expect based on what we see day-to-day in the clinic," says study leader Dr. Akinlolu O. Ojo, an associate professor of medicine at Michigan. "A number of 20 percent is higher than one would come up with if one had to make a guess."

The numbers come from a study of nearly 70,000 persons who received other-than-kidney transplants (liver, heart, lung, heart-lung or intestine) in the United States in the 1990s. Overall, 11,426 of those patients suffered kidney failure in the first three years after surgery, an incidence of 16.5 percent.

"While this report does not specifically say so, previous work would suggest that the main cause of kidney disease that arises after transplantation are these drugs," says Dr. Colin C. Magee, a staff physician in the renal division of Brigham and Women's Hospital, the teaching hospital of Harvard Medical School.

Two drugs are the mainstays of efforts to prevent the immune attack that kills transplanted tissues -- cyclosporine, whose appearance in the early 1980s revolutionized transplantation, and tacrolimus, which was introduced later.

"It is important to remember that these are drugs are lifesaving drugs," Magee says. "Without these drugs, transplantation would not be possible."

But the high incidence of kidney failure after transplantation not only worsens the quality of life but also can translate into a requirement for artificial kidney treatment or kidney transplants for many thousands of patients, which can strain medical resources, Magee says. While fewer than 1 percent of Medicare patients have kidney failure, they account for almost 6 percent of the Medicare budget, the editorial says.

There are ways to lessen the problem, Ojo and Magee say. It might be possible to use lower doses of cyclosporine and tacrolimus in selected patients, and to use newer rejection-preventing drugs in those patients, Magee says. But doctors will be cautious about changing the existing regimens, because any new dosage schedules might not be as effective, he says.

Ojo proposes a strategy based on other findings of the survey — that a number of factors other than drug therapy contribute to the risk of kidney failure. Those factors include older age, being a woman, having hepatitis C infection, high blood pressure and diabetes, the survey shows. Those factors can be combined in a formula to determine a patient's overall risk, he says.

"We need a way to stratify people before they get transplants so that we could reduce the amount of drugs we use or use the newer drugs in these patients to avoid toxicity," Ojo says. But he advises caution in use of the newer drugs, because they may not be as effective in preventing rejection as the two older medications.

Transplant centers, including the one at Michigan, are not now using the risk-stratifying strategy because the risk factors have not been laid out clearly, Ojo says. The surgery results may help promote the strategy, he says.

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September 4th, 2003

High body mass index is a risk
factor for nonresponse to treatment in hepatitis C
by gastrohep.com

Physicians from Canada find that obesity is an independent negative predictor of patients' response to hepatitis C treatment.

The aim of this study, published in the latest issue of Hepatology (Hepatology 2003; 38: 639-44), was to determine whether body mass index (BMI) predicts response to antiviral therapy for chronic hepatitis C.

A team of doctors performed a retrospective review of all patients with chronic hepatitis C treated with antiviral medication at a single center, between 1989 and 2000.

They defined a sustained response as either negative hepatitis C virus (HCV) RNA by PCR and/or a normal alanine aminotransferase (ALT) level 6 months after the completion of treatment.

The team divided patients into 3 groups according to their BMI. These were <25 kg/m2 (normal), 25 to 30 kg/m2 (overweight), and >30 kg/m2 (obese).

A total of 253 patients were treated with either interferon (IFN) monotherapy or IFN in combination with ribavirin.

Patients were excluded if predetermined clinical characteristics were unavailable.

Hepatic steatosis was not an independent risk factor for response to antiviral treatment.

The team used logistic regression to analyze the data.

After adjusting for several variables, they found that there were significant differences in the patients' response to treatment according to BMI group, virus genotype, and cirrhosis.

Patients with genotypes 2 or 3 had an odds ratio (OR) for success of 11.7 when compared with those with genotype 1.

In addition, the team determined that cirrhotic patients had an OR of 0.15 compared with noncirrhotic patients, and obese patients had an OR of 0.23 compared with normal and overweight patients.

However, the researchers did not find that hepatic steatosis was an independent risk factor for response to antiviral treatment.

Dr Brian Bressler's team concluded, "Obesity, only when defined as a BMI greater than 30 kg/m2, is an independent (of genotype and cirrhosis) negative predictor of response to hepatitis C treatment.

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September 5th, 2003

A Summary Review of Steps in the Management of Chronic Hepatitis C
by hivandhepatitis.com

Treatment options for chronic HCV infection have evolved significantly over the last few years, and current therapy with pegylated interferon and ribavirin is effective in 50% to 60% of patients with previously untreated infection.

Although there is some encouraging progress in new antiviral drug development for hepatitis C, it will be several years before any of these novel compounds are available in clinical practice.

In the interim, pegylated interferon and ribavirin remain the cornerstone of therapy. Healthcare providers have an important role in educating and selecting appropriate patients for therapy, recognizing common side effects, establishing a team approach to the management of chronic HCV infection, and keeping abreast of changes in treatment guidelines.

Following are brief excerpts on approaches to the treatment and management of chronic HCV from an article by Drs. Keyur Patel and John G. McHutchison.

Before initiating therapy, ensure there are no contraindications to interferon alfa (or peginterferon) and ribavirin.

These include:

For Interferon Alfa or Peginterferon Alfa:
* Decompensated liver disease
* Autoimmune hepatitis
* Severe neuropsychiatric illness
* Unstable coronary artery disease
* Unstable epilepsy
* Poorly controlled diabetes

For Ribavirin:
* Anemia (hemoglobin, <11 g/dL)
* Hemoglobinopathies (thalassemia major, sickle cell disease)
* Ischemic heart disease
* Cerebrovascular disease
* Pregnancy
* Refusal to practice barrier contraception
* Chronic renal impairment (creatinine clearance, <50 mL/min)

There are 10 steps with which patient and physician should move forward:

1. Ensure there are no contraindications to therapy.
2. Assess carefully for comorbid conditions (including depression, hypothyroidism, cardiac disease, and diabetes) that should be evaluated and controlled before starting antiviral therapy.
3. Determine HCV genotype and HCV RNA level.
4. Obtain liver biopsy to assess disease severity.
5. Discuss with the patient the side effects and possible treatment outcomes.
6. If appropriate, start therapy with pegylated interferon and ribavirin.
a) Determine dose of ribavirin according to genotype and weight.
b) Continue treatment for 24 or 48 weeks, according to genotype.
7. Perform laboratory monitoring.* (see Table 1).
8. Carefully perform a clinical evaluation monthly (or more often) for depression and other side effects; assess treatment adherence.
9. For genotype 1 infection, measure HCV RNA level at week 12.
a) Continue treatment for another 36 weeks if the patient has an early
virologic response.
b) Consider terminating therapy if there is no early virologic response.
10. Measure HCV RNA level at end of treatment. If HCV RNA is still not present at 6 months post-therapy (a sustained response), long-term eradication is likely to have occurred.

Table 1. A proposed laboratory monitoring schedule during combination therapy monitoring schedule during combination therapy for chronic hepatitis C

* Pregnancy tests should continue to be given every month for 6 months post-therapy.
** Except in patients with genotype 2 or 3 infection.

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Oral piercings can lead to gum disease, infections and fractures
by Frank D. Roylance

People who jab gold studs through their lips and pierce their tongues with silver bars are not usually eager to hear a lecture on gum disease.

But Dr. John K. Brooks tries anyway: Oral jewelry, the dentist tells them, can cost you a tooth.

"The patients I've been successful with are the ones that had pain and infection. They're much more ready to be convinced," Brooks says.

Brooks and two colleagues at the University of Maryland Dental School say there is growing clinical evidence that oral piercings increase the risk of gum disease, painful infections and tooth loss.

They present their case in the July issue of the Journal of the American Dental Association. "The profession does not advocate people wearing piercings," Brooks says, "and we want to discourage those people who wear piercings."

With professors Kenny A. Hooper and Mark A. Reynolds, Brooks' report on five patients who suffered gum loss and other dental problems were traced to their lip and tongue studs.

People who insist on wearing studs in their mouths "have to maintain exquisite oral hygiene, brushing and flossing," says Brooks. But even so, "there is no escaping that they will be at risk for damage to their gums and their teeth."

One of the subjects, a healthy 19-year-old with a barbell-shaped stud in her tongue, developed a case of worsening gum disease where the jewelry rubbed against the inside of a lower front tooth.

Another patient, a 24-year-old woman, came to the dental school's clinic complaining of painful teeth. She has lost a significant amount of the gum in front of her lower front teeth, next to her lip stud. The dentist also found related bone loss. Warned of the damage, the woman agreed to quit wearing the lip jewelry, the journal article says.

Chips and fractures
The JADA paper is the latest of several that have appeared in medical literature since 1997, raising alarms about the dental consequences of oral piercing. There have been no large-scale studies so far, and the warnings are based on reports of a few dozen individual cases.

The most common injuries are chips and fractures—in as many as 80 percent of the patients in one small survey cited by Brooks. Twenty percent of patients in another small survey had suffered at least some gum loss adjacent to their studs.

But that's not likely to come as news to many piercees.

"I chipped a tooth on it when I first got it," says Julia Racicot, 24, who works in the bookstore at the Maryland Institute College of Art and has worn a barbell in the center of her tongue since she was 19.

But she removes the stud, cleans it regularly, and goes to the dentist every six months. "I don't have any gum disease or anything else," Racicot says

At MICA, where students say you're likely to stand out if you don't have anything pierced, there are stories of students who aren't so lucky.

Racicot said she heard of one young man who complained that his labret (a lip stud) was "pulling down" his gum. "His dentist told him, 'I'll fix it for you for free if you'll take (the labret) out,' " Racicot says. The man took the advice and began warning others about the danger.

Wear and tear on the gums
Reynolds, co-author of the JADA paper and a gum disease specialist, says the association between oral jewelry and gum disease seems clear: Gum loss occurs near studs, in places where young people without the jewelry rarely experience it.

How does this happen?
Brooks says the relentless wear and tear on the gums leads to chronic inflammation as the body tries to guard against infection, remodel and repair the tissues. The gum tissue breaks down and deeper down "you begin to have destruction of the tissues that hold the gum to the roots," he says.

Bacteria that live naturally in the mouth rush in, and their chemical byproducts create pockets behind the gums. More food and bacteria accumulate, adding to the damage. The consequences are pain, infection and tooth loss.

As if that weren't enough, the medical literature has reported cases in which oral piercings have led to hepatitis, tetanus, angina, heart-valve infections, brain and breast abscesses and inflammation of the sac that surrounds the heart.

Piercing risks

* Infection. Infection is a possibility with any opening in skin or oral tissues. Given that the mouth is teeming with bacteria, oral piercing carries a high potential for infection at the site of the piercing. Handling the jewelry once it has been placed also increases infection risk.
* Prolonged bleeding. Damage to the tongue's blood vessels can cause serious blood loss.
* Swelling. Swelling is common after oral piercing. Unlike an earlobe that is pierced, the tongue is in constant motion, which can complicate the healing process. There have been some reports of tongue swelling serious enough to block the airway.
* Bloodborne disease transmission. Oral piercing has been identified by the National Institutes of Health as a possible factor in transmission of hepatitis B, C, D and G.
* Endocarditis. Oral piercing carries a potential risk of endocarditis, a serious inflammation of the heart valves or tissues. The wound created during oral piercing provides an opportunity for oral bacteria to enter the bloodstream, where they can travel to the heart. This presents a risk for people who have cardiac abnormalities, on which the bacteria can colonize.
* Injury to gums. Metal jewelry can injure gums, and if placed so it makes constant contact with the gums, can cause them to recede.
* Damage to teeth. Contact with the jewelry can chip or crack teeth. Teeth that have restorations can be damaged if jewelry strikes them.
* Interference with oral function. Oral jewelry can stimulate excessive saliva production, impede the ability to pronounce words clearly, and cause problems with chewing or swallowing. Metal alloys used to make oral jewelry may cause allergic contact dermatitis.
* Interference with oral health evaluation. Jewelry in the mouth can block the transmission of X-rays. Clear X-rays are essential to a complete oral health evaluation. Jewelry can prevent an X-ray from revealing abnormalities such as cysts, abscesses or tumors.
*Aspiration. As with any loose object in the mouth, jewelry that comes unfastened can be a choking hazard.

Source: American Dental Association

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Grant targets Southeast Asian health education
Barbara Anderson

Southeast Asian immigrants will learn how to prevent and manage diabetes and hepatitis B under a program that trains lay members of the community to teach the causes, signs and symptoms of the diseases.

The Khmer Society of Fresno received a three-year, $413,235 grant for the Southeast Asian Community Health Cluster Project from The California Endowment.

The grant will enable the society to hire three people who are fluent in Southeast Asian languages and aware of the culture. Sequoia Community Health Foundation will train the lay health workers on how to provide health education in family homes.

The Khmer Society of Fresno cites a 2000 Fresno County Southeast Asian Health Promotion Survey that found Cambodian and Laotian communities have high rates of diabetes and hepatitis B, yet are unaware of the diseases' causes and symptoms.

"Most of our folk don't know what is hepatitis B and what is diabetes," said Tia Lam, executive director of the Khmer Society of Fresno. "All of a sudden they get it, and they're not aware of how they get it."

The health cluster project will be the first time the community will have an opportunity to learn about the diseases in its own language, she said.

The grant will focus primarily on Cambodian and Laotian communities, but will be available to any Southeast Asian in need of the services, Lam said. The goal is to serve a minimum of 200 adults annually.

The three-year grant will "ensure that Southeast Asian communities in Fresno have access to the culturally competent services they need," according to a statement from The Endowment's program officer, Carole Chamberlain.

The Endowment, a private statewide health foundation, will present a check to The Khmer Society of Fresno on Friday at a traditional Buddhist blessing. The society is a Cambodian, community-based nonprofit agency that supports Cambodian and Laotian families in obtaining self-sufficiency through employment, education and cultural preservation.

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Operative morbidity of living liver donors in Japan

In contrast to western countries, no perioperative mortality has been recorded in living liver donors in Japan, find researchers in the latest issue of the Lancet (Lancet 2003; 362: 687-90).

Deaths of living liver donors have been reported in western countries.

However, the morbidity and mortality of living liver donors in Japan has not been studied.

In this study, a team of physicians reviewed the operative morbidity and mortality of these donors.

They studied 1853 donors of 1852 living liver transplants at 46 centers.

These donors were registered in the database of the Japanese Liver Transplantation Society.

Overall, the team analyzed the data of 1841 donors for 8 donor-related factors of morbidity and mortality.

Complications were significantly higher in right lobe donors.

No perioperative mortality was recorded between the inception of the liver transplantation program in 1989 and 2002.

The researchers found that there were 244 postoperative complications were reported in 228 donors.

They determined that complications were significantly higher in right lobe donors, compared to those involving the lateral segment, and the left lobe.

Furthermore, postoperative hospital stay was significantly longer in right lobe donors.

The doctors found that re-operation, related to donor hepatectomy, occurred in 23 donors.

Dr Koji Umeshita's team concluded, "By contrast with western countries, no perioperative mortality was recorded in living liver donors in Japan".

"However, a proportion of these donors developed serious complications".

"This morbidity should be reduced to maintain zero mortality in living liver donors".

Fibromyalgia and chronic hepatitis C infection share many clinical features including prominent somatic complaints such as musculo-skeletal pain and fatigue. There is a growing body of evidence supporting a link between cytokines and somatic complaints.

This review by researchers in the Division of Arthritis and Rheumatic Diseases, Oregon Health & Science University, discusses alterations of cytokines in fibromyalgia, including increased serum levels of interleukin (IL)-2, IL-2 receptor, IL-8, IL-1 receptor antagonist; increased IL-1 and IL-6 produced by stimulated peripheral blood mononuclear cell in patients with FM for longer than 2 years.

Other cytokine alterations discussed include:

* increased gp130, which is a neutrophil cytokine transducing protein;
* increased soluble IL-6 receptor and soluble IL-1 receptor antagonist only in patients with fibromyalgia who are depressed; and
* IL-1 beta, IL-6, and TNF-a by reverse transcriptase-polymerase chain reaction in skin biopsies of some patients with fibromyalgia.

In addition, this review describes the mechanism by which alterations in cytokines in fibromyalgia and chronic hepatitis C infection can produce hyperalgesia and other neurally mediated symptoms through the presence of cytokine receptors on glial cells and opiate receptors on lymphocytes and the influence of cytokines on the hypothalamus-pituitary-adrenal axis such as IL-1, IL-6, and TNF-a activating and IL-2 and IFN-a down-regulating the HPA axis, respectively.

The association between chronic hepatitis C infection and fibromyalgia is discussed, including a description of key cytokine changes in chronic hepatitis C infection. Future studies are encouraged to further characterize these immunologic alterations with potential pathophysiologic and therapeutic implications.

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September 8th, 2003

Interferon and Ribavirin Safe for Patients with Hepatitis C-Related Renal Insufficiency
By Emma Hitt, PhD

Interferon and ribavirin appear to be safe for use in patients with hepatitis C virus (HCV)-related vasculitis and glomerulonephritis, irrespective of renal function, a small study published in Nephrol Dial Transplant 2003;18:1573-1580 suggests.

