Thyroid disorders in chronic hepatitis C.

New Pegasys Study data: 43% of non-responders have histological improvement

Chronic hepatitis C and no response to antiviral therapy: potential current and future therapeutic options

By Anna Poppa

June 2, 2004 — The assumption that sustained virologic response (SVR) in treated HCV patients represents viral eradication has been challenged by evidence that low levels of HCV RNA are readily identifiable in serum and lymphoid cells from such patients when enhanced methods of detection are employed. These so-called "ultra-sensitive" assays also detected persistent HCV genomic material in patients who spontaneously cleared HCV following acute infection. These findings may have implications for the long-term health of people with apparent resolution of HCV infection, and infer that blood and organ donations from these individuals may present a risk of HCV transmission.

Data describing HCV persistence were reported by Tomasz Michalak's group at Memorial University, Newfoundland, Canada. Ten years ago, Michalak was among the first to report evidence of persistent hepatitis B virus (HBV) DNA in patients with serologic and clinical recovery from acute HBV infection, now termed occult HBV infection. Using an animal model for HBV, Michalak later demonstrated that occult HBV can be transmitted between woodchucks, raising concern over the implications of occult infection in humans.

Michalak's group has since turned their attention to HCV persistence. Sixteen randomly selected patients with serologic and clinical evidence of resolution of HCV infection formed the cases in their latest study. Five had been followed for between 12 and 36 months after spontaneous clearance of acute HCV infection, during which time they had remained negative for HCV RNA using standard assays and had repeatedly normal liver function tests. The other 11 individuals had obtained SVR following antiviral treatment with standard interferon for chronic HCV, and had since been followed for between 1 and 5 years.

Using an enhanced reverse transcriptase-polymerase chain reaction (RT-PCR) nucleic acid hybridization assay, 10 times more sensitive than standard RT-PCR assays in common use, HCV RNA was detected in serum in 14 of the 16 cases, and in peripheral blood mononuclear cells (PBMCs) in 10. All 16 cases were positive for HCV RNA in at least 1 of these tests. In 7 patients in whom dendritic cells could be harvested from PBMC, 6 had detectable HCV RNA in this cell line as well.

PBMCs from patients whose PBMC sample tested positive for HCV RNA were cultured with a mitogen, which stimulated their proliferation. This process revealed the presence of HCV RNA negative strand in 9 of 12 samples, an observation which suggests virus replication is occurring.

The clinical implications of these findings are unknown. For Michalak's group, these data present a potential future risk of reactivation of HCV in patients with successfully-treated disease. Further, they raise the possibility that blood and organ donations screened using standard HCV assays may continue to pose a route of transmission.

Reference

Pham TNQ, MacParland SA, Mulrooney PM, Cooksley H, Naoumov NV, Michalak TI. Hepatitis C virus persistence after spontaneous or treatment-induced resolution of hepatitis C. J Virol. 2004;78:5867

http://www.clinicaloptions.com/hep/news/news_imed_212.asp

As Doctor Writes Prescription, Drug Company Writes a Check
Gardiner Harris
Source: The New York Times

The check for $10,000 arrived in the mail unsolicited. The doctor who received it from the drug maker Schering-Plough said it was made out to him personally in exchange for an attached ''consulting'' agreement that required nothing other than his commitment to prescribe the company's medicines. Two other physicians said in separate interviews that they, too, received checks unbidden from Schering-Plough, one of the world's biggest drug companies.

''I threw mine away,'' said the first doctor, who spoke on the condition of anonymity because of concern about being drawn into a federal inquiry into the matter.

Those checks and others, some of them said to be for six-figure sums, are under investigation by federal prosecutors in Boston as part of a broad government crackdown on the drug industry's marketing tactics. Just about every big global drug company -- including Johnson & Johnson, Wyeth and Bristol-Myers Squibb -- has disclosed in securities filings that it has received a federal subpoena, and most are juggling subpoenas stemming from several investigations.

The details of the Schering-Plough tactics, gleaned from interviews with 20 doctors, as well as industry executives and people close to the investigation, shed light on the shadowy system of financial lures that pharmaceutical companies have used to persuade physicians to favor their drugs.

Schering-Plough's tactics, these people said, included paying doctors large sums to prescribe its drug for hepatitis C and to take part in company-sponsored clinical trials that were little more than thinly disguised marketing efforts that required little effort on the doctors' part. Doctors who demonstrated disloyalty by testing other company's drugs, or even talking favorably about them, risked being barred from the Schering-Plough money stream.

Schering-Plough says that the activities under investigation occurred before its new chief executive, Fred Hassan, arrived in April 2003, and that it has overhauled its marketing to eliminate inducements.