Hepatitis C virus (HCV) infection is associated with kidney problems, including glomerulonephritis and focal segmental glomerulosclerosis. HCV is generally treated with interferon and ribavirin, but ribavirin is contraindicated in patients with renal insufficiency due to concerns with side effects.

Annette Bruchfeld, MD, with the Department of Clinical Science at the Karolinska Institute, Sweden, and colleagues treated 7 patients with a combination of interferon (2 of whom received pegylatedinterferon) and ribavirin (average daily dose of 200 to 800 mg).

Two of the patients had cryoglobulinaemia, vasculitic manifestations, and glomeru-lonephritis; 4 had membrano-proliferative glomerulonephritis; and 1 had focal segmental glomerulosclerosis. All had renal insufficiency, with a glomerular filtration rate (GFR) between 10 and 65 mL/min. One patient had HCV genotype 1, the rest had HCV genotype 2 and 3. Patients were treated for 6 to 12 months depending on genotype.

Six of the patients became HCV-RNA-PCR negative, and 4 out of 7 maintained both virological and renal remission, while 1 patient maintained virological and partial renal remission. One patient did not tolerate interferon but achieved renal remission with low-dose ribavirin. One vasculitis patient went into complete remission, but relapsed virologically and had a minor vasculitic flare after 9 months.

"Only one patient with vasculitis had low-dose immunosuppression in addition to anti-viral therapy," the researchers note. In addition, ribavirin-induced anaemia was managed in 5 of the 7 patients with low-dose iron and erythropoietin.

"In our experience it is reasonably safe to use interferon and ribavirin in HCV-related vasculitis and GN irrespective of renal function," Dr. Bruchfeld and colleagues conclude. "However, the use of ribavirin in renal insufficiency should be used with caution and ribavirin plasma monitoring as well as surveillance of side effects is recommended," they add.

They suggest that implementing interferon and ribavirin treatment could improve treatment options for HCV-related renal disease "and form a foundation for controlled clinical studies in the field."

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Hassan Taps His Buddy List
by Matthew Herper

Several weeks after Schering-Plough slashed its dividend by 68% and announced plans to trim 1,000 jobs through an early retirement program, Chief Executive Fred Hassan says that the Kenilworth, N.J.-based company continues to lose market share for its top four drugs. But he still hopes to affect a turnaround, just as he did at his last company, Peapack, N.J.-based Pharmacia. To do that, he is calling in some help.

Hassan announced this morning that he has tapped Michael J. DuBois to run global licensing at Schering. Like Carrie Cox, who is global head of pharmaceuticals at Schering, he held the exact same position at Pharmacia before it was bought by Pfizer for $60 billion in April. DuBois will report directly to Hassan.

His job will be an important one. Schering's top sellers are hobbled. Hassan noted that sales of Claritin, once the world's best-selling allergy pill, have "evaporated." Patients have not switched to a very similar follow-up, Clarinex, as quickly as Schering hoped. Its hepatitis C medicines, Rebetol and Peg-Intron, are facing tough competition from a new entrant from Roche, a Basel, Switzerland-based drug giant. Nasonex, a steroidal nasal spray used to treat allergies, is also losing market share, although Hassan hopes he can turn that around.

There are three ways for Schering to grow. First, it can introduce new medicines. Hassan said he sees a promising pipeline, but developing new drugs can take a long time. Second, the company has lot riding on Zetia, a cholesterol medicine that Schering is co-developing with Merck. If the two companies can show that a combination of Zetia and Merck's Zocor is safer or more effective than existing cholesterol medicines, the combination could become a mega-blockbuster. But it could take years to convince doubters that the combination clears arteries or prevents heart attacks as well as existing drugs.

In the meantime, there is the third path: find new drugs being developed by other companies or academic labs, and license the right to sell them for a cut of the profits. But the competition for such deals is fierce. This morning, French drug giant Aventis announced that it will pay up to $510 million to Regeneron Pharmaceuticals for a drug that is only in the first of three stages of clinical trials. And Schering looks weak right now, which may not make it exactly the partner of choice.

DuBois could face a tough task finding new medicines to license. His boss could face an even tougher task getting Schering on course.

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September 10th, 2003

S.E.C. Penalizes Schering-Plough Over a Fair Disclosure Violation
by Floyd Norris

Using inside information, institutional investors were able to save tens of millions of dollars by selling stock before the public found out how badly profits were deteriorating at Schering-Plough, the Securities and Exchange Commission said yesterday.

The commission brought administrative proceedings against the drug company and its former chief executive, Richard J. Kogan. It issued cease-and-desist orders barring future violations of Regulation FD, for fair disclosure. But it took no action against the institutions that profited from the inside information.

Schering-Plough agreed to pay a $1 million penalty, the largest imposed for a violation of the fair disclosure regulation. Mr. Kogan, who has retired from the company, agreed to pay $50,000. He is the first individual to be penalized for violating Regulation FD, which was adopted more than two years ago. Neither admitted nor denied the accusations.

''Fair disclosure means creating a level playing field for all investors,'' said Stephen M. Cutler, the commission's director of enforcement. ''Bestowing an informational advantage on a select few at the expense of others undermines investor confidence and cannot be tolerated.''

Schering-Plough shares closed at $21.32 on Sept. 30, 2002, before beginning a fall that cut 17.6 percent from the share price over three days without the company making any public announcement. That came as Mr. Kogan met with executives of four institutional investors on the evening of Sept. 30 and during the day Oct. 1, and then met with a larger group of analysts on Oct. 3.

Late on Oct. 3, after the stock had fallen to $17.64, the company put out a news release giving some of the bad news, the S.E.C. said. The shares opened the next day at $16.10, as public investors sent in sell orders.

The stock rallied above $23 in January, but the share price has since declined. Yesterday, the shares rose 45 cents, to $16.

According to the S.E.C., Mr. Kogan provided a litany of negative information, in what he said and in his manner, in meetings with the institutional investors.

''Providing guidance to a select few through a combination of spoken language, tone, emphasis and demeanor, is precisely the kind of unfair advantage that the S.E.C. wants to prevent,'' said Paul R. Berger, the associate director of enforcement at the commission.

On the evening of Sept. 30, Mr. Kogan met with executives from Wellington Management. That firm's drug analyst maintained her buy rating after the meeting, but the next day several of the firm's portfolio managers sold, the S.E.C. said. The price of the stock ranged from $19.45 to $21.80 that day.

On the morning of Oct. 1, Mr. Kogan met with executives of Massachusetts Financial Services, a unit of Sun Life Financial, and then with Fidelity Investments, a unit of FMR, and Putnam Investments, a unit of Marsh & McLennan. The M.F.S. analyst was already cautious on the stock, and that firm owned few shares. But the Fidelity and Putnam analysts, who had been supporters of the stock, turned negative, issuing sell or underperform recommendations the next morning.

Fidelity and Putnam each sold more than 10 million shares from Oct. 1 through Oct. 3, the S.E.C. said, accounting for more than 30 percent of the trading volume in the period. Compared with the prices immediately after the public disclosure, they saved at least $2 a share.

The shares fell further on Oct. 3, during the meeting with other analysts. At that meeting, the S.E.C. said, Mr. Kogan said earnings in 2003 would be ''terrible.''

One Putnam portfolio manager who attended the meeting and sold shares said in a telephone conversation with a Putnam trader, which was recorded, that the meeting had made it clear Schering-Plough would not meet profit expectations.

''It's certainly why we are selling,'' he said, adding that he was at a health conference where other investors were speculating about the weakness in Schering-Plough.

''So, the larger community, anyone who didn't meet with them over the last couple days, doesn't have a clue as to what's going on,'' the Putnam portfolio manager said.

Nancy Fisher, a spokeswoman for Putnam, declined to comment directly about the recorded statements, but said the firm had started selling days before the meeting and that the firm's analyst had indicated that he planned to downgrade the stock.

Anne Crowley, a spokeswoman for Fidelity, said, ''We complied with all rules and regulations in our meeting with Schering-Plough and in our conduct thereafter.'' A call to Wellington Management was not returned.

Under federal law, it is often viewed as insider trading when a trader receives a tip from a company executive about material nonpublic information. But to bring such charges the commission would have to prove that the money managers knew the information was confidential and should not be disclosed. S.E.C. officials would not comment, but there is no indication that any action is contemplated against the institutional investors.

A lawyer for Mr. Kogan, Stanley Sporkin, said: ''There is no evidence that Kogan profited from this. He did not buy or sell stock.''

Mr. Sporkin, a former federal judge and before that the director of enforcement for the S.E.C., added: ''The real message is that C.E.O.'s of companies have to be very careful when they go one-on-one with analysts.''

Schering-Plough announced the S.E.C. settlement but did not comment on it.

Chart: ''For Big Investors, Advance Warning''
Schering-Plough and its former chief executive, Richard J. Kogan, agreed yesterday to pay penalties for what the S.E.C. said were violations of the commissions fair disclosure regulation last fall. At that time the company gave bad news to selected institutional investors before disclosing it to the public .

SEPT. 30 -- Mr. Kogan briefs officials of Wellington Management in the evening.
OCT. 1 -- Mr. Kogan meets with officials of Massachusetts Financial Services, Fidelity Investments and Putnam Investments.
OCT. 2 -- Analysts at Fidelity and Putnam advise managers to sell the stock before trading begins.
OCT. 3 -- Mr. Kogan meets with more analysts and says profits in 2003 will be terrible. At 10:45 p.m., company discloses part of what was told to analysts.

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Hepatitis C virus infection among drug users in Italy
by gastrohep.com

Anti-HCV status is independently associated with drug use duration and route of administration, find doctors in the September issue of the Journal of Viral Hepatitis (J Viral Hepatitis 2003; 10(5): 394-400).

This study, conducted by researchers from Italy and the United States, assessed the rates and predictors of hepatitis C virus (HCV) infection in drug users receiving treatment for opiate addiction.

The team evaluated a cohort of 1095 participants in 16 centers for drug users in north-eastern Italy.

They collected data using standardized face-to-face interviews in 2001. 74% were HCV seropositive.

The team found that, of 1095 participants, 74% were HCV seropositive.

They determined that anti-HCV status was independently associated with drug use duration >10 years, injecting, as well as hepatitis B (HBV) and HIV seropositivity.

The physicians analyzed subjects further, based on duration of heroin use (greater or less than 10 years).

They found that both the route of drug administration and HBV status were associated with HCV seropositivity in both groups. However, less education was associated with HCV in the shorter term drug users.

Both HIV status and having a sexual partner with a history of drug use were associated with HCV seropositivity in longer term drug users.

Dr Quaglio's team concluded, "Half of the short-term heroin users were still HCV seronegative when starting treatment, suggesting opportunities for reducing new HCV infections."

"Remarkable was the relationship between vaccination for hepatitis B and HCV serostatus."

"Being HBV seropositive was strongly associated with being HCV seropositive."

"But heroin users who had been vaccinated for HBV were not significantly more likely to be HCV seropositive than heroin users who were HBV
seronegative."

"HBV vaccination does not provide biological protection against HCV; however, vaccinating heroin users against HBV may help to create a stronger pro-health attitude among heroin users, leading to a reduction in HCV risk
behavior."

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September 12th, 2002

Nigeria bans dangerous relaxant drugs from China

The Nigerian government has banned a family of relaxant drugs imported from China, said to have possible serious side-effects including hepatitis, cirrhosis and liver failure, an official statement said.

The National Agency for Food and Drug Administration and Control (NAFDAC), the state-run regulatory agency for all drugs in the country, warned Nigerians of the harmful effects of products containing kava-kava and kavaine, said the statement.

Such products, which are easily obtainable on the Nigerian market, are used in the treatment of conditions such as nervous anxiety, stress and restlessness, and to treat the symptoms of menopause, the NAFDAC statement said.

But the drugs—banned by most drug regulatory authorities worldwide and the World Health Organization—have been implicated in serious liver diseases, including hepatitis, cirrhosis and liver failure, it also said.

A top NAFDAC official told AFP Friday that the dangerous drugs have been in circulation in Nigeria for the past three years. Efforts have been stepped up to withdraw them from the market.

Drug importers and the Chinese embassy in Nigeria are cooperating with NAFDAC to enforce the ban, said the official who declined to be named.

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Life-insurance ban is unfair for many with HIV: Study

A ban on life insurance for people with the AIDS virus is in many cases unjustified, according to the first study to provide hard actuarial evidence about the benefits of anti-retroviral drugs.

Life insurance companies, scared by the mortality rates seen in the early years of the AIDS epidemic, routinely deny insurance to people with the human immunodeficiency virus (HIV ) and this can cause big problems for those individuals, in their business and personal lives.

But a Swiss study says the automatic ban fails to take into account the success of antiretrovirals—the drug "cocktail" that emerged in the mid-1990s and which, for many people with HIV, has otherwise prolonged their survivability.

People who respond well to HIV and who do not have hepatitis C have a short-term mortality rate that can be even lower than people who have been successfully treated for cancer and who are usually able to get life insurance, the study says.

Amongst the HIV group, the excess death rate—a figure that compares patients to people without the disease—was below five per thousand patient-years.

Amongst the cancer group, the rate varied from five to 20 per thousand patient-years.

The study, published in this Saturday's issue of the British medical weekly The Lancet, "provides preliminary evidence that life coverage could be considered under specific conditions," the authors say.

However, short-term mortality was significantly higher among HIV patients who had failed to respond to antiretrovirals or who had hepatitis C, a disease linked to intravenous drug use.

The research was led by Bernard Hirschel of Geneva University Hospital, and drew on figures from a six-year-old, ongoing study of Swiss patients with HIV and from national mortality statistics.

Antiretrovirals contain the spread of HIV virus so that the body's immune system remains intact and does not reach the stage of full-blown AIDS, when death can be caused by opportunistic diseases.

These drugs are not a cure, however, and can have toxic side effects.

Their cost, too, is a barrier to treatment. Only recently has the price been lowered sufficiently for developing countries to contemplate distributing the treatment on a wide scale.

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Prison outreach for the diagnosis and prevention of hepatitis C
by gastrohep.com

Prison outreach clinics are effective in delivering health education, but have a limited effect in eradicating hepatitis C virus in prisoners, finds a team of physicians in the October issue of Gut (Gut 2003; 52: 1500-4).

Hepatitis C virus (HCV) infection is a major public health problem

A prison environment provides the opportunity for healthcare workers to focus on traditionally hard to reach patients.

In this study, researchers from Southampton, England, assessed the prevalence of HCV infection in a prison cluster. They also evaluated the effectiveness of a prison outreach service for hepatitis C.

The team established a nurse specialist-led clinic within the prisons. This offered health education on hepatitis C, advice on harm minimization, and HCV testing.

Any prisoners infected with HCV were offered access to treatment.

30% of the prisoners tested had active HCV infection.

The research team measure the level of service uptake, and diagnosis and treatment of hepatitis C.

Overall, the team found that 9% of 1618 prisoners in this study accepted testing. They found that 30% of these prisoners had active HCV infection.

However, most prisoners were ineligible for treatment due to psychiatric illness, or did not receive treatment for logistic reasons.

The researchers determined that injecting drug use was the major risk factor in all cases.

The team also found that only 7% of HCV polymerase chain amplification positive inmates received treatment while in prison.

Dr Skipper's team concluded, "There is a large pool of HCV infected prisoners at risk of complications, constituting a source of infection during their sentence and after discharge."

"A prison outreach clinic and care pathway was perceived as effective in delivering health education, reducing the burden on prison and hospital services."

"It provided an opportunity for intervention but had a limited effect in eradicating HCV in prisoners and it remains unclear how this might be achieved."

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September 14th, 2003

Warning of disease risk on body art
by Mark Gould

Once the preserve of fetish clubs and tribal groups, body art has fought its way into mainstream culture as tattoos and piercings have become the must-have adornment for the young and famous.

David Beckham's body artwork has undermined tattoos' reputation as symbols of rebellion, while Madonna's pierced belly button and Zara Phillips's tongue stud have given body-piercing a more respectable public image. The craze has even reached the aisles of Selfridges, which opened a tattoo and body-piercing concession earlier this year called Metal Morphosis.

But doctors are now warning such fashion accessories could be fatal. Tattoos and body-piercing could lead to a risk of contracting the liver disease hepatitis B, which can be passed on via infected needles.

The Royal College of General Practitioners is urging the fashion-conscious to avoid piercing altogether and opt for stick-on tattoos because hepatitis B rates have doubled in the past 10 years. Dr George Kassianos, a GP and spokesman for the RCGP, said: 'The risk is too great that the (tattoo) parlour has cut corners by re-using tattoo needles or not sterilising equipment. If you want to decorate your body get a transfer - they are usually better quality anyway."

In December last year Sheffield teenager Daniel Hindle, 17, died when he contracted blood poisoning after having his lip pierced. In June a tattoo and piercing parlour in Dundee was closed down amid fears of a hepatitis B infection when health officials found equipment and skin cream contaminated with blood. Public health doctors have found no evidence of hepatitis B but are screening more than 60 customers. The disease can be passed from mothers to newborn babies, and by using infected needles, razors, or toothbrushes and by having unprotected sex.

The risk of passing on the infection is so great that blood donors are banned from donating for 12 months after they have been tattooed or pierced. The National Blood Agency says that one in 10 donors are turned away on any one day because of a new piercing or tattoo.

Last month local authority inspection and hygiene rules previously restricted to body art parlours in London were extended across England in a bid to crack down on infections and botched piercings.

But the doctors' warning prompted a sharp response from body artists. Curly, a tattooist from the Tattoo Club of Great Britain, in Oxford, thought the RCGP's advice was 'unbelievable.'

'What kind of moron says a thing like that? As long as you take sensible hygiene precautions it's perfectly safe. People have been doing it for thousands of years. Twenty or 30 years ago we used the same needle all day without sterilising it and nobody got hepatitis. Now I have got an autoclave where I sterilise the needles and I keep a record of the temperatures they are heated to. I just think people are taking this health and safety thing a bit too far.'

Metal Morphosis 'director and celebrity piercer' David Potasnick said he set up the International School of Body Piercing to raise standards of skill and safety.

'I would like to see stricter regulations placed on piercing to ensure better quality of service through out the industry and I would urge anyone considering getting a piercing to fully research the studio beforehand to ensure that they are in the hands of a licensed professional,' Potasnick said.

There are around 180,000 people with hepatitis B in the UK. But Public Health Laboratory Service figures show that in the past decade the number of new cases has doubled from 400 to more than 800 a year with many new cases in refugees and asylum-seekers.

Kassianos said official fig ures mask a larger group who don't know they have the disease. 'It's estimated there are around 800 new cases a year but there could be as many as 3,500 people newly infected who don't know it and are passing it on.'

The problem is becoming so acute that the government's Joint Committee on Vaccination and Immunisation is considering setting up a 2childhood hepatitis B immunisation programme.

Kassianos wants immunisation introduced as soon as possible. 'This is not a racist measure or anti-refugee - the fact that we can all move about the world so easily means that hepatitis B is a problem for the whole population of the UK.'

Last year the prestigious Mayo Clinic carried out the only scientific research on the extent of body art in an unnamed American university. It found that half of all the undergraduates had some form of body piercing. One in five suffered injury or prolonged bleeding and one in 10 had a bacterial infection.

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September 15th, 2003

Is It Too Late To Save Schering? ; CEO Fred Hassan has a hair-raising task: fixing the drugmaker's problems in the lab, in the plants, and in the market.
John Simons

Fred Hassan talks like a professional therapist. Not in a cooing, I-feel-your-pain, Oprah sort of way, but with a gentle authority that, no matter how harsh the pronouncement, is still soothing. Schering-Plough needs such treatment. Since taking over as CEO of the troubled pharmaceutical company four months ago, Hassan has had to fire senior managers, cut salaries, and shut down research. At the same time, he is campaigning to restore morale within the company and trust outside it. It's a tricky prescription, but his verbal balm is soothing.

On a Friday in July, Hassan is doing it again, this time in a small meeting room on the grounds of Schering's sprawling Kenilworth, N.J., headquarters. Eleven midlevel researchers are seated around the table eating cold cuts and potato salad. Hassan has called them together to hear their opinions on what ails Schering. A computer technician speaks up, arguing that new drug applications go through too many hoops before going to the Food and Drug Administration. "I'm sensing that because we made mistakes in the past, 'speed' is a bad word around here," says Hassan in his mild Pakistani accent. "Am I right?" Everyone nods. The technician, as if waiting for years for someone to utter those words, lets out a long "yessss."

His management style may seem soft and fuzzy, but Hassan insists that it is the stuff of which great CEOs are made. Doing well in business, he says, is about "getting to the hearts of people—that's something you don't learn in business school. Can you teach someone to engender trust? That separates leaders from managers."

All that's nice. But no one will really care unless it means Hassan can fix Schering. With annual sales of $10.1 billion, it is the country's ninth-largest drug firm. It specializes in allergy and respiratory drugs and anti-infection, cancer, and cardiovascular treatments. The company is best known for Claritin, the breakthrough allergy medicine that didn't make users drowsy. Schering also produces such respiratory drugs as Afrin and Nasonex; foot-care products like Dr. Scholl's insoles; antifungal medicines Lotrimin and Tinactin; Coppertone and Bain de Soleil sunscreen products; and animal health treatments.

Until recently investors loved Schering-Plough, and it's easy to see why. In 2000 the company posted its 15th consecutive year of double-digit growth in earnings per share and raised its dividend for the 17th time since 1986. During the 1990s its shares soared 978%.

But Big Pharma is suffering through difficult times. Since 2000 the S&P pharmaceuticals index has fallen 19%, while the S&P 500 is off 13%, and the drug industry has not recovered as fast. While every drug company faces serious challenges in one or two areas, Schering has problems in all of them—sales, marketing, research, and manufacturing. Take a look at sales. The most important thing to know is that revenues are dwindling--fast. At its peak in 2001, Claritin generated $3.2 billion, almost a third of Schering's total revenues. Since Claritin lost its patent protection last year, cheaper knockoffs have cut its sales by 97%, and management bungled the introduction of its successor, Clarinex. Schering's next- largest franchise, the Intron family of hepatitis C medicines (sales in 2002: $2.7 billion), is also losing ground.

In the labs Schering is mediocre at turning R&D investment into patents (see chart). The single bright spot is Zetia, a cholesterol- lowering drug developed as a joint venture with Merck. Zetia could generate $711 million for Schering by 2006.

The manufacturing division is even more troubled. Executives entered a consent agreement in May 2002 in response to the FDA's accusations of unsafe manufacturing practices, such as the production of defective tablets and asthma inhalers (see "Bitter Medicine," on fortune.com). The FDA imposed its largest fine ever-- $500 million--and forced Schering to bolster its oversight of production, which is proving costly.

Schering is also the subject of a separate FDA criminal investigation into whether company officials knowingly distributed faulty products. In addition, the attorneys general of Massachusetts and Pennsylvania are investigating allegations that the sales division marketed certain drugs for unapproved or "off label" uses. And the SEC is looking into a charge of selective disclosure of financial information.

Put it all together, and it is no surprise that Schering's net income for the first half of 2003 dropped 71%, to $355 million, from $1.2 billion the previous year. The stock has lost almost 75% of its value since November 2000 (see chart) and could drop further after the recent announcement of a sharp cut in the dividend. Hassan did not help matters when he failed to participate in an Aug. 21 conference call to explain the decision. Even friendly analysts were piqued by his absence.

Ducking the analysts was uncharacteristic for Hassan. What sets him apart from other CEOs in the industry is that he is, first and foremost, a communicator. Sure, he's been known to stand at a podium flipping slides while droning on about "seamless product flow." And he isn't exactly Mr. Flair. His suits range in color from slate to charcoal. His ties run the gamut from red to maroon. His shirts are white. It's a safe bet that his base annual salary of $1.5 million (through 2006), plus stock and options worth $14 million, will not be spent on frippery.

His formal demeanor, however, is not a forbidding one. Hassan likes to talk tactics with salespeople and show off his scientific background with the techies. In the numerous large town-hall meetings and smaller roundtables he has held to engage workers, people are not afraid to say tough things. One evening in early August, for example, he's having dinner with salespeople from the New York--New Jersey region. He has barely stuck a fork into his roasted chicken when the complaints start: The staff wants more products to sell and is tired of fending off rants about the company's problems. The main question: Is he planning to do away with the 60-40 salary-commission split? Hassan gives it to them straight. "The problem," he says, is that the commission is "just too high." The industry standard is 30%.

After each meeting, Hassan answers employees via e-mail. As with the salespeople, he cannot always tell employees what they want to hear. Still, the fact that he is trying to communicate comes across loud and clear. After one roundtable, a researcher comments, "I couldn't tell you what the former CEO [Richard Jay Kogan] looked like. We got an e-mail from him once a year. That was it."

One asset Hassan can count on is that Schering's 30,000 employees haven't given up. "When I leave here sometimes around seven at night, I still see many cars in the parking lot. That's a good sign," he says. "Now, whether they're waiting for traffic on the New Jersey Turnpike to clear up is another question."

Farid Hassan (his original name) left Pakistan at age 17 to study chemical engineering at the University of London. He stumbled into business when he returned to Pakistan in 1967 and began a painfully boring job at a fertilizer plant. In the meantime he met his wife, Noreen, whom he credits with helping him recognize his aptitude for management. By the summer of 1970 the newly married Hassan was off to Harvard Business School. After graduation he took a job with Sandoz Pharmaceutical Corp. (now Novartis). It was there that he began pulling off a string of turnarounds. In 1975, Sandoz executives sent Hassan to Lincoln to reorganize a marketing unit in disarray. He did. Five years later he went back to Pakistan to run the company's then-miserable operations. Within three years the unit went from the No. 15 drug seller to No. 4. By 1987, Hassan had become CEO of Sandoz. He left to take the top job at Wyeth in 1989. In 1997, he became CEO of Pharmacia, two years into a disastrous merger of Sweden's Pharmacia and Upjohn Co. of Kalamazoo, Mich.

Cultural differences were at the heart of the problem. In one case Pharmacia's European managers—who ran their own marketing and research operations—ignored a promising antibiotic known as Zyvox simply because it had been developed in Kalamazoo. Rather than fight one cultural battle after another, Hassan moved the company's headquarters from England to northern New Jersey. That consolidated the company in new territory. He also merged the various marketing and research efforts.

On Hassan's watch Pharmacia's revenues grew from $8.9 billion to $14 billion, while earnings per share tripled. In 2000 he orchestrated a merger with Monsanto, which brought in Celebrex, the company's top-selling arthritis pain reliever (sales last year: $3 billion). Pfizer took notice, paying $60 billion to acquire Pharmacia in 2002. Critics say that a genuine turnaround would have enabled Pharmacia to stay independent. That is a debate for the business schools: The fact is, Hassan put himself out of a job— and made Pharmacia shareholders very happy.

If he can turn around Schering, Hassan could become one of the most influential pharma executives in the country. True to his orderly ways, he ticks off a plan: "One, stabilize; two, repair; three, turn around; four, build the base; and five, break out." For the past few months he has tackled the first and second steps: investigating problems, looking at the books, and figuring out where to cut costs. In late August he announced plans to eliminate nearly $200 million in annual spending. A thousand jobs will go, as well as the company jet, merit salary increases, the executive dining room, and bonuses (including his own). In an e-mail to employees Hassan reinforced the new tenor of austerity. "We must attack our cost structure with a renewed sense of urgency," he wrote. "Each person in our organization must think like an owner." The most draconian measure was to cut the annual dividend from 64 cents a share to 22. The immediate response of many shareholders who had held onto the stock solely because of its dependable dividend record was to cash in. The share price dived.

As for the rest of Hassan's revival plan, he will devote the immediate future to addressing the company's legal and regulatory issues. Six to nine months from now he plans to turn his attention to further reducing costs and wringing more productivity out of the company's labs, so that "we're no longer relying on just a single blockbuster" like Claritin. On that basis, the company can turn itself around, and in five to eight years be in good shape.

That's the idea, but almost no one on Wall Street is convinced. "I don't see what's driving this company or how it can spend money to revitalize earnings growth," says Herman Saftlas, a senior investment analyst at Standard & Poor's. The five-point program is "not growth-driving. I'm just not positive on this company." Barbara Ryan of Deutsche Bank is a rare analyst who is comparatively bullish on Schering, but her praise is damningly faint. "I love this stock because everyone else is wringing his hands about it."

The key to success, says Hassan, is step five (breakout), which he vaguely describes as doing something that sets Schering apart. How could that happen? Some lucky researchers could develop two or three Claritin-sized blockbusters. Or maybe Schering could license a few breakthrough medicines from biotech firms. The problem is that each of those breakout strategies is far-fetched. The company admits it doesn't have any likely blockbusters in the pipeline, much less a series of them. As for licensing, why would a biotech company hoping to hit it big go with Schering rather than better- financed Merck or Pfizer? Hassan insists that Schering can compete because he knows how to form personal relationships with managers. If charm could buy bestselling medicines, Schering would indeed be well positioned. But it can't.

Some Wall Streeters speculate that the only chance for Schering to turn around its financial performance is for Hassan to tend to the legal problems, pare down operations, get rid of noncore businesses like Dr. Scholl's, and then sell the rest to Merck, with which it has a good track record, thanks to the Zetia joint venture. Merck executives say they're not interested. (Merck hasn't made a major drug company acquisition in 50 years.) Neither is Hassan. "We have the ability to do a lot with the company," he says. "Why would selling be the alternative?"

It's a good question, and one that comes up in every single meeting Hassan has with Schering employees. Many of them wonder if his grand plan is to sell Schering off, as he did Pharmacia. He is adamant that the company can and will go it alone. "This is a fix- and-build thing," Hassan says. "Not fix and sell." Granted, it's hard to raise morale with the rallying cry of "Let's make ourselves good enough to be eaten by Pfizer!" But Hassan cannot really be that certain of Schering's destiny.

Given the realities of industry consolidation, soaring costs, rising competition, and looming legal woes, it's hard to see how Schering can survive as an independent player. A much safer bet is that within five years Schering-Plough will add another hyphen to its name (or lose it altogether).

Sure, it's possible that the clouds will part and that labs will save the company by churning out a slew of profitable new products that hit the market without delay. Or that licenses will rain down on Schering like manna. Such developments would, however, border on the miraculous. If the goal is to keep Schering independent while making it profitable, Fred Hassan may be heading toward his first high-profile failure. Hassan "did a nice job at Pharmacia," concludes Tony Butler, senior pharmaceutical analyst at Lehman Brothers, "but this is a different bag of rocks to turn into diamonds."

Hepatitis C Virus; Early Response to Therapy Allows Accurate Prediction Of Treatment Success
by NewsRx.com

Early virologic response (EVR) in patients with chronic hepatitis C following 12 weeks of individualized, weight-based dosing of PegIntron (peginterferon alfa-2b) and Rebetol (ribavirin) combination therapy can accurately predict the likely outcome of a full, 48-week course of treatment, according to a paper appearing in Hepatology ((Davis GL, Wontg JB, Wong JB, et al., Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology, 2003;38(3):645-652).).

The findings show that EVR is important to physicians in making treatment decisions and to patients as a treatment milestone. This analysis is consistent with the current European Union (E.U.) labeling for PegIntron.

As noted in the paper, 76% of patients demonstrated an EVR following 12 weeks of individualized, weight-based dosing of PegIntron and Rebetol combination therapy, and, of those, 80% of patients went on to achieve a sustained virologic response (SVR) after full treatment. EVR is defined as at least a 99% (2 log10) reduction in hepatitis C virus (HCV) load at week 12 of therapy. SVR is defined as the sustained undetectability of HCV 6 months following 48 weeks of treatment and is the accepted criterion for efficacy.

The paper also noted that, of the patients who failed to attain an EVR at 12 weeks, none achieved an SVR (100% negative predictive value). When cost was considered, it was estimated that discontinuing treatment in early nonresponders could reduce total overall drug treatment costs nearly 20%.

"A 12-week EVR provides patients and physicians with an early goal, and, for the majority of patients who attain EVR, can motivate treatment adherence and completion to achieve a sustained virologic response," said Michael P. Manns, MD, professor, department of gastroenterology and hepatology, Medical School of Hannover, Germany. "On the other hand, as noted in the E.U. labeling for PegIntron, for patients who do not demonstrate an EVR or take longer to respond to therapy, physicians should consider discontinuing treatment or continuing it based on other prognostic factors," he added.

Manns said that the positive predictive value of individualized, weight-based dosing of PegIntron and Rebetol combination therapy in this study is very encouraging in that, of those patients who achieved an EVR, 80% went on to achieve an SVR. He also stated that the 100% negative predictive value of this combination therapy indicates that physicians can predict, with a high degree of confidence, which patients will not respond to further treatment, and ensure that therapy is not prematurely discontinued for any potential responders.

PegIntron and Rebetol combination therapy is the most prescribed treatment for hepatitis C worldwide and is indicated for the treatment of chronic hepatitis C in patients with compensated liver disease who have not been previously treated with interferon alpha and are at least 18 years of age.

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New process prolongs blood platelets' shelf life
by Karla Gale

By adding a type of sugar to donated blood platelets, scientists may have discovered a way to refrigerate these tiny blood cells and increase their shelf life.

Not only could this dramatically boost the supply of these often life-saving blood components, the sugar solution could enhance the quality of platelets so patients would require fewer transfusions.

Platelets are necessary for normal blood clotting, and they protect against blood loss by clumping together at the site of a vessel injury. A lack of platelets due to bone marrow failure can lead to life-threatening bleeding, and less severe deficiencies can spur bleeding after surgery or injury.

Platelet transfusion—performed more than 4 million times in the US each year—can counter these problems.

Until now, platelets had to be kept at room temperature because refrigeration causes them to be attacked by a recipient's own immune system. But after more than five days in storage, bacteria could grow and cause severe disease in recipients. As a result, up to half of the US platelet supply goes to waste.