At the heart of the various investigations into drug industry marketing is the question of whether drug companies are persuading doctors -- often through payoffs -- to prescribe drugs that patients do not need or should not use or for which there may be cheaper alternatives. Investigators are also seeking to determine whether the companies are manipulating prices to cheat the federal Medicaid and Medicare health programs. Most of the big drug companies, meanwhile, are also grappling with a welter of suits filed by state attorneys general, industry whistle-blowers and patient-rights groups over similar accusations.

In many ways, the investigations are a response to the evolution of the pharmaceutical business, which has grown in the last quarter-century from a small group of companies peddling a few antibiotics and anti-anxiety remedies to a $400 billion behemoth that is among the most profitable industries on earth.

Offering treatments for almost any affliction and facing competition in which each percentage point of market share can represent tens of millions of dollars, most drug makers now spend twice as much marketing medicines as they do researching them. Their sales teams have changed from a scattering of semi-retired pharmacists to armies of young women and men who shower physicians with attention, food and -- until the drug industry recently agreed to end the practice -- expensive gifts, just to get two to three minutes to pitch their wares. A code of conduct adopted in 1990 by the American Medical Association suggests that doctors should not accept any gift worth more than $100, but the guidelines are widely ignored.

A quarter-century ago, the Food and Drug Administration was the lone cop on the drug industry beat. But the F.D.A.'s enforcement powers over drug marketing have been severely curbed since 1976 by a series of court rulings based mainly on the companies' free-speech rights. That left a vacuum that many companies decided to exploit, said William Vodra, a former F.D.A. lawyer.

''A lot of people decided there was no check on what they were allowed to do,''
Mr. Vodra said. Using fraud, kickback and antitrust statutes, federal prosecutors, state attorneys general and plaintiffs lawyers stepped into the void, asserting that the companies' sales pitches have cost the government billions of dollars in payments for drug benefits.

This legal scrutiny can be expected to intensify. Once the new Medicare drug benefit takes full effect in 2006, the government will pay for almost half of all medicines sold in the nation. So the marketing programs will cost the government even more money and, if they are uncovered and determined to be illegal, will probably result in even larger fines.

Last month, Pfizer agreed to pay $430 million and pleaded guilty to criminal charges involving the marketing of the pain drug Nuerontin by the company's Warner-Lambert unit. AstraZeneca paid $355 million last year and TAP Pharmaceuticals paid $875 million in 2001; each pleaded guilty to criminal charges of fraud for inducing physicians to bill the government for some drugs that the company gave the doctors free.

Over the last two years, Schering-Plough, which had sales of $8.33 billion last year, has set aside a total of $500 million to cover its legal problems -- mainly for expected fines from the Boston investigation and from a separate inquiry by federal prosecutors in Philadelphia who are investigating whether Schering-Plough overcharged Medicaid.

Besides looking into whether Schering-Plough paid doctors large sums to prescribe the company's drug for hepatitis C, prosecutors are investigating whether many company-sponsored clinical trials for the drug were simply another way to funnel money to doctors.

Dr. Chris Pappas, director of clinical research for St. Luke's Texas Liver Institute in Houston, said that Schering-Plough ''flooded the market with pseudo-trials.''

Dr. Pappas and eight other liver specialists who were interviewed say the system worked like this: Schering-Plough paid physicians $1,000 to $1,500 per patient for prescribing Intron A, the company's hepatitis C treatment. In conventional clinical trials, participants are given drugs free, but the doctors said that in these cases the patients or insurers paid for their medication. Because patients usually undergo Intron A treatment for nearly a year and the therapy costs thousands of dollars, Schering-Plough's payments to physicians left plenty of room for the company to profit handsomely, the doctors said.

In return for the fees, physicians were supposed to collect data on their patients' progress and pass it along to Schering-Plough, the doctors said. But many physicians were not diligent about their recordkeeping, and the company did little to insist on accurate data, according to Dr. Pappas and the others.

One of the nation's most prominent liver disease specialists, who spoke on condition of anonymity for fear of angering big drug makers, called the trials ''purely marketing gimmicks.''

''Science and marketing should not be mixed like that,'' the doctor said.

Schering-Plough did more than encourage physicians to place patients on Intron A, many of the physicians said. They said the company would remove any doctor from its clinical program -- and shut off the money spigot -- if he or she wrote prescriptions for competing drugs, participated in clinical trials of alternatives to Intron A or even spoke favorably about treatments besides Intron A.

The main competitor to Intron A, which Schering-Plough now sells as Peg-Intron, is Roche's comparably priced drug Pegasys.