Dr. Karin M. Hoffmeister, of Brigham and Women's Hospital, Boston, and colleagues recently found that chilling causes molecules called von Willebrand factor receptor to form clusters on the platelet surface. This
causes a recipient's immune system to attack and destroy the platelets when they're transfused.

Using human platelets in test tubes, the researches have now shown that adding a sugar called uridine diphosphate-galactose to platelets allows them to be stored at reduced temperatures for up to 12 days.

The sugar solution "does not prevent the clustering of the von Willebrand factor receptors," Dr. Hoffmeister explained in an interview with Reuters Health. "It just 'covers up' the exposed clusters," masking them from the recipient's immune system.

As the team reports in the journal Science, the process does not impair platelet function. Treated platelets circulate well after being transfused into mice and they are more efficient at clotting blood.

Their findings could substantially improve patient care and save money at the same time, Hoffmeister added. Currently, supplies of platelets in blood banks are rotated, with the oldest batches, up to five days old, being used first. "Imagine if you left cheese out for five days at room temperature," she pointed out. "The quality would be bad."

Because of the poor quality, patients must often undergo repeat transfusions.

"If we could increase platelet inventories by storing them at 4 degrees, that would be great," Hoffmeister said.

Because uridine diphosphate-galactose is a normal constituent of human cells, she hopes that the FDA will quickly approve clinical trials.

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North America's first supervised heroin injection site opens

The first supervised heroin injection site in North America officially opened in this west coast Canadian city, with supporters saying it will likely help reduce drug overdose deaths.

Organizers of the initiative estimate that as many as 800 addicts a day will go to the site to shoot up, instead of using local back alleys.

Supporters hope the site will reduce the number of overdose deaths, already at 37 this year, and curb AIDS and hepatitis infections among drug users.

"It's going to make a large difference," said Vancouver's Mayor Larry Campbell. "This is a historic day for Vancouver and a turning point in our approach to dealing with addictions."

There is massive public support for the site. Campbell, a former coroner and policeman, won a landslide election last year mainly on his drug platform.

The facility on Hastings Street is in the centre of a gritty neighbourhood known locally as the Downtown Eastside. The population of some 25,000 includes thousands of drug addicts and it is Canada's most impoverished neighbourhood.

Campbell cautioned that "no one should expect the Downtown Eastside drug scene to change overnight."

"However, in combination with other prevention, treatment and policing efforts, we hope to reduce drug related deaths, and see injection drug users get the health care, treatment and support they need to live healthier lives," he said.

The storefront facility is modelled on sites in some 50 other cities in Europe and Australia.

But in North America, which mostly regards addiction as a law enforcement rather than health issue, the site is extremely controversial.

Vancouver is being closely watched by some right-wing opposition politicians in Canada, who vehemently opposed the site, as well as drug authorities in the United States.

US drug czar John Walters, who earlier this year travelled to Vancouver to speak out against Canada's approach to drugs, called the injection site "state-sponsored personal suicide."

While the doors of the site officially opened Monday, it will be at least another week before users are able to access the facility.

The site has been organised by the Vancouver Coastal Health Authority.

Users will be attended by 16 nurses as well as several counselors, who will offer medical treatment, watch for overdose, and give advice about rehabilitation options.

Addicts, however, will have to bring their own drugs with them, which they still have to purchase illegally from street vendors.

The relaxation of Canadian drug laws does not include selling heroin to addicts.

The Vancouver facility was approved after heated debate in June by the Canadian government, after an 18-month investigation.

"We have to talk about (illegal drugs) as a health issue and not as a moral issue," said Liberal MP Paddy Torsney, chair of an all-party Special Committee on Non-Medical Use of Drugs, which unanimously approved a new national drug strategy aimed at prevention and education.

The Vancouver site is part of that national plan, and is funded by the federal and British Columbia provincial governments as a three-year research project and harm-reduction trial.

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Vancouver Opens Safe-Injection Site for Addicts
by Allan Dowd

Vancouver opened North America's first government-sanctioned injection site for addicts on Monday, saying it will save lives but won't solve the Canadian city's drug problems.

The facility in Vancouver's poor Downtown Eastside neighborhood has been criticized by U.S. officials, who say it is an example of Canada becoming lax in the battle against illegal drugs.

"We lost a lot of people along the way, but this is a day of celebration," Dean Wilson, president of the Vancouver Area Network of Drug Users, told a dedication ceremony.

The Downtown Eastside has been called "Canada's poorest postal code." It is home to addicts who have drifted from across the country and they can be seen injecting drugs or smoking crack cocaine openly in its putrid alleys.

The neighborhood of 16,000 people is estimated to have 4,700 intravenous drug users. Up to 40 percent of those addicts have HIV or AIDS and 90 percent have hepatitis C, largely because of sharing needles, officials estimate.

At the injection site, addicts get clean needles and inject themselves at small booths in a room supervised by a nurse. After shooting up, they go to a "chill-out room" before returning to the streets. Up to 800 people are expected to use the facility each day.

Supporters say allowing people to inject in a clean place and with ready access to medical help will reduce the spread of deadly disease and cut accidental overdose deaths.

An average of 115 people a year have died from drug overdoses in the Pacific Coast city annually since 1995.

"We're never ever going to cure drug addiction. But what we can do is help those who have that addiction stay alive," said Mayor Larry Campbell, a former coroner who was elected last year largely because of his support for the site and more drug treatment facilities.

Canada's health department allowed the injection site to open by giving it an exemption from federal drug possession laws, and it is funding a study to track its use and the impact on drug-related problems and deaths in the city.

Police have agreed not to harass addicts entering the C$2 million ($1.5 million) facility, which is modeled on sites in Europe and Australia. Twenty seven cities around the world have similar operations.

Critics, including U.S. drug czar John Walters, have complained the facility will only encourage people to continue using illegal drugs, and have described it as "state-sponsored personal suicide."

U.S. officials are already upset over Ottawa's plan to decriminalize the possession of small amounts of marijuana, a move that prompted warnings from Washington that it may tighten security along the border.

Vancouver police have been divided on whether to support the facility, and Chief Constable Jamie Graham said officials know critics will be watching closely for any missteps.

Graham said police will turn a blind eye to addicts taking illegal drugs into the facility, but it will not be a "sanctuary" for people wanted for other crimes, and drug-dealing will not be condoned near it.

"We're going let this site have to best chance of success, but let there be no mistake as to our resolve to enforce the law," Graham said.

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Variceal hemorrhage in patients with cirrhosis
by gastrohep.com

Despite effective drugs and endoscopic therapy for variceal bleeding, almost a quarter of deaths occur very soon after bleeding onset, find physicians in the October issue of the Journal of Hepatology (J Hepatology 2003; 39(4): 509-14).

Studies have suggested that the prognosis of patients with cirrhosis and variceal hemorrhage has improved more recently.

Physicians from France performed a prospective cohort study where the choice of prophylactic therapy was left to each practitioner. The team followed cirrhotic patients with medium and large varices in order to determine which factors predict bleeding and death.

There were 314 patients with grades 2 or 3 esophageal varices enrolled in the study. Of these, 173 had no previous history of variceal bleeding.

Not all patients were receiving some form of prophylactic therapy. While 100% of patients with prior variceal hemorrhage were receiving prophylactic therapy, only 61% of patients without prior hemorrhage were.

Overall, the median follow-up was 18 months.

9 deaths occurred within 24 hours of bleeding onset.

The physicians found that there were 76 bleeding events and 14 related deaths. They determined that 9 of the deaths occurred within 24 hours of bleeding onset.

In addition, there were 25 deaths that were not due to bleeding, but were related to cirrhosis.

Using a Cox model, the physicians identified that the presence of tense ascites (relative risk 3.4), and a history of hemorrhage (relative risk 4.4) were independent predictors of variceal hemorrhage.

They also found that in patients with no history of bleeding, bleeding risk was higher with prolonged prothrombin time, and lower when patients were receiving propranolol.

Dr Delphine Nidegger's team concluded, "Despite the advent of effective drugs and endoscopic therapy for variceal bleeding, about a quarter of deaths occur very early after bleeding onset, confirming the need for rapid specific management."

September 17th, 2003

Effective Methadone Dose Does Not Harm Newborns
by Karla Gale

Treating heroin-addicted pregnant women with the most effective dose of methadone does not increase their infants' symptoms of withdrawal after they are born, new study findings suggest.

Instead, methadone appears to reduce risks to both mother and infant by preventing illicit drug use.

Methadone is often substituted for heroin and other opiates when patients are treated for their addiction. When the methadone dose is high enough, it blocks the effects of heroin and reduces addicts' craving for the drug.

Many physicians believe that methadone doses should be kept no higher than 20 milligrams per day when women are pregnant, lead investigator Dr. Vincenzo Berghella told Reuters Health. But effective doses for pregnant women range from 50 to 200 mg daily.

Therefore, his research group, based at Jefferson Medical College of Thomas Jefferson University in Philadelphia, examined the records of 100 mother-newborn pairs treated in their comprehensive program for drug-addicted pregnant women. Methadone doses ranged from 20 to 200 mg per day, they note in their article in the American Journal of Obstetrics and Gynecology.

Their study differed from previous research, they point out, because it examines higher average doses and the last dose prior to delivery. They also scored the newborns' withdrawal problems using an objective measure of clinical signs and symptoms, called the Newborn Abstinence Score (NAS).

Birth weight, highest NAS, presence of neonatal withdrawal, and average duration of treatment for withdrawal did not differ significantly between the higher doses and lower doses of methadone.

"I was happily surprised when our data confirmed that using an effective dose is best for both the women and their babies," Berghella said.

He added that prior research demonstrated that methadone has no long-term effects on the fetus, "just short-term withdrawal," which occurred in 60 percent of the babies.

"Effective maintenance prevents drug hunger and craving and blocks the euphoric effect of illicit drugs," he noted. As a result, the fetus is not exposed to erratic maternal opioid levels, protecting it from repeated episodes of withdrawal.

Furthermore, he said, "by preventing drug-seeking behavior, women are less likely to engage in prostitution or other behaviors that increase their risk of HIV, hepatitis infection, and other sexually transmitted diseases."

He advises heroin-addicted women to check into a program that not only helps them with their symptoms of withdrawal, but also addresses psychological and social issues. The program at Jefferson Medical College "even helps women find housing, stay away from an abusive partner, and provides basic preventive medical care.

"That way, people can become clean and can stay clean," Berghella concluded.

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Dude! You Call This Medicine?
by Franco Pingue

Canada's government-grown marijuana is unfit for human consumption and makes some patients sick, people who have tried it said on Tuesday.

The federal government has permitted more than 600 Canadians to legally buy medical marijuana, the first country in the world to do so. They are patients whose doctors prescribed pot after conventional treatments failed.

"It's not marijuana, it's ground-up stems, twigs and beads and it's not fit for human consumption," said Jim Wakeford, who uses marijuana to battle AIDS symptoms. "The marijuana was offensive and obnoxious smelling, it was not helpful and it gave me bad headaches the two times I tried it."

Marco Renda, who smokes marijuana to help symptoms of liver disease hepatitis C, said he temporarily used government dope after someone stole his marijuana plants.

"I don't like it, and even my doctor advised me not to use it because it does nothing to help my symptoms," said Renda.

A recent study by patients-rights group Canadians for Safe Access claims government dope contains 3 percent of delta-9 tetrahydrocannabinol, or THC, the main active ingredient, not the 10 percent the government says.

Phillipe Lucas, a spokesman with Canadians for Safe Access, who smokes marijuana to ease hepatitis C symptoms, said he canceled his government-ordered dope.

Despite the complaints, Health Canada said its dope is effective and cannot be returned for refunds.

"We question the validity of the test results that they have put forward because they haven't been open and transparent about where the tests were done," said Krista Apse, spokeswoman at Health Canada.

Canadians for Safe Access, which said test marijuana was obtained through a reliable source with access to government pot, urged the government to conduct more tests.

But the government said the medical marijuana is produced using "quality standardized marijuana" and its THC content level is about 10 percent.

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Description of Entecavir Resistance-associated Mutations
by Brian Boyle, MD

Entecavir (ETV) has been shown to have potent antiviral activity in lamivudine resistant (LAMR) patients with chronic hepatitis B virus (HBV) infection. It has also been shown that, as with all antivirals, resistance to ETV can occur.

Among the >500 ETV-treated patients in phase II trials, 2 heavily pretreated patients had a significant rebound in viral load and were evaluated regarding their virologic evolution.

The first patient received 0.5 mg ETV for 52 wk with ~2 log HBV DNA reduction, followed by treatment that included 0.5 mg ETV + LAM before having a virologic a rebound at week 100. At study entry, LAMR substitutions L180M, M204V and V173V/L were present, with substitutions I169T (B Domain) and M250V (E Domain) selected on treatment with both ETV and LAM. Reduced ETV susceptibility required M250V in addition to LAMR mutations.

In another patient, a liver transplant patient who had failed famciclovir, ganciclovir, foscarnet, and LAM therapy, and had RT changes S78S/T, L180M, V173V/L, T184T/S and M204V at study entry, ETV (1.0 mg) was given and viral rebound occurred after 80 weeks of that therapy. At that time the additional substitutions A38E, T184G (B domain) and S202I (C domain) had been selected. Phenotypic assays showed reduced ETV susceptibility when both the T184G and S202I changes were combined with the LAMR mutations. HBV recombinants that had subsets of these mutational changes were HBV replication impaired and retained ETV susceptibility.

The authors conclude, "Additional RT mutations that can lead to reduced ETV susceptibility appear to emerge infrequently on a [LAMR] backbone following prolonged ETV treatment in heavily pretreated patients."

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Hepatic injury in patients taking the herbal weight loss aids
by hivandhepatitis.com

Investigators from Japan find that the herbal weight loss aids Chaso and Onshido may be associated with acute liver injury.

The Chinese herbal supplements Chaso and Onshido are used for weight loss in Japan. However, the safety of these preparations is unknown.

In this study, published in the latest issue of the Annals of Internal Medicine (2003; 139(6): 488-92), researchers describe patients who developed liver injury while taking Chaso or Onshido.

The team evaluated 6 patients who took Chaso and 6 patients who took Onshido before presenting with liver injury.

Patients developed acute liver injury.

They performed pathologic, clinical, and laboratory evaluations and chemical analysis of these herbal weight loss aids.

The investigators found that all 12 patients developed acute liver injury, which was characterized by a marked increase in serum liver chemistry values.

Furthermore, 2 patients developed fulminant hepatic failure. Of these, 1 patient required liver transplantation, and the other patient died.

The team determined that N-nitroso-fenfluramine, a variant of the appetite-depressant drug fenfluramine, was present in these products.

Dr Masayuki Adachi's team concluded, "The use of the weight loss aids Chaso and Onshido may be associated with acute liver injury."

"N-nitroso-fenfluramine is a possible hepatotoxic ingredient."

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Hep C blood 'went untreated'

Patients in Scotland were still contracting hepatitis C from contaminated blood products after the NHS knew that heat treating would kill off the virus, it has been claimed.

More than 500 Scots are thought to have contracted the deadly liver disease during transfusions and other blood treatment in the 1980s before proper screening measures were introduced in 1991.

Now a lawyer representing victims has said that patients are coming forward who had contracted the condition from blood treatments as late as 1995.

Health Minister Malcolm Chisholm last week promised to consider any fresh allegations.

These included claims health chiefs were also aware of the risks of infected blood long before it was officially acknowledged in 1986.

But Solicitor Advocate Frank Maguire, who is acting for many of the patients, has said that new cases are coming forward all the time.

"I'm becoming very disturbed at what I'm finding," he told BBC Scotland's Politics Scotland programme.

"The year 1986 is the date by which these products should have been super-heat treated, recognised by everyone that they should have been super-heat treated, so you would never get the virus.

"But I'm getting cases of 1987, of 1988, of 1989, of 1990, of 1991, of 1994 and of 1995.

"Now that to me says that something has gone far wrong with the NHS and the distribution of blood products and administering them."

NHS Scotland said the allegations were a matter for the Scottish health committee.

'Political will'
Meanwhile, the judge who chaired an expert group which looked into compensation has criticised the Scottish Executive's #45,000 maximum payout offer for living victims.

The group recommended a far more wide-scale compensation deal.

Lord Ross said: "Surely this is something that the country can afford, this is an executive which has accepted that their parliament building may cost #400m instead of #40m.

"The group of which I was chairman was satisfied that given the will the executive could find the money and indeed should find the money."

But Health Minister Malcolm Chisholm insisted that the payments, which have yet to be issued, were adequate.

"I've got to look at this issue within the context of 101 other demands on the health budget," said Mr Chisholm.

"I've got to make a fair and reasonable offer, but people will also understand the other pressures on the health budget, so I think that I've made the right decision and targeted the resources.

"And it's a lot of money, it's #15m in the immediate future but it could well be #15m or more thereafter and I think that should be targeted on people who are still alive."

The health minister added that payments would definitely be made within the next year.

September 18th, 2003

Isis Optimistic About Latest Antisense Compounds
by Deena Beasley

LOS ANGELES (Reuters) - Isis Pharmaceuticals Inc. on Thursday said early clinical trials of its second generation experimental arthritis and diabetes drugs confirm that they are active against targeted human proteins, paving the way for larger studies.

"These trials are evidence that we can produce antisense pharmacology in man," said Dr. Stanley Crooke, the biotechnology company's chief executive.

Isis, based in Carlsbad, California, is a pioneer in the field of antisense drugs, which are meant to work at the genetic level to prevent production of disease-causing proteins. It makes the only commercial antisense drug, a treatment for a rare type of eye infection.

Despite the promising science, results for most antisense compounds have been underwhelming. Isis itself has abandoned experimental therapies for diseases like HIV and genital warts. In March, the company said Affinitak, an experimental lung cancer drug it is developing with Eli Lilly & Co., failed a late-stage trial.

But Crooke maintains that the greater potency, stability, lower cost and better side effect profiles of its latest-generation drug candidates serve to validate the field.

"This is the embodiment of our strategy to use a series of second-generation drugs to help guide dose selection and scheduling ... in order to enhance efficacy trials (phase 3)," he said.

The improved chemistry is also allowing Isis to develop therapies for chronic conditions like diabetes and cardiovascular disease, as opposed to its earlier efforts against diseases like cancer and hepatitis C.

A 20-patient trial of a drug known as Isis 104838, which is designed to block a protein called TNF-alpha, showed that it significantly reduced joint swelling in rheumatoid arthritis patients compared to placebo, according to researchers.

The complete trial results are scheduled to be presented at a meeting next month of the American College of Rheumatology in Orlando, Florida.

Crooke said results from a second 160-patient study of Isis 104838—this one measuring improvement in arthritis symptoms—will be available later this year.

Earlier this week, Isis reported results from an early-stage trial of a drug called Isis 113715, which is designed to enhance insulin's ability to transport glucose, or blood sugar, into cells. The drug is a potential therapy for diabetes and possibly obesity, Crooke said.

"At the top two doses, we saw a dramatic increase in glucose tolerance," Crooke said. Isis plans to start a Phase 2 diabetes trial as soon as possible.

The drugs are given by injection or infusion, but it is possible to make antisense pills, he said.

"We have treated about 150 patients with these second-generation compounds and there have been no meaningful side effects," Crooke said.

He said drugs like Isis 104838 would have a competitive advantage over antibody-based therapies that target the same protein—like Amgen Inc.'s Enbrel —because they are safer.

"These drugs are not proteins. There is no antibody response so administration is enhanced and efficacy is improved. There would also be a dramatic reduction in cost," Crooke said.

Amgen officials were not immediately available for comment.

Meanwhile, the company continues to develop several earlier-version antisense drugs, including Affinitak. Lilly is expected to announce results from a second pivotal-stage trial of the lung cancer drug in mid-2004.

Isis expects around the same time to have results from a Phase 3 trial of Alicaforsen in Crohn's disease and a Phase 2 study of the same drug in ulcerative colitis, Crooke said.

Last week, Genta Inc. and Aventis SA said they would seek approval for experimental skin cancer drug Genasense, even though the antisense compound showed only limited effectiveness in late-stage trials.

September 19th, 2003

Resection of hepatocellular carcinoma in patients eligible for transplantation
by gastrohep.com

Partial hepatectomy in patients with early hepatocellular carcinoma can be performed with minimal morbidity, finds a team of investigators in the September issue of the Annals of Surgery (Ann Surg 2003; 238(3): 315-23).

There has been a 75% increase in hepatocellular carcinoma (HCC) in the United States the last decade.

Liver transplantation is an acceptable treatment for patients with early HCC, even when they have adequate liver function.

In this study, investigators from New York, USA, assessed the long-term outcome of patients with early HCC who were treated with partial hepatectomy, rather than transplantation.

The team evaluated 611 patients with HCC, between 1989 and 2001. Of these, 180 patients underwent partial hepatectomy; 20% of these patients satisfied the accepted criteria for transplantation.

The investigators used Kaplan-Meier analysis to measure patient survival.

5-year disease-free survival was 48%.

The team found that the median tumor size was 3.5 cm, and the median number of lesions was 1.

Overall, 78% patients had pathologically confirmed cirrhosis, and 86% had normal liver function (Child class A).

The researchers found that perioperative morbidity was 25%. There was 1 perioperative death.

The team calculated the 1-, 3-, and 5-year overall survival as 85%, 74%, and 69%, respectively. Median survival was 71 months.

They also found that 5-year disease-free survival was 48%, with a median of 52 months.

Dr Charles Cha's team concluded, "Partial hepatectomy in patients with early HCC who are otherwise eligible for transplantation can be performed with minimal morbidity."

This procedure, "Can achieve comparable 5-year survival to that reported for liver transplantation."

"Resection should be considered the standard therapy for patients with HCC who have adequate liver reserve."

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VA Seeks Former POWs for Possible Benefits
by T. Hanby

The Department of Veterans Affairs (VA) is asking former prisoners of war not currently using VA benefits to contact VA to find out if they may be eligible for disability compensation and other services.

More than 23,000 former prisoners of war (POWs) already receive compensation from VA. This year, the department mailed information about benefits to another 4,700 known ex-POWs not on its rolls. However, VA estimates there could be as many as 11,000 more POWs for whom it does not have an address.

Today, on National POW-MIA Recognition Day, VA is asking former POWs not receiving benefits who did not receive a VA letter recently to call the department at 1-800-827-1000.

Secretary of Veterans Affairs Anthony J. Principi said VA has expanded policies to cover increasing numbers of former POWs as new illnesses have been found related to captivity. The administration currently is pressing to get even more compensation and medical care benefits for former POWs.

"These veterans sacrificed for their country in time of war, and it's the nation's turn to serve them, to help them determine if they are entitled to compensation, health care or other services," Principi said.

Nine out of ten former POWs are veterans of World War II, and their service predates the use of Social Security numbers as a military "service number."

That, coupled with the decades that have elapsed since their service, makes it difficult for VA to track down those who have not opened a file with VA in recent years.

"On this POW-MIA Recognition Day, VA is asking veterans and all Americans who know of a former POW to help spread the word that benefits and services may be just a phone call away," Principi said.

The most recent expansion of VA benefits for former POWs was a July regulation that added cirrhosis of the liver to the list of diseases to which entitlement to disability compensation is presumed in former POWs.

Similar policies making it easier for former POWs to obtain compensation have been enacted for POWs detained for 30 days or more who develop specific
illnesses.

Former POWs have a special eligibility for enrollment in VA medical care and are exempt from making copayments for inpatient and outpatient medical care.

They have the same copay rules as other veterans for medications and for extended care. Free dental treatment for any dental condition is available
to former POWs held for more than 90 days.

More information about VA services for former POWs is available at
http://www.vba.va.gov/bln/21/Benefits/POW/.

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September 21st, 2003

Cheaper Doesn't Mean Better. Ask a Canadian
by Sally C. Pipes

Four years ago, my uncle was diagnosed with non-Hodgkin's lymphoma, a cancer of the lymphatic system. He was like a father to me, so the news was extremely upsetting. Wanting to do something to help, I delved into possible treatments for his condition, beyond the chemotherapy he was receiving at the British Columbia Cancer Agency in Vancouver, where he lived. I came up with some good news: There was a new drug, Rituxan, that was having great success combating lymphoma in patients in the United States. And I came up with some bad news: Rituxan wasn't yet available in Canada.

The doctor suggested that if my uncle wanted to try Rituxan, he should go to Seattle, a two-and-a-half-hour drive across the border. But my uncle decided that at 86, that was too much of an effort for him. He died six months after his diagnosis—right around the time that Rituxan was approved for use in Canada.

I offer this sad story as a cautionary tale to Americans, whose politicians have been singing the praises of the Canadian drug-pricing system and loading seniors onto buses to head north across the border in search of discount medications. I live in the United States now, but I grew up in Canada, all my family and friends still live there, and this is what we can say to those politicians: The system that produces cut-rate Celebrex and Vioxx may look attractive if you're seeking to save your constituents a few dollars on prescriptions, but it comes with a pretty severe, and rarely mentioned, side effect: It restricts Canadians' access to the newest cutting-edge drugs.

And this means I'm watching the latest development in America's prescription drug war with trepidation. Illinois Gov. Rod Blagojevich—following in the footsteps of Springfield, Mass., Mayor Michael Albano—has won kudos from many quarters for his plan to purchase inexpensive drugs from Canada for his 240,000 state employees and retirees. But I'm afraid that if Congress legalizes such purchases through a pending drug importation bill, the result could be even more diminished options for Canadian health-care customers —and ultimately reduced options for Americans, too.

American pharmaceutical companies, which must somehow recoup the roughly $800 million it costs to develop a new drug, will have no incentive to send critical new drugs north to Canada if they're only going to make their way back into the States at discounted prices. Meanwhile, Canadian pharmacists will be faced with making a choice about the drugs they do get: whether to sell them at the normal pace at home, or send them south in bulk for a quick profit. If they choose the latter, as they likely will, Canadians will have to go without, or be forced south in even greater numbers in search of the medicines they want and need.

There's an irony here. While Americans are flocking to Canada to get inexpensive drugs, Canadians have for years been going in the opposite direction, desperately seeking new and necessary medicines that they can only obtain in the United States. They're willingly paying top-dollar for them, out of their own pockets.

A friend of mine in New Brunswick, who suffers from Type 2 diabetes, is a case in point. He found that Glucophage XR, an oral blood-sugar-control medication from the U.S. manufacturer Bristol-Myers Squibb that his doctor was able to obtain in small amounts, was the most effective drug for him. But it isn't available in New Brunswick. So he has to travel to Bangor, Maine, about four and a half hours' drive away, to get it.

Canada's drug regulatory system, controlled by the Patented Medicines Prices Review Board (PMPRB)—Canada's version of the FDA—is a complex web of federal and provincial bureaucratic barriers to entry for drugs such as Glucophage XR. The PMPRB, which was established to ensure that drug prices are not excessive, strictly monitors the prices at which manufacturers may sell drugs to wholesalers and pharmacies, and at which pharmacies may sell to the public. In addition, each of Canada's 10 provinces also maintains a government-approved formulary, which determines which drugs will be available to Canadians. Once approved by the PMPRB, medication must then get the nod from each of the provincial formularies. Many provinces approve fewer than half of all the new drugs the board has okayed.

To save funds, Canadian health officials delay the introduction of new and more expensive drugs. As a result it takes considerable time for new and more expensive medications to make it into the medicine chests of Canadians. Some never do. One hundred new drugs were launched in the United States from 1997 through 1999. Only 43 made it to market in Canada in that same period. Canadians are still waiting for many of them.

This process may save the government money, but it shifts costs to patients, who pay in the form of increased pain and a diminished life—or in significant out-of-pocket dollars if they choose to seek the drugs over the border. So while U.S. politicians such as Blagojevich celebrate the low prices Canadians pay for drugs, patient advocates in Canada find themselves, because of those same low prices, fighting to give Canadians a shot at securing the most effective medications.

Dennis Morrice is CEO of Canada's Arthritis Society and co-chair of Canada's Best Medicines Coalition, a group founded two years ago to ensure that patients get the drugs they need.

According to Morrice, some 4 million Canadians suffer from some form of arthritis, the largest cause of long-term disability in Canada. Yet highly effective drugs such as Enbrel and Remicade, long available to patients in the States, may or may not be available to Canadians, depending on which province they live in. As recently as 2002, only two provinces—Saskatchewan and Ontario—listed the drugs. Says Morrice, "Many people still can't get them."

The problem cuts across diseases. "It takes twice as long to get AIDS drugs approved in Canada [as in the United States]," says Durhane Wong-Rieger, a prominent Canadian patient advocate. "And these are high-priority drugs." Wong-Reiger points to numerous drugs that Canadians simply can't acquire, either because they haven't been approved for use in Canada, haven't been approved for use in specific provinces, or simply have not been marketed to Canada by companies that lack an economic incentive to do so.

AIDS medication Reyataz, manufactured by Bristol-Myers Squibb and approved by the FDA earlier this year, hasn't even begun the approval process in Canada. The same is true of Pegasys, produced by Hoffman-La Roche Inc. and approved by the FDA last year for the treatment of hepatitis C. It's a good illustration of the general problem. In the States, it's already been approved for a new combination therapy with Hoffman-LaRoche's Copegus antiviral medication to help fight hepatitis C. Canadians, however, still don't have access to the original therapy.

For some drugs that are unavailable in Canada, such as Paxil CR, an improved version of Paxil to treat depression and anxiety, or Niaspan, which treats high cholesterol, patients can hop a bus south to pick up the pills at U.S. prices. But Pegasys is an intravenous medication, so traveling to obtain it isn't a viable option. Starting on an older, less effective treatment and then switching when a drug becomes available is no better. "I get patients who are not taking any drugs because they are waiting for this drug," says Wong-Rieger. "It's a Catch-22. They can take the drug that's on the market and it won't do the job, or they can wait and get sicker."

In the battle over whether to purchase drugs from Canada for U.S. citizens, all that supporters see are the potential savings to their constituents. Says Blagojevich, "I am optimistic we will be able to save literally millions of dollars for the taxpayers." But there's more to the issue than that.

Even if we leave aside the costs to America's Canadian neighbors, who look at the wealth of medications available to Americans with envy and longing, there's the very real prospect that the politicians' scramble to get cheap drugs from next door can backfire on Americans in the long run.

Most drug manufacturers can afford to sell their pills to smaller customers like Canada (which has only 33 million citizens) at discounted prices and make a lower profit, but selling them to everyone at these prices, which are well below the average cost of production of a new medication, would be prohibitive. It would mean, in effect, that drug companies would have no motivation to research and develop ever newer and better drugs. The losers in that case? Both Americans and Canadians—not to mention the rest of the world.

The lesson to be learned from Canada is not that cheaper drugs are possible, but that price controls reduce the availability of critical life-saving drugs. Americans have access to the best, most effective drugs in the world. Congress's latest crusade against the pharmaceutical industry will only further lower the quality of health care for Canadians. If Blagojevich and others get their wish, the United States may not be far behind.

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September 22nd, 2003

Matria Healthcare Signs Strategic Disease Management Agreement with Schering Corporation

Matria Healthcare, Inc. (NASDAQ:MATR) today announced that it has signed a letter of intent with Schering-Plough Corporation (NYSE:SGP) to provide patient support and educational services for the innovative and highly successful Schering "Be In Charge" (BIC) program for patients infected with hepatitis C virus (HCV). Schering-Plough, developer of the most frequently prescribed treatment for hepatitis C, continues to lead the way in HCV research, and is the HCV market leader.

More than 80,000 patients around the country have participated in the company's "Be In Charge" program, which provides patients being treated with Peg-Intron(R) (pegylated interferon alfa-2b/Schering-Plough Corporation) combination therapy with an extensive set of support and educational services, including access to a personal nurse counselor, and website. The program already has been shown to help patients complete their individualized Peg-Intron therapy regimen, providing their best chance for achieving sustained viral response (SVR). SVR refers to hepatitis C viral levels being below the level of detection for a sustained period of time, usually 24 weeks.

Through this agreement, Matria will provide personalized patient support and education to patients enrolled in the BIC program. The addition of Matria's comprehensive services to support these patients is designed to enhance the outcomes for people with HCV. Additionally, Matria will be working with Schering to expand the program, bringing its benefits to more of the estimated four million Americans infected with HCV - a larger group than suffers from HIV infection.

Matria Healthcare is the leading provider of comprehensive disease management programs to health plans and employers. Matria manages the chronic diseases and episodic conditions representing the greatest cost to the healthcare system...diabetes, cardiovascular diseases, respiratory disorders, high-risk obstetrics, cancer, chronic pain and depression. Headquartered in Marietta, Georgia, Matria has more than 40 offices in the United States and internationally. More information about Matria can be found online at www.matria.com.

Predictive factors for early mortality following liver transplantation
by gastrohep.com

Investigators, in the latest issue of Clinical Transplantation (Clin Transplant 2003; 17(5): 401-11), find that pre-transplantation renal insufficiency is the most significant risk factor for early mortality in liver transplant patients.

In this study, investigators from Spain reviewed their liver transplant performance to identify factors influencing outcomes.

The team examined the clinical records of 190 patients who had liver transplants performed between 1991 and 1997. The prognostic model obtained was prospectively evaluated in 55 patients undergoing transplant between 1999 and 2000.

No donor factors were significant.

Main indication for transplant was post-necrotic cirrhosis, and the majority of patients were Child-Pugh C status.

The investigators found that post-operative mortality at 3 months was 15%. They identified the risk factors predicting death as Child-Pugh C status (OR 1.3), pre-liver transplant renal insufficiency (OR 5.8), malnutrition (OR 2.9), and technically complex surgery requiring cross-clamping (OR 4.9).

They did not find that any of the donor factors were significant.

When the model was prospectively applied it had a sensitivity of 80% and a specificity of 89%. It also had a positive predictive value of 62% and a negative predictive value of 95%.