Dr. Donald Jensen, the hepatology director at Rush University Medical Center in Chicago, said he wanted to perform clinical trials using drugs from both Schering-Plough and Roche. ''I was told by Schering-Plough that I couldn't do both -- that I had to sign an exclusive agreement with them,'' Dr. Jensen said. ''That was the juncture when Schering and I parted ways.''

Six specialists in liver disease said Schering-Plough also paid what it called consulting fees to doctors to keep them loyal to the company's products. The letter accompanying a check for $10,000 explained that the money was for consulting services that were detailed on an accompanying ''Schedule A,'' said a doctor who insisted on anonymity. But when the doctor turned to the attached sheet, he said, ''Schedule A'' were the only words printed on an otherwise blank sheet of paper.

Dr. Pappas, who in the past has consulted for Schering-Plough and worked for Roche, said that stories about the enormous sums that Schering-Plough paid its consultants were common among liver specialists. ''These were very high-value consulting agreements with selected opinion leaders that looked like payments of money with no clear agreements on what was supposed to be executed,'' Dr. Pappas said.

In an interview, Mr. Hassan and other top executives declined to discuss past marketing practices. Richard Kogan, the company's previous chairman and chief executive, declined to be interviewed.

Schering-Plough's current management says that much has changed at the company since Mr. Hassan took over. The company no longer allows sales representatives or marketing executives to have any say over its clinical trials, physician education or medical consulting, they said. And in all clinical trials begun in the last year, they said, drugs have been provided free to the enrolled patients, rather than being billed to them or their insurers.

''The temptation to give clinical grants to high prescribers and consulting agreements to high prescribers is why we pulled those decisions out of the hands of the sales representatives,'' said Brent Saunders, who was named senior vice president for compliance and business practices last year. ''Sales representatives had an input into that process before, which I think is still fairly normal in the industry.''

In the separate Philadelphia investigation, Schering-Plough is expected to plead guilty soon to charges that it failed to provide Medicaid with its lowest drug prices, as is required by law, and to pay a fine. Investigators are examining whether Schering-Plough, to gain sales with some private insurers, offered premiums, such as free patient consulting arrangements, with its drugs.

Prosecutors are arguing that such incentives had a market value and meant that Schering-Plough was offering drugs to private payers at prices well below those offered to Medicaid. Many other drug companies are the targets of similar inquiries.

The Boston inquiry into suspected kickbacks and improper marketing by Schering-Plough could take months more to resolve, people close to the investigation say. Schering-Plough may also be charged with obstruction of justice and document destruction as part of the Boston inquiry, according to the company's filings with securities regulators.

Industry experts say the federal inquiries into Schering-Plough and the other drug giants have led some companies to adopt significant changes in the way they peddle drugs to doctors. Other companies have been slower to react. ''These investigations came out of left field, and no one saw them coming,'' said Peter Barton Hutt, a former F.D.A. general counsel who now advises drug companies.

"The industry has since had to reshape entirely what they are doing, but it was too late to redo what they'd been doing for years.''

Tony Farino, leader of the pharmaceutical consulting service at PricewaterhouseCoopers, said that as a result of the investigations many companies in the drug industry were hiring executives to police marketing and sales practices.

''Reputational risk is something they're all trying to manage,'' Mr. Farino said, ''because the damages from failure can be significant.''

Improvements Made over Time in Right Lobe Living Donor Liver Transplants
Source: www.gastrohep.com

A study reported in the journal Annals of Surgery has evaluated the first 100 adult right lobe living donor liver transplants in a single center to determine whether technical modifications and better experience have improved results.

Chung-Mau Lo and colleagues examined 100 consecutive adult right lobe living donor liver transplants (LDLT) performed between May 1996 and May 2002.

The LDLTs were studied retrospectively, to determine whether the numerous modifications in technique and better experience would improve results.

The first 50 patients (group 1) were compared with the last 50 patients (group 2), with a median follow-up of 37 (27 to 79) months and 15 (7 to 27) for each group respectively.

The characteristics of donors and liver grafts were similar. However, in group 2 fewer recipients required a visit to an intensive care unit or had hepatorenal syndrome before transplantation. There was also a lower disease severity as shown by a lower Child-Pugh score and Model for End-Stage Liver Disease (MELD) score.

In both operation line, blood loss, ICU stay and postoperative complication rate of the donors significant improvements were noted in group 2.

In addition, operation time, transfusion requirements, number of reoperations, ICU stay and hospital stay were all also lower for group 2 compared to group 1.

The hospital mortality rate of recipients was reduced from 16% to 0%, while graft survival rates at 12 months and 24 months were improved from 80% and 74%, respectively, in group 1, to 100% and 96%, respectively, in group 2.

Commenting on the findings, Dr Lo concluded, “There is a learning curve in adult right lobe LDLT. The results have significantly improved with technical refinement and better experience.”

Ann Surg 2004; 240(1): 151-158
 

Re-Examining Questions about Hepatitis C
The Star-Ledger
SourceURL:http://www.nj.com/

Thanks for writing about the aunt who had a hepatitis C infection. I’m the “aunt,” asking if there are conflicting thoughts on a person with hepatitis C touching or hugging a baby? I’m having a relative visit with her 4-year-old. I don’t feel I have to warn her about my medical situation; I know my responsibilities and precautions. Am I out of line in my thinking?

Inflammation of the liver is termed hepatitis. The diagnosis of hepatitis is made by testing for elevation of liver enzymes. Determining whether the hepatitis was caused by a virus is done by looking for evidence of specific viral particles or the body’s response to specific viral types. Hepatitis C virus is one member of a viral family that preferentially invades the liver for reproduction. The other members include Hepatitis A, B, D and E.

Hepatitis C is almost always spread through contact with infected blood. Most patients with viral hepatitis have a self-limited course that resolves without treatment. Some individuals will be unable to eliminate the virus completely and remain chronically infected. They can potentially develop long-term liver problems and are sources for future spread of the infection.

The issue of disclosure of about an infection or disease that a person might have should be individualized and determined by the person infected. Medical information is confidential and recent laws have been passed (Health Insurance Portability and Accountability Act) to help insure the privacy rights of individuals. I’ve always believed that common sense should be used in determining who and what should be told to others regarding medical illnesses.

In the case of infections with hepatitis C, the vast majority of infections occur after exposure to blood containing the live virus. Infection from sexual contact is possible, but statistically unlikely. Touching, holding, hugging or playing with another person is not a likely method of transmission, unless there is blood exposure from the infected person to an uninfected person. A reasonable person, understanding the facts, should not fear risk of infection from the type of contact expected during the visit from your relatives.

I do not think that you have an obligation to inform your relatives of your infection status prior to their visit. You should take the necessary precautions to prevent possible exposure to your blood, which might be on items such as toothbrushes or razors. It’s also important to look into, if you haven’t already, combination therapies that have been able to eradicate the virus to non-detectable levels in the blood of chronically infected patients.

Write to Dr. Kendall Sprott , at Children’s Hospital of New Jersey at Newark Beth Israel Medical Center, 166 Lyons Ave., Newark, N.J. 07112. Or e-mail him at ksprott@sbhcs.com.

 

Racial Differences in Chronic Hepatitis C-Related Liver Inflammation and Fibrosis
Source: www.gastrohep.com

Variance in hepatic iron loading does not explain the differences in liver histology between black and white patients with chronic hepatitis C, suggests a study in the journal Clinical Gastroenterology and Hepatology.

Hepatitis C virus (HCV) infection is more prevalent in black Americans than their white counterparts. Yet the natural course of HCV in black patients has not been defined.

In an attempt to remedy this, Kester Crosse and colleagues from The University of Maryland Baltimore School of Medicine, in Baltimore, Maryland, USA, performed a retrospective comparison of 87 black and 136 white American chronic hepatitis C patients.

Initial liver tests, HCV genotype and viral liver load as well as liver histology findings were assessed from the subjects, who had all been evaluated at the University of Maryland between 1995 and 1998.

Liver biopsy examinations were interpreted using the Knodell Histologic Activity Index (HAI) criteria.

The findings of the study show that black patients were older (46.3 years compared to 43.3 years for white patients). They were also more likely to be infected with HCV genotype 1 (95% versus 75%).

There was no major difference in the modes of HCV transmission, estimated duration of HCV infection or prevalence of alcohol abuse between either group.

“Liver necroinflammation was more severe in white patients than black patients.” Clinical Gastroenterology & Hepatology

Despite this, black patients had lower mean total HAI scores (7.6 vs. 8.7), periportal hepatocyte necrosis scores and liver fibrosis scores.

Black patients were found to have a lower mean serum alanine transaminase level (85.5 vs. 122.7), a result in keeping with lower hepatic necroinflammatory activity.

Serum iron levels were also lower in black patients than white patients, although there were no racial differences in the prevalence of increased iron studies and hepatic iron loading.

The researchers conclude that back chronic HCV patients have milder liver necroinflammation and fibrosis than white patients with similar HCV duration. They add that differences in liver histology were not explained by a variance in hepatic iron loading.

Clin Gastroenterol Hepatol 2004; 2(6): 463