Dr Itxarone Bilbao's team concluded, "Pre-liver transplantation renal insufficiency is the most significant risk factor for early mortality".

"Liver transplantation should be performed before evidence of irreversible renal insufficiency becomes manifest".

September 23rd, 2003

Hepatitis Threatens to Wipe Out Two Amazon Tribes

The United Nations said Tuesday it had launched a vaccination campaign to save two tribes in the remote Peruvian Amazon threatened with extinction by a mysterious hepatitis B outbreak.

"Local leaders warned that (the two tribes) could face extinction within 10 to 12 years, if preventive action, especially among children, is not taken," the U.N. children's fund UNICEF said in a statement.

Peru's Health Minister asked UNICEF for help after 40 deaths were recorded in 2002 in one of the tribes, the Candoshi, with only 2,500 members. They suffered 145 cases in 2001 but it was not known how many people died that year.

There was no data for a neighboring tribe, the Sharpas, who were also at risk.

UNICEF aims to vaccinate all the tribes' 150 babies three times before they are one year old to try to stamp out the disease, which can cause liver failure.

The cause of the outbreak was a mystery as was the reason for the "amazingly" high mortality rate in a disease that often takes 20 to 25 years to manifest itself, said UNICEF spokesman Damien Personnaz.

The tribes live along the Pastaza and Morona rivers in an area of the Amazon basin so remote that travel from any of the 124 communities in which they live to the nearest health center can take four days.

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UNICEF hopes to save two ethnic groups in Peru after hepatitis outbreak

The United Nations Chidren's Fund (UNICEF) said it had launched a major vaccination campaign to save two ethnic groups in Peru from extinction after a mysterious outbreak of hepatitis B.

"The Ministry of Health asked us to carry out immunisation ... to save some 3,000 people," the UNICEF's spokesman in Geneva, Damien Personnaz, said Tuesday.

The project, which cost about 100,000 dollars (87,200 euros) and was funded jointly by the Peruvian government and UNICEF, began vaccinating the Candoshi and Sharpa people last week.

Local leaders had warned that both ethnic groups, who live in 124 tiny communities dotted around the High Amazon region, could be wiped out within 10 to 12 years if the disease was not tackled, UNICEF said in a statement.

Access to the remote area has been a logistical "nightmare," admitted Personnaz, when explaining the relatively high cost of the rescue mission which is due to conclude on Wednesday.

The vaccines had to be kept cold and transportation to most of the villages took around four days, he said.

Last year some 40 deaths due to hepatitis B, which is transported through sexual intercourse and blood, were reported but no one knows why the disease hit the region.

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Insurers issue new rules on gays
by Jill Treanor

Male ballet dancers, hairdressers and cabin crew should no longer face discrimination from insurance companies assessing risks of HIV/Aids as a result of new proposals published yesterday.

The Association of British Insurers has issued five principles that insurers should follow when considering applications for life cover and other protection.

The ABI is trying to prevent insurers from making assumptions about applicants' risk of HIV/Aids or sexuality as a result of their occupation.
The industry group is also trying to enforce a requirement that applicants are not asked whether they have been tested for HIV but only if they have tested positive or are awaiting the result of a test.

The ABI is suggesting new wording for application forms about tests for HIV, hepatitis B or C and visits to countries where there might be a risk of HIV infection.

Richard Walsh, the ABI's head of health, said the proposals were intended to make customers feel they were being treated with respect and not being overcharged for their policies.

The proposals, which are out for consultation in the industry, have been put together with the support of the Terrence Higgins trust and pinkfinance.com.

The ABI is looking for views from other relevant organisations, such as gay and African rights lobbies, doctors, patient support groups and financial advisers, before publishing a final version of the code.

Chris Morgan of pinkfinance.com said the guidelines demonstrated a "new level of respect towards gay men". He noted a clause had been introduced for a "new respectful and relevant question" about safe sexual behaviour that was applicable to all risk groups, not only gay men.

Martin Kirk of the Terrence Higgins trust welcomed a pledge from insurers to conduct a review of policies on HIV/Aids in three years. The ABI's first statement on the issue was published in 1994 and updated in 1997.

The proposals recommend that when communicating with applicants' GPs, insurers should not ask them to speculate on whether the applicant is at higher risk than normal.

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September, 25th, 2003

Molluscs could help fight cancer
by Caroline Ryan

The sea has provided what could be an important chemotherapy drug for patients with hard-to-treat cancers.

The drug Kahalalide F is a protein produced when molluscs eat the sea slug Elysia rufescens.

A trial looking at its effectiveness in treating liver cancer is about to start, researchers told the European Cancer Conference in Copenhagen.

Liver cancer is one of the hardest cancers to treat because it is extremely aggressive.

Surgery is the main treatment available, but it is not suitable for all patients.

The cancer has also shown considerable resistance to conventional chemotherapies, so the development of new agents is a key aim of cancer doctors.

Common cancer
It is also one of the most common cancers worldwide, with two to five cases per 100,000 people in Europe and the US.

The number of cases is rising, largely because of the spread of hepatitis C infections.

Kahalalide F is extracted from the molluscs in the Pacific and was shown to be an effective chemotherapy agent in laboratory and animal tests.

Early trials on 60 patients with cancers of the prostate, breast, liver and colon which had not responded to other cancers showed promising results and demonstrated what the ideal dose was.

This means researchers know what dosage to give patients in the next stage of research, which has just started to recruit patients.

Ana Ruiz-Casado, a cancer specialist from Pharma Mar in Madrid, who is involved in the research, told BBC News Online: "There are some tumours, such as liver, melanomas and mesotheliomas that we do not have many active drugs that we can use.

"So if we have anything, it's better than having nothing."

Kahalalide F is not the only potential cancer drug which could come from molecules found in the sea.

Dr Ruiz-Casado said: "Many people are trying to identify molecules in the sea.

"It's very difficult to find active molecules in the earth - now many people are interested in the sea."

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September, 26th, 2003

Hepatitis A Boosters May Be Unnecessary

Most people don't need booster shots once they've been vaccinated for hepatitis A, a new British study contends.

A complete course of the vaccination, usually two to three doses, protects against the disease for more than 10 years and perhaps as many as 25 years -- at least among people with healthy immune systems, the researchers say. That makes booster shots unnecessary, they add.

Protection stems from the immune system's long-term memory, the study says, and persists even after protective antibodies can no longer be detected. Results appear in the Sept. 25 issue of The Lancet.

However, whether booster shots can be eliminated in people with immune system problems or for people who initially received only a single dose of the vaccine is not yet known, the study says.

Hepatitis A is a liver disease caused by hepatitis A virus. Symptoms may include fever, tiredness, loss of appetite, nausea, abdominal discomfort, dark urine, and jaundice (yellowing of the skin and eyes), according to U.S. health officials.

About 1.4 million cases of hepatitis A are reported each year, although experts suspect that 10 times that many people worldwide actually contract the disease. People most susceptible are those living in or traveling to less-developed parts of the world.

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'Whitey' from 'Leave It to Beaver' Dies
by Steve Gorman

Former child actor Stanley Fafara, who played Beaver's pal Whitey on the idyllic family sitcom "Leave It to Beaver" but descended into a real-life adulthood of drugs, alcohol and petty crime, has died at age 53, friends said on Friday.

Fafara died in a Portland, Oregon, hospital on Saturday, Sept. 20, of complications from surgery he underwent last month to repair a constricted intestine caused by a hernia, according to Tom Hallman Jr., a reporter for the Portland Oregonian who knew him.

Hallman, who had kept in touch with Fafara since writing a profile of him in December 2002, said the former actor already was weakened by a hepatitis C infection contracted years ago from intravenous drug use. Hallman said friends of Fafara told him the former actor ultimately was removed from life support after slipping into a coma.

His death capped a tragic adult epilogue to the boyhood celebrity Fafara enjoyed as a young actor portraying "Whitey" Whitney, the tow-headed pal of the title character played by Jerry Mathers on "Leave It to Beaver."

The show, set in the fictional suburban town of Mayfield, aired on CBS and ABC from 1957 to 1963.

Fafara, who grew up in the Los Angeles suburbs of Studio City and was pushed into acting by his mother, landed the part as Whitey after doing a number of commercials. He also had appeared in an episode of "The Adventures of Rin Tin Tin."

In a recent online interview, Fafara said it was Whitey who uttered the first line spoken on the show, asking Mathers' character, "What did she do to you, Beaver?" as the Beav emerged from his teacher's classroom with a note to bring home to his parents.

But the innocent, sheltered suburbia depicted on "Leave It to Beaver" was a far cry from the lifestyle Fafara assumed after the series ended its run.

By his own account, he began drinking and doing drugs as a teenager and briefly lived in a house with members of the rock band Paul Revere and the Raiders. Sent off to live with his sister in Jamaica, he returned to Los Angeles at age 22 and started dealing drugs.

By the early 1980s, he was breaking into pharmacies and was eventually sentenced to a year in jail for burglary. After his release, he worked a number of odd jobs and resumed drug dealing to support his habit.

In and out of jail and rehab, he moved to Portland in the early 1990s hoping to get off drugs. But he ended up as a junkie living in a rented motel room, then the streets, before finally checking himself into a detox center in August 1995.

Clean and sober since then, he moved into a halfway house for recovering addicts and alcoholics, then into a subsidized apartment on the edge of Skid Row, where he scraped by on Social Security checks until being hospitalized, Hallman said.

Near the end of his life Fafara took some acting classes, but his aspirations to return to show business never gelled.

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Sex with Strangers Dogging English Parks
Jason Hopps

Voyeurs and exhibitionists drawn to outdoor fun have discovered erotic pleasures in normally placid English parks that have nothing to do with walking the dog.

"Dogging," a term that loosely describes a variety of sex acts performed outdoors or in parked cars in front of strangers (and sometimes with them), has become such a craze that health authorities have warned against its dangers.

The term "dogging" apparently comes from those who claim only to be "taking the dog for a walk"—but are actually on the prowl for something more.

Web sites have sprung up across Britain extolling the pleasures of sex under the stars and online message boards list the best parks and carparks to watch people express themselves.

An academic who set out to study anti-social behavior in parks and stumbled on a thriving dogging underworld said dangers were also lurking in the bushes.

"The problem is people are leaving behind condoms, lubricants and sometimes clothing at family sites and causing cleaning headaches for groundspeople," Richard Byrne, a countryside management lecturer at Harper Adams College, told Reuters on Friday.

"Prostitutes have been moving into some of these areas and I know of cases where some people have been attacked while dogging," he said.

Byrne said he surveyed park managers, rangers and wardens across England and found dogging sites existed in every English county—hundreds are dotted across the country—from the south coast to the Scottish border.

"I soon realized that dogging was being driven by the Internet and was very widespread and that some doggers take it quite seriously, wearing camouflage and even keeping diaries of their experiences," he said.

FLASHING LIGHTS
Among the dozens of dogging Web sites, several offer tips on finding the best locations, how to meet people "to dog" with and how to signal you want to watch—or be watched.

"There's loads of signals that doggers use, the most common are flashing lights. Leaving the inside car light on means they want to be watched. If they wind down the window, this means they want to be fondled," one site advises.

Health authorities in southeast England posted warnings on dogging web sites after discovering several cases of sexually transmitted diseases linked to the outdoor pursuit. "We noticed a more than usual number of notifications of Hepatitis B and when we were investigating we found that some of them were involved in the practice of having sex with strangers in open places," said Dr. Mathi Chandrakumar, head of the Kent Health Protection Unit.

"We are not passing moral judgment, we are only giving advice about the dangers," he said.

While acknowledging doggers are a determined breed, Byrne said he had proposed several ways to prevent the behavior—including more police patrols—but he has already ruled out one remedy.

"We thought better lighting in parks might prevent it but it actually allows to see what they're doing better," he said.

Obesity is an independent negative predictor of response to treatment for chronic hepatitis C virus (HCV), according to the results of a retrospective review published in the September issue of Hepatology (Hepatology, 2003;38:557-559, 639-644).

"Although the efficacy of antiviral therapy in chronic hepatitis C has improved since standard interferon (IFN) monotherapy was introduced, nonresponse to the current therapies remains common," write Brian L. Bressler, from the University of Toronto in Ontario, Canada, and colleagues. "Several factors have been shown to influence response; these include viral factors (particularly genotype) and host factors, which may be genetic (sex, HLA type, cytokine polymorphisms), and others such as age, presence of cirrhosis, and race..... Obesity, a modifiable risk factor, may have a deleterious effect on treatment response to both pegylated and standard IFN monotherapy."

From 1989 to 2000, 253 patients at a single center were treated for chronic HCV with either IFN monotherapy or IFN in combination with ribavirin. A sustained response was defined as either negative polymerase chain reaction for HCV RNA and/or normal alanine aminotransferase (ALT) level, only in those treated before availability of HCV RNA testing, six months after completion of therapy. Normal weight was defined as body mass index (BMI) less than 25 kg/m2; overweight as BMI 25 to 30 kg/m2; and obesity as BMI greater than 30 kg/m2.

Logistic regression with adjustments for age, sex, history of alcohol consumption greater than 50 g/day, cirrhosis on pretreatment biopsy, and BMI revealed significant differences in response to treatment according to BMI group (P = .01), genotype (P < .01), and cirrhosis (P < .01).

Compared with patients with genotype 1, those with genotypes 2 or 3 had an odds ratio (OR) for treatment success of 11.7, and cirrhotic patients had an OR of 0.15 compared with noncirrhotic patients. Compared with normal and overweight patients, obese patients had an OR of 0.23 for treatment success. Hepatic steatosis was not an independent predictor of response to antiviral treatment.

"Obese patients as judged by their BMI, independent of genotype and cirrhosis, had approximately an 80% lower chance of a sustained response to therapy compared with normal or overweight patients," the authors write. "The mechanism whereby obesity may affect the antiviral response to treatment is not completely understood."

In an accompanying editorial, Arthur J. McCullough, MD, from Case Western Reserve University in Cleveland, Ohio, discusses the interrelationship of body fat mass and hepatic steatosis with the presence and progression of fibrosis in HCV.

Despite the limitations inherent in a retrospective design, as well as other methodological shortcomings, "the two important observations in the current study appear valid," he writes. "Weight loss in obese patients may improve the efficacy of HCV treatment.... HCV's resistance to treatment is being nurtured by obesity, a 'terrain' that reflects the excesses of an affluent society."

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September 27th, 2003

Ribavirin ANDAs Still Waiting For FDA; Other Generic Issues Have Priority
by The Pink Sheet

FDA's final decision on the approvability of ANDAs for ribavirin is taking longer than expected while the agency resolves other complex generic drug issues.

A decision appears to have been put off into late October as FDA works through two other unrelated regulatory questions.

Three generic companies seeking to launch versions of Schering-Plough/ICN's Rebetol won a favorable patent ruling July 14 (The Pink Sheet, July 21, 2003, p. 12).

However, approval of the ANDAs filed by Three Rivers, Geneva and Teva awaits a decision by FDA on a citizen petition submitted by ICN. The company maintains that that the agency cannot "carve out" protected labeling covering the use of ribavirin in combination with pegylated interferon (The Pink Sheet, Aug. 18, 2003, p. 17).

The generic companies expected the issue to be resolved in time for an August launch. However, FDA's Office of the Chief Counsel has had to address two other issues that have consumed considerable resources and delayed the ribavirin decision.

First, FDA was under a court order to produce an administrative record behind its approval of the NDA for Collagenex Periostat (doxycycline).

FDA was enjoined from approving generic versions of the dental agent pending a review by the court of the record to determine whether the product was properly classified as an antibiotic (The Pink Sheet, July 28, 2003, p. 10).

FDA had a Sept. 22 deadline to submit the record. The deadline was extended by two days because of the government shutdown during Hurricane Isabel; FDA filed the record Sept. 24.

The agency's next priority appears to be resolving issues raised in a series of petitions about use of the 505(b)(2) NDA process. FDA plans to respond to the petitions by Oct. 13, and is likely to face litigation if it does not meet that deadline (see 4preceding story).

FDA needs to craft a thorough response to the ribavirin issues given the likelihood that it will face litigation no matter how it answers the ICN petition.

September 28th, 2003

Hepatitis virus could be passed on by kissing
By Maxine Frith

The potentially fatal hepatitis C virus can be passed on more easily than doctors have thought, a study shows.

Researchers have found traces of the virus in the saliva of people infected with hepatitis C, meaning it could be contracted from simple acts such as kissing or sharing a toothbrush.

Millions of people who suffer from gum disease could be particularly at risk, the scientists said.

Around 400,000 people in Britain have hepatitis C, although 90 per cent are unaware they are infected because they have no symptoms.

Around one in five sufferers manages to get rid of the virus without experiencing any problems, and 40 per cent of the rest can be cured with combination drug therapy.

For some patients, however, the virus remains in the body and can cause fatal liver damage. The virus is carried in the blood and can also be caught through sexual contact.

Researchers at the Interscience Conference on Antimicrobial Agents in Chicago say that infected people carry the virus in their saliva.

Scientists from the University of Washington in Seattle tested the saliva of 12 people who were infected with hepatitis C every day for 21 consecutive days.

Of the 248 samples taken, 52 or one in five tested positive for the virus. Traces were found in the saliva of seven of the volunteers.

Those most likely to have traces of the virus in their saliva had relatively high levels of the virus in their body. They were also more likely to detect the virus in saliva if the volunteer had gum disease.

The scientists said this may occur when the gums bleed after brushing, leaving tiny drops of blood in the saliva.

"This study suggests that the saliva of individuals infected with hepatitis C may be infectious," they said.

"Microscopic amounts of blood in the saliva due to gum disease may be responsible.

"People with HCV (hepatitis C virus) are cautioned not to share toothbrushes with other people in the household."

The findings suggest the virus could also be spread from kissing.

Basil Williams, chief executive of the UK's National Hepatitis C Resource Centre, said more research is needed to determine if it is possible to catch the virus from kissing.

He said: "It is technically possible to catch hepatitis C from kissing, but the risk appears to be very small."

State grant provides Broward fire-rescue workers with free hepatitis C tests
By Nicole T. Lesson

Fire-rescue workers will now have hepatitis C screenings paid for by a new state grant.

Hallandale Beach Fire-Rescue was awarded a $64,000 grant on behalf of 11 fire departments, including Miramar and Cooper City in south Broward County.

With the grant money, Hep-C Alert, a nonprofit organization that educates the public about hepatitis C and assists people affected by the disease, will train and screen about 1,500 fire-rescue employees.

Hepatitis C, a virus that attacks the liver, is transferred through exposure to bodily fluids. Firefighters and emergency medical workers have basic knowledge about the dangers of the disease and how to protect themselves, but the grant will pay for advanced training and screening tests.

"Hep C is becoming more of an issue with the public safety sector and being more recognized," said Hallandale Beach Fire Lt. Alex Baird. Early detection is key, he added.

In March and April 2000, North Miami-based Hep-C Alert collaborated with University of Pittsburgh researchers to test municipal firefighters, paramedics and emergency medical technicians in Miami-Dade County.

Of the 1,314 participants, 2.7 percent tested positive for the antibodies of the virus, and 1.5 percent had the disease, according to the study. In the age group of men 50 and older, 3.7 percent tested positive for the antibodies of the virus.

"We have found in the fire-rescue industry that the veterans have the highest incidence of Hep C because at that time we were always getting bloody, and it was before we took universal precautions."

Universal precautions translate to fire-rescue workers using rubber gloves, masks, glasses and other safety measures to protect themselves from the spread of fluids or liquids. These precautions have been practiced for about 15 years.

"We are dealing with body fluids—and a glove can rip. And there is always a chance of exposure when you are out there working in a medical field," Baird said. "This is a disease. It can lie dormant for a decade and the results of this disease can include drug therapy, liver failure and liver transplant."

Hallandale Beach Fire-Rescue applied for the grant to finance the screening of its employees, but did not wait long enough for grant funds to pay for the tests. As a result, the department will not share in the grant's proceeds.

"Originally when we started we were halfway through the grant procedure and then the city was able to find the funding," said Lori Williams, the grant writer for Hallandale Beach Fire-Rescue. "We found the money in the budget to screen police, fire and public works personnel."

Miramar, Cooper City, Coral Springs, Lauderdale Lakes, Lauderhill, Lighthouse Point, Margate, Parkland, Plantation, Pompano Beach and Sunrise are the fire-rescue departments that will share the funds provided by the new state grant.

Hep-C Alert will begin training and screening the employees as soon as the county approves a purchase order needed for the program to begin.

The cost of training and screening each fire-rescue worker will be about $45. The cost would be about $75 for screening alone if done by a private physician, according to Hep-C Alert.

Baird, who also is the training and marketing coordinator for Hep-C Alert, will teach a majority of the instruction sessions.

"We are going to provide the education and an opportunity to be tested after the training," said Baird, who hopes to start the sessions in November.

The fire departments will require their employees to attend the training, but the screening for the disease will be optional. Results will be kept confidential.

A person who tests positive for hepatitis C can still work, but if the disease is left untreated it can cause major health problems, Baird said. Those infected may not show symptoms for 20 years, according to Hep-C Alert.

The grant money will be generated by a surcharge on traffic ticket fines, and is distributed through the state's EMS Trust Fund. The Broward Regional Emergency Medical Services Council, a group of emergency service professionals that provides advice on EMS issues to the County Commission, recommended that the
grant be approved.

Cooper City Deputy Fire Chief Michael Campbell said the grant would benefit 38 people in his department.

"We will do anything for employees, as they are the most valuable resource we have," he said. "We had no funding for the screening, but got the training."

Miramar Fire-Rescue and its 120 firefighters will receive funds from the grant as well.

"It's a nasty disease," said Bill Huff, division captain of emergency medical services. "The numbers are twice as much as AIDS. Hepatitis C is of great concern, and B is spreading like wildfire. This will help educate our crew members on the hazards of Hep C and the steps to take to prevent contraction of the disease."

About six years ago, a Miramar firefighter contracted hepatitis C. It was presumed that he was infected by tainted blood on broken glass at the scene of a traffic accident. He is now on disability, Huff said.

"If someone is stuck with a needle or exposed to blood or other body fluids, we make arrangements for treatment and counseling," said Huff, who also serves as the city's infection control officer.

Baird thinks that the grant will benefit the lives of fire-rescue workers.

"The fire department is a brotherhood, and we don't want to see our brothers get sick," Baird said. "If we discover this early on it can help prevent long-term effects."

Hepatitis C seen as 'the new epidemic'. Virus is four times more common than HIV, experts say
by Stacey Range, Lansing State Journal

Rachel Maddow spent much of the past decade consulting prison staff around the country on how to treat inmates with HIV.

But with an explosion of prisoners carrying a new, more common and deadly disease, Maddow changed her focus last year to hepatitis C.

"It's the new epidemic," Maddow said. "The AIDS of the new century."

Four times more prevalent than HIV, health experts say hepatitis C, a potentially fatal virus that attacks the liver, is now the infection causing the greatest threat to public health in modern times.

A third of all cases are among prisoners.

Consider these facts from the U.S. Centers for Disease Control and Prevention:

In the 14 years since its discovery, hepatitis C has become the most chronic blood-borne infection in the United States.

It's the No. 1 reason for liver transplants nationwide, accounting for about 1,000 procedures a year - about 50 of those in Michigan.

By 2010, hepatitis C will kill 30,000 people a year - twice as many Americans as AIDS.

"This is a huge public health issue that must be addressed, or it will only get worse," said Dr. Robert Griefinger, former chief medical officer for the New York State Department of Correctional Medical Services.

Hepatitis is inflammation of the liver, which fights infection, filters toxicants and stores energy.

The main difference between various strains of hepatitis is the intensity with which it attacks.

Hepatitis C is the only strain of the virus for which there is no vaccine or cure. But drug therapy can reduce the virus to undetectable levels in up to 80 percent of patients.

The CDC estimates that 4 million Americans have hepatitis C antibodies. Of those, about 2.7 million have active hepatitis C infection. About 750,000 Americans are infected with HIV.

The time frame from exposure to infection is vital, said Dr. Cindy Weinbaum of the CDC.

Often called the "silent virus," hepatitis C can hibernate for decades, giving little or no indication to its host until the liver becomes inflamed.

Weinbaum says that's the reason for the surge of cases today. It's not that more people are becoming infected. Since 1989, the number of new infections each year has dropped by more than 80 percent to about 41,000 new cases in 1998.

But because it takes so long for the virus to develop, many cases are coming to light now, and more do not even realize that they have the disease.

"This will become even more visible in the next five, 10 and 15 years as more and more people start coming in for help," Weinbaum said.

Hepatitis C is more difficult to spread than other infectious diseases. Unlike the common cold and influenza, which can travel through the air, hepatitis C must pass from one blood source to another.

Sharing drug needles - a common activity among prisoners - is the greatest source of hepatitis C.

The virus also can be passed by sharing toothbrushes, razors and other sanitary goods.

Blood transfusions were the largest source of hepatitis C transmission until blood tests for the virus became available in 1992.

Health care and public safety workers are considered to be at high risk for contracting hepatitis C. Other potential risks include tattoos and body piercing - both popular trends today.

Although a relatively new discovery, advances in treatment have more than doubled response rates.

Health studies of a new combination of a longer-lasting cancer drug and the antiviral drug Ribavirin have found that in half of cases, the virus is undetectable after six to 12 months.

But experts say advancements still are needed to bolster success rates and cut costs, which can run $8,000 to $20,000 per person for a year of standard treatment.

"We've made some headway, but we've got a long way to go," Weinbaum said.

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September 29th, 2003

Nucleonics Receives NIH Grant Supporting Research Partnership Aimed at Developing RNAi Approach to Treatment of Hepatitis B Infections

Nucleonics, Inc.,a biotechnology company focused on the development of novel RNA interference-based (RNAi) therapeutics for viral and other diseases, today announced the receipt of a research grant from the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH). The grant, totaling $1.6 million over four years, supports collaborative research aimed at developing nucleic acid reagents and methods for silencing Hepatitis B virus (HBV) gene expression and replication in vivo. The researchers will also evaluate in clinically relevant animal models the best DNA vector, delivery system and target HBV sequence to advance to clinical trials.

Nucleonics is collaborating on this effort with scientists at Scripps Research Institute, La Jolla, CA in the laboratory of Nucleonics collaborator and scientific advisor Francis Chisari, M.D., as well as in the laboratories of the Hepatitis B Foundation in Doylestown, PA.

"Chronic HBV infection represents an ideal target for potential RNAi-based therapeutics since RNA is an intermediate in both HBV replication and expression, and the reduction of both processes is expected to ameliorate disease," said Nucleonics Senior Director of Biology, Catherine Pachuk, Ph.D. "Furthermore, a post-transcriptional gene-silencing therapeutic, unlike current nucleoside analogue therapies, could not only decrease viral titers but also decrease viral antigen load, reducing risks of long-term immune-mediated liver damage in those chronically infected. In addition, no significant homology exists between HBV and humans or other mammals, which makes it likely that any gene silencing achieved is exclusive for HBV."

Post-transcriptional gene silencing, also known as double-stranded RNA (dsRNA) interference or RNAi, is a phenomenon in which genes are silenced in a sequence-dependent manner at the level of mRNA degradation. Researchers believe RNAi may offer potential as a novel way to silence genes involved in disease, including genes encoded by viruses such as Hepatitis B, Hepatitis C and HIV, or genes involved in the establishment of cancer and inflammatory diseases. While some researchers have sought to deliver RNA sequences themselves as therapeutics, such strategies face significant challenges relating to manufacturing, delivery and the triggering of an interferon-mediated stress response that can limit effectiveness and may cause significant safety issues.

Nucleonics, in contrast, employs an expressed interfering RNA (eiRNA) approach. Scientists insert plasmid DNA coding for dsRNA into cells, letting the cells themselves carry out the dsRNA production and delivery process.

Nucleonics researchers have shown the ability of long or short dsRNA strands produced in this way to stably silence target genes, including Hepatitis B and HIV, in relevant human cell lines. Moreover, they have silenced multiple genes in adult mice utilizing the company's proprietary delivery technology without triggering an interferon response. The plasmid DNA approach, which is used by Nucleonics for expression of dsRNA, has demonstrated human safety in over 500 patients to date as part of research in the field of DNA-based vaccines.

"If this research effort is successful in effectively reducing the expression and replication of HBV in mouse models of HBV infection, Nucleonics intends to advance the best-performing gene silencing vectors and formulations into clinical development," said C. Satishchandran, Ph.D., vice president, research & development at Nucleonics. "Using RNAi therapy to reduce viral load, either on its own or in combination with other antiviral drugs, could reduce the severity of disease in patients chronically infected with HBV. Moreover, an effective RNAi therapy could potentially be used for healthy carriers of HBV, a patient population for whom no current therapy exists and in whom a reduction in viral antigen expression could lead to a reduction in immune-related liver injury with its long-term consequences of cirrhosis of the liver and liver cancer."

About Nucleonics, Inc.

Nucleonics, founded in January 2001, is an emerging biotechnology company focused on the development of novel RNA interference-based therapeutics for viral and other diseases. The company believes its proprietary technology and delivery systems for expressed interference RNA offers advantages over other RNAi approaches in terms of safety and efficacy that will enable Nucleonics to become a leader in this emerging field. The company is headquartered in Malvern, Pennsylvania and is privately owned.

A new survey has found half of all Internet marketers of herbal products have violated federal law by making false claims or omitting legally required disclaimers and medical warnings. The findings suggest many consumers are vulnerable to purchasing substandard or potentially dangerous products by patronizing the illegal sites.

The rapid growth in the herbal supplements market over the past five or so years coincided with the explosive growth of the Internet over the same period. The twin booms led to the popular practice of consumers purchasing herbal products online requiring nothing more than a credit card number and a shipping address, but the herbal product manufacturers do not always keep consumers fully informed about the supplements' limitations.

"The (herbal) industry is primarily regulated at the post-marketing level," Dr. Charles Morris, an internist at Brigham and Women's Hospital's division of pharmacoepidemiology and pharmacoeconomics in Boston, told United Press International. That means the government does not have the authority to step in unless an herbal product has been found faulty or dangerous, if advertising information on the product makes unauthorized health claims to directly cure disease, or if the product labeling states unsubstantiated claims.

"It's up to federal agencies to police the Internet," Morris commented.

Morris and colleagues analyzed 443 Web sites by using online search engines to find information on the eight top-selling herbs: St. John's wort, echinacea, ginseng, garlic, saw palmetto, ginkgo biloba, kava kava, and valerian root. Of the 338 sites examined that sold herbal products, 81 percent made one or more health claims. Among this group of sites, 55 percent claimed to treat, prevent, diagnose or cure a specific illness. At the same time, they frequently failed to mention risks. Morris said several sites failed to disclose, for example, recent research linking kava kava use to liver toxicity -- although those findings remain controversial.

Under the 1994 Dietary Supplement Health Education Act, federal law prohibits dietary supplement manufacturers from making specific claims that their products treat or cure particular diseases. For example, an herbal product label can state "garlic may help promote healthy circulation," but it cannot state "garlic prevents heart attacks."

Unlike prescription and over-the-counter drug manufacturers, however, makers of herbal products are not required to submit their health claims to the Food and Drug Administration in advance of marketing their product. Morris said this legal framework sets up the federal government to play catch-up with the herbal industry.

"DSHEA has certainly changed or impaired the federal government's ability to regulate this industry," Morris said. "A lot of what consumers can now find and read on the Internet is somehow indirectly or directly related to the legislation in 1994. We would strongly call for the consideration of pre-marketing regulations, like (for) prescription or over-the-counter drugs."

The alternative therapy craze is not fading. Morris said 2001 data show half of the U.S. adult population spent about $18 billion on herbal remedies. This is consistent with a 2002 survey, conducted by the Pew Charitable Trusts, which found 62 percent of online users that year searched the Web for health information, with more than half reporting they were looking for information on alternative medicine.

"We've always been concerned about consumers who don't have the ability to determine what's reasonable and credible information on the Web," Mark Blumenthal, executive director of the American Botanical Council in Austin, Texas, told UPI. "We don't think (manufacturers) should be making claims beyond what the law allows. There are definitely products that have been reported to be misleading. Some of the stuff on government, "dot-gov" Web sites aren't necessarily all that reliable."

However, he added, "just because a claim on the Internet might be illegal because it doesn't fit technical requirements of the regulatory system doesn't mean that it's not true."

Blumenthal suggested more regulations might not be the answer. "I don't think there's any legislation needed," he said. "It's an issue of needing more active self-regulation by companies making their claims."

Michael McGuffin, president of the American Herbal Product Association in Washington, a trade group representing about 200 companies, said he "would love to see more active enforcement" by the Federal Trade Commission, the agency overseeing advertising regulations, to prevent misleading herbal information from being distributed online.

"It's important to our trade that the regulators do their job because if they don't do their job, it's bad business for all of us," McGuffin told UPI. "The Internet is just such a rampant business opportunity. If you're in business today in the U.S.A., you have a Web site. It behooves (every company) to make sure the information on (its) Web site is accurate and legal."

McGuffin said he thinks most herbal manufacturers obey federal law. "The majority of companies marketing their goods in the United States are doing the right thing." But physicians like Dr. Bishmal Ashar, an assistant professor of medicine at Johns Hopkins University in Baltimore, who see patients experimenting with herbal products online, question whether that statement is true.

The Internet is such a fluid medium that companies can change their Web sites within a few minutes, Ashar said. He recently conducted his own research investigating ephedra, the popular Chinese herb used for weight loss, and found Internet claims on the product were not always truthful. "When you run across an ad that sounds so good and you want lose weight and nothing's worked before, it's very enticing to want try these products," he told UPI.

"It's very difficult to track and follow and keep up with companies who just want to change Web sites," Ashar added. "It's a very difficult enforcement problem. Patients should just be wary of anything that sounds too good to be true."

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September 30th, 2003

Obesity as a risk factor for cirrhosis-related death or hospitalization
by gastrohep.com

Obesity is a risk factor for cirrhosis-related death or hospitalization in people who consume little or no alcohol, find investigators in the October issue of Gastroenterology (Gastroenterology 2003; 125(4):).

In this study, a team of investigators from the United States determined whether increased body mass index (BMI) was associated with cirrhosis-related death or hospitalization.

The team evaluated 11,465 individuals, aged between 25 and 74 years, without evidence of cirrhosis. These subjects were followed-up for a mean of 12.9 years.

Participants were grouped using BMI into normal-weight (BMI <25 kg/m2), overweight (BMI 25 to <30 kg/m2), and obese categories (BMI 30 kg/m2).

The investigative team found that cirrhosis resulted in death or hospitalization of 89 participants during 150,233 person-years of follow-up.

"Cirrhosis-related death or hospitalization was more common in obese and overweight subjects."
Gastroenterology

They determined that cirrhosis-related deaths or hospitalizations were more common in obese and overweight subjects, when compared with normal weight subjects.

Furthermore, in subjects who did not consume alcohol, the team identified a strong association between obesity or overweight and cirrhosis-related death or hospitalization.

This association was weaker in study participants who consumed up to 0.3 alcoholic drinks per day, and was absent in those who consumed more than 0.3 alcoholic drinks per day.

Dr George Ioannou's team concluded, "Obesity appears to be a risk factor for cirrhosis-related death or hospitalization among persons who consume little or no alcohol."

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Transmission of Hepatitis B and C Viruses in Outpatient Settings—New York, Oklahoma, and Nebraska, 2000--2002

Transmission of hepatitis B virus (HBV) and hepatitis C virus (HCV) can occur in health-care settings from percutaneous or mucosal exposures to blood or other body fluids from an infected patient or health-care worker. This report summarizes the investigation of four outbreaks of HBV and HCV infections that occurred in outpatient health-care settings. The investigation of each outbreak suggested that unsafe injection practices, primarily reuse of syringes and needles or contamination of multiple-dose medication vials, led to patient-to-patient transmission. To prevent transmission of bloodborne pathogens, all health-care workers should adhere to recommended standard precautions and fundamental infection-control principles, including safe injection practices and appropriate aseptic techniques.

In the four investigations, a case of acute HBV infection was defined on the basis of a positive test for IgM antibody to hepatitis B core antigen. A case of past or current HCV infection was defined on the basis of a confirmed positive test for HCV RNA or for antibody to HCV; patients known to have been infected before visiting the health-care facility were excluded. Patients with chronic or acute infection were considered to be potential sources for transmission to susceptible patients. Patients were categorized as having clinic-acquired infection on the basis of evidence that included epidemiologic findings, temporal associations between patients and procedures, documented seroconversion, signs and symptoms of acute viral hepatitis, traditional risk factors for HBV or HCV infection, or genetic relatedness among viral isolates.

HCV Transmission in a Private Physician's Office—New York City

In May 2001, a physician notified the New York City Department of Health (NYCDOH) of seven patients who had acute HCV infections after undergoing endoscopic procedures at the same office in March 2001. The office voluntarily ceased performing such procedures in late April 2001.

During the 9-day period encompassing the procedure dates of these seven patients, 68 patients underwent procedures in this practice.

Among 61 (90%) patients who were tested, five additional acute HCV infections were identified, and a chronic infection in a patient whose procedure preceded the 12 acute HCV cases was identified. All 12 patients had a procedure performed within 3 days after the chronically infected patient. This chronically infected patient and six of the acutely infected patients had HCV genotype information available; all were genotype 2c, which is rare in the United States (1). On the basis of these results, patients who underwent endoscopic procedures since the office opened in January 2000 were notified and offered testing for HCV, HBV, and human immunodeficiency virus (HIV). Results were available for 1,315 (60%) of 2,192 eligible patients; seven additional patients were identified as having HCV infections that probably were acquired in the office. No evidence of HIV transmission was observed; HBV infection was noted among some patients, but epidemiologic links among such office patients could not be established.

A retrospective case-control study indicated that clinic-acquired HCV infection was not associated with type of endoscopic procedure, specific endoscope used, whether a biopsy was performed, type of biopsy, or anesthesia type or dose. However, the investigation revealed inappropriate infection-control and injection practices, which indicated that the probable route of transmission was contamination of multiple-dose anesthesia medication vials. In April 2002, after corrections to infection-control practices were made by the office, the New York State Department of Health allowed the office to resume gastrointestinal procedures.

HBV Transmission in a Private Physician's Office—New York City

In December 2001, NYCDOH was informed of two elderly patients (aged >75 years) who had acute HBV infection diagnosed and who had visited the office of the same physician (physician A) during their incubation periods. A preliminary investigation by NYCDOH identified 19 additional cases of acute HBV infection.

On the basis of these results, NYCDOH offered testing for HBV, HCV, and HIV infection to 1,042 patients of physician A; 38 patients, including the 19 previously identified, had acute HBV infection during February 2000--February 2002. HBV DNA genetic sequences of 24 patients with acute infection and four patients with chronic infection were identical in the 1,500—base-pair region examined. No evidence of HCV or HIV transmission was observed.

A retrospective cohort study was conducted among the 275 patients attending physician A's office during the 10 months preceding outbreak detection. Of 91 patients with serologic results and available medical records that were included in the cohort study, 18 were infected. Among 67 patients who received at least one injection, 18 (27%) had acute HBV infection, compared with none who received no injections (relative risk [RR] = 13.6; 95% confidence interval [CI] = 2.4—undefined). Patients with HBV infection received a median of 14 injections (range: 2—25), compared with susceptible patients, who received a median of two injections (range: 0—17) (p<0.001). Typically, injections included doses of atropine, dexamethasone, and vitamin B12 drawn from multiple-dose vials into one syringe. The same workspace was used to prepare, dismantle, and dispose of injection equipment.

In December 2001, NYCDOH ordered physician A to stop administering injections. In April 2002, physician A retired and closed his office permanently. In response to this outbreak and the outbreak described above, NYCDOH sent a letter (available at http://home.nyc.gov/html/doh/pdf/chi/ltr22002.pdf) to all city clinicians outlining the need for all staff to adhere to infection-control and bloodborne pathogen precautions, including single use of needles and syringes and appropriate use of multiple-dose vials to prevent cross contamination.

HBV and HCV Transmission in a Pain Remediation Clinic—Oklahoma

In August 2002, the Oklahoma State Department of Health (OSDH) was informed of six patients with suspected acute HCV infection who had received treatment from the same pain remediation clinic. A preliminary investigation by OSDH found that a certified registered nurse anesthetist (CRNA) reused needles and syringes routinely during clinic sessions. A single needle and syringe was used to administer each of three sedation medications (Versed. [midazolam HCl], fentanyl, and propofol) to up to 24 sequentially treated patients at each clinic session. These medications were administered through heparin locks that were connected directly to intravenous cannulas.

On the basis of these findings, the clinic was closed, and an investigation was initiated. Serologic testing for HCV, HBV, and HIV infection was completed for 793 (87%) of the 908 patients attending the clinic. A total of 69 HCV and 31 HBV infections were identified that probably were acquired in the clinic; no HIV infections were identified. Receiving treatment during a clinic session after a patient who was anti-HCV—positive was a statistically significant risk factor for acquiring HCV infection (RR = 9.2; 95% CI = 3.7—22.5). Receiving treatment after a patient who was hepatitis B surface antigen--positive was a significant risk factor for acquiring HBV infection (RR = 8.5; 95% CI = 4.2—17.0). In June 2002, before this investigation, the CRNA ceased reuse of needles after a complaint was filed by staff nurses. After June 2002, no evidence of HBV or HCV transmission associated with receiving treatment at the clinic was found.

The state board of nursing revoked the CRNA's license and imposed a $99,000 fine. In response to this outbreak, the American Association of Nurse Anesthetists (AANA) sent mailings to all AANA members and students, nurse anesthesia school program directors, and hospital administrators reminding them that needles and syringes are single-use items and should not be reused.

HCV Transmission in a Hematology/Oncology Clinic—Nebraska

In September 2002, a gastroenterologist reported four patients with recently diagnosed HCV infection to the Nebraska Health and Human Services System (NHHSS). All of these patients had received chemotherapy at the same hematology/oncology clinic. A preliminary investigation identified 10 cases of recently diagnosed HCV infection among clinic patients. Of the six patients for whom HCV genotype was available, all were genotype 3a, which is rare in the United States (1). A patient with a previous diagnosis of chronic HCV genotype 3a infection began attending the clinic in March 2000. The investigation revealed that the health-care worker responsible for medication infusions routinely used the same syringe to draw blood from patients' central venous catheters and to draw catheter-flushing solution from 500-cc saline bags that were used for multiple patients. The clinic staff reported that by July 2001, this practice was corrected through changes in personnel and infection-control practices. NHHSS conducted an investigation among all living patients examined at the clinic during March 2000—December 2001. Of 613 eligible patients, 486 (79%) underwent HCV testing; 99 patients with clinic-acquired HCV infection were identified. HCV genotype information was available for 95 patients; all isolates were genotype 3a. During March 2000—June 2001, 85 (61%) of 139 patients with an implanted central venous catheter became infected with HCV, compared with 14 (6%) of 228 patients without an implanted catheter (RR = 10.0; 95% CI = 5.9--16.8). No evidence of HBV or HIV transmission or of HCV transmission after June 2001 was found. The clinic closed in October 2002.

Reported by: S Balter, M Layton, K Bornschlegel, New York City Dept of Health and Mental Hygiene; PF Smith, New York State Dept of Health. M Crutcher, S Mallonee, J Fox, P Scott, Oklahoma State Dept of Health. T Safranek, D Leschinsky, K White, Nebraska Health and Human Svcs System. JF Perz, IT Williams, BP Bell, Div of Viral Hepatitis; L Chiarello, AL Panlilio, Div of Healthcare Quality Promotion, National Center for Infectious Diseases; M Phillips, M Marx, A Macedo de Oliveira, D Comstock, N Malakmadze, T Samandari, TM Vogt, EIS officers, CDC.

Editorial Note:
These four outbreaks are among the largest health-care--related viral hepatitis outbreaks reported in the United States and share several common characteristics. All occurred in outpatient settings and were reported to public health authorities by clinicians who suspected these infections might have been health-care--related. The investigations were resource-intensive and involved notification, testing, and counseling of hundreds of patients. Transmission probably occurred indirectly from patient to patient after exposure to injection equipment that was contaminated with the blood of one or more source patients. All of these outbreaks could have been prevented by adherence to basic principles of aseptic technique for the preparation and administration of parenteral medications (2—7).

Health-care—related exposures are a well-recognized but uncommon source of viral hepatitis transmission in the United States (7—10). The majority of outbreaks identified previously have been associated with unsafe injection practices, primarily reuse of syringes and needles or contamination of multiple-dose medication vials. However, because the majority of patients with acute HBV or HCV infection are asymptomatic, clusters of patients infected in the health-care setting might be unrecognized. Health-care--related transmission should be suspected when cases are detected among persons without traditional risk factors for infection. State and local health authorities should consider strategies to improve case identification, such as targeting intensive follow-up for persons who typically are at low risk for infection (e.g., persons aged >60 years).

In the outbreaks described in this report, health-care workers did not adhere to fundamental principles related to safe injection practices, suggesting that they failed to understand the potential of their actions to lead to disease transmission. In addition, deficiencies related to oversight of personnel and failures to follow up on reported breaches in infection-control practices resulted in delays in correcting the implicated practices. To prevent health-care—related transmission of bloodborne viruses, certification and training programs need to reinforce infection-control principles and practices, including aseptic techniques and safe injection practices. These principles should be reviewed with frequent in-service education for health-care staff, including those who work in outpatient settings, and practices should be monitored as part of the institutional oversight process. Finally, written policies and procedures to prevent patient-to-patient transmission of bloodborne pathogens should be established and implemented among all staff involved in direct patient care. CDC is working with professional organizations, advisory groups, and state and local health departments to address these issues.

References
1. Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 1999;341:556--62.
2. Chiarello LA. Prevention of patient to patient transmission of bloodborne viruses. Sem Infect Contr 2001;1:44--8.
3. Garner JS, Hospital Infection Control Practices Advisory Committee. Guideline for isolation precautions in hospitals. Infect Control Hosp Epidemiol 1996;17:53--80.
4. CDC. Guidelines for the prevention of intravascular catheter-related infections. MMWR 2002;51(No. RR-10).
5. CDC. Guidelines for environmental infection control in health-care facilities. MMWR 2003;52(No. RR-10).
6. CDC. Guideline for hand hygiene in health-care settings. MMWR 2002;51(No. RR-16).
7. Alter MJ. Prevention of spread of hepatitis C. Hepatology 2002;36:93--8.
8. Alter MJ. Epidemiology and prevention of hepatitis B. Seminars in Liver Disease 2003;23:39--46.
9. Goldstein ST, Alter MJ, Williams IT, et al. Incidence and risk factors for acute hepatitis B in the United States, 1982--1998: implications for vaccination programs. J Infect Dis 2002;185:713--9.
10.CDC. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR 1998;47(No. RR-19).

October 1st, 2003

Neb. Dr. in Hepatitis Case Loses License

The state revoked the license Wednesday of a doctor accused of causing one of the nation's largest hepatitis C outbreaks, with at least 99 patients infected and one death.

In a settlement with the state, Dr. Tahir Javed did not contest allegations that he used unsanitary practices at his Fremont Cancer Clinic, where many of his patients contracted hepatitis C in 2000 and 2001. State officials alleged those practices included reusing syringes.

At least 81 lawsuits have been filed against Javed on behalf of his former patients.

Javed is now a health minister in Pakistan. Last month, he told a Pakistani newspaper that the allegations are part of anti-Muslim propaganda since the Sept. 11 terrorist attacks.

Hepatitis C is a viral infection of the liver. It can lead to cirrhosis or liver cancer.

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Probe Ends in Schering-Plough Drug Case
By Linda A. Johnson

Federal prosecutors have closed their investigation of certain drugs made at Schering-Plough Corp.'s manufacturing plants in Puerto Rico, ending one of the company's many legal problems.

The plants in Manati and Las Piedras, Puerto Rico, as well as two in New Jersey, have been operating under extra scrutiny from federal regulators since May 2002 because of sloppy testing procedures, deficient paperwork and other problems uncovered by Food and Drug Administration inspectors.

The U.S. Attorney's Office in Newark notified the company on Monday that it has wrapped up its investigation, Schering-Plough spokesman Bob Consalvo said Wednesday. He said no charges, orders or fines resulted from the investigation, which had been started by the FDA's Office of Criminal Investigation and later was transferred to the U.S. Attorney's Office.

Michael Drewniak, a spokesman for U.S. Attorney Christopher Christie in Newark, confirmed that the criminal investigation had ended.

"The U.S. Attorney's Office has closed its investigation into whether Schering-Plough used improper pharmaceutical ingredients that were not approved for use in the United States," Drewniak said.

Drewniak would not give any further details about the ingredients or medications in question. Federal prosecutors generally do not discuss investigations unless charges are filed.

Consalvo said the products investigated included ribavirin, one of the hepatitis drugs that are the company's key product group since its blockbuster allergy drug Claritin went over-the-counter in December. That eliminated nearly one-third of the Kenilworth-based company's roughly $9 billion in annual revenues.

Problems at the Puerto Rico manufacturing plants and ones in Kenilworth and Union, N.J., were disclosed by the company in February 2001. Schering-Plough later agreed to pay the FDA a record $500 million fine for deficiencies at those plants ranging from paperwork problems to inaccurate expiration dates on some drugs and retesting of some drug batches repeatedly until acceptable results were reached.

The fine was part of a legal agreement under which all four plants get extra inspections and must file additional reports through 2005 as changes and upgrades are made to ensure all products meet required specifications.
"The company has made progress in putting in place enhancements to its manufacturing and quality control procedures and processes," Consalvo said. "But a lot remains to be done."

He said the company is on schedule with those improvements. He said Schering-Plough paid the second $250 million installment of the fine in May; the first was paid a year earlier.

"As we move forward with our action agenda to stabilize and then turn around Schering-Plough, it is vitally important to resolve the legal and regulatory matters facing our company," chairman and chief executive officer Fred Hassan, who took over the company in April, said in a prepared statement.

Following a Securities and Exchange Commission investigation, the company and former CEO Richard Kogan last month agreed to pay civil fines totaling $1.05 million to settle the regulators' allegations Schering-Plough illegally revealed financial information to stock analysts and some of its biggest investors ahead of the public last fall.

Remaining troubles include shareholder lawsuits accusing company officials of breaching their fiduciary duty and failing to disclose key information affecting the company's future, and investigations of the company's pricing practices by the U.S. Department of Justice, the Department of Health and Human Services and the U.S. Attorney's Office in Philadelphia.

Schering-Plough's shares rose 61 cents, or 4 percent, to close at $15.85 on the New York Stock Exchange.

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