PORTLAND, Ore. (AP) - One person died and five others have fallen ill after receiving organ or tissue transplants from a man who had the liver disease, hepatitis C, doctors said.

The Oregon Health Division said the case involves more than three dozen people who received tissue or organs from the infected man, who died of a hemorrhage inside his skull two years ago. Neither the man, tested for the disease in Oregon, nor the recipients, from 14 states and two other countries, were identified.

"This is probably a very rare case," said Dr. Ann Thomas, a state medical epidemiologist who is investigating.

The case — first reported by The Oregonian — exposes an Achilles heel in the system that tests organ donors for hepatitis C, a disease that leads to chronic liver disease in 70 percent of infected people.

The organ donor, like all such donors, was tested for hepatitis C with a test that detects antibodies, virus fighters the body produces in response to an invasion by disease organisms. But the body takes six to eight weeks to produce the antibodies that specifically fight hepatitis C, Thomas said. During that time, a patient is unaware he or she has been infected.

That leaves a six- to eight-week window in which an infected donor can appear to be healthy.

"This was the classic window case," said Mike Seely, executive director of the Portland-based Pacific Northwest Transplant Bank, which arranged the original testing of the infected man.

Besides lacking hepatitis C symptoms, the man did not show any sign of being at significant risk for contracting the disease, such as being an intravenous drug user.

The case caught the attention of doctors in May, when a patient developed symptoms of an acute hepatitis C infection, according to a presentation last weekend by Dr. Barna D. Tugwell at the Interscience Conference on Antimicrobial Agents and Chemotherapy in San Diego.

Six weeks earlier, the patient had received a knee ligament from the infected man, who had died in late 2000, reported Tugwell, an epidemic intelligence officer with the Oregon Health Division and lead investigator for this case.

In July, the donor's stored blood serum was tested both for the presence of hepatitis C antibodies and for the virus itself. Again, the antibody test was negative for the disease. But the direct test for the virus was positive for hepatitis C.

The Oregon Health Division immediately began notifying doctors of 40 patients who had received kidneys, lungs, liver, heart, vein, tendons, skin, bone and corneas.

So far, 18 of the 40 patients have concluded their tests for hepatitis C. Six were found to have become infected after their surgeries. Nine had no infection. Three had already been infected with hepatitis C before their transplants.

Tests on the remaining 22 patients are continuing.

Battleground: Schering and Roche Duke It Out Over the

Huge Hepatitis C Market As Concerns Arise for Some Patients

TAGline - Volume 8 Issue 8 - October 2001

"Neither kinder nor gentler"

Observing the race between Roche and Schering for FDA approval of the two pegylated interferons (interferon as monotherapy as well as interferon in combination with ribavirin)--and a lion's share of the hepatitis C market--makes the race in the mid-1990s for FDA approval of the HIV protease inhibitors look like child's play. There is absolutely no love lost between the hep C clinical and marketing teams of the two companies. It's said that a Roche employee nearly had his lawyers file a cease and desist order against someone on the Schering team who continuously bad mouthed Pegasys at hepatology conferences. Michael Marco brings the laundry out for air.

The competitiveness with which the companies release data is like a carefully orchestrated fencing match. Hoffmann-La Roche filed a new drug application (NDA) with the FDA nineteen months ago for its pegylated interferon (Pegasys). During this time, hep C kingpin and marketing maven Schering-Plough sailed through the FDA approval process with its pegylated interferon (PEG-Intron), with not just a monotherapy indication, but also a recent combination therapy indication for use with its ribavirin. It is unfortunate that the FDA did not grant Roche's NDA a much-deserved "expedited" review (6 vs. 12 months) for use in treating HCV-positive cirrhotics.

Roche beat Schering with publishing its monotherapy study first--and in the New England Journal to boot--while Schering was reduced to Hepatology. But Schering then snuck by Roche with the publication of its combination therapy study in the Lancet--while Roche's data are still in abstract form.

Roche is planning on filing its NDA for Pegasys and ribavirin in the current quarter. The FDA granted Roche's Pegasys/ribavirin combination therapy NDA an "expedited" review. Roche will also be filing a separate NDA for approval of its own manufactured ribavirin. The goal is to have Pegasys and ribavirin available by the first half of 2002. Jesus Leal, Roche's HCV marketing director, said that Pegasys and ribavirin will be sold as separate products and no plans have been made to bundle them. Schering, in its usual arrogant and cagey way, will not commit to not bundling peginterferon and ribavirin (like it did with its standard interferon+ribavirin formulation, Rebetron) or making them individually so costly that one has no choice but to by the bundled product.

Roche has studied its pegylated interferon in over 1,000 HIV/HCV co-infected patients (compared to Schering with <200) and is currently conducting a Phase III trial in this population. Once they receive monotherapy approval, Roche plans to seek a supplemental NDA for the use of Pegasys in treating HIV/HCV co-infected patients.

Combination therapy data from Roche and Schering's Phase III registrational pegylated interferon plus ribavirin studies have recently been presented and published.

Schering conducted a 3-arm 1,500 patient study comparing two doses of peginterferon plus ribavirin against standard interferon+ribavirin for 48 weeks. According to the FDA's analysis--stricter than Schering's and thus differs from the Lancet piece--52% of individuals in the 1.5 mcg/kg arm achieved a sustained viral response compared to 47% and 46% of those in the low-dose peginterferon (0.5 mcg/kg) and interferon+ribavirin arms, respectively. When broken down according to genotype, 41% of the genotype 1 individuals in the high-dose peginterferon arm achieved a sustained viral response compared to 33% of the interferon+ribavirin ones. In genotype 2/3 individuals, there were no differences in response rates between the three arms with all achieving an &#tilde;80% sustained viral response.

As for side effects, in the Schering phase III (PEG-Intron) combination trial (which compared high-dose peginterferon+ribavirin vs. low-dose peginterferon+ribavirin vs. standard interferon+ribavirin) neutropenia occurred in 26% of the high-dose peginterferon+ribavirin study volunteers compared to 14% of those in the standard interferon+ribavirin arm. Anemia occurred in 12% and 17% of the volunteers, respectively. Approximately 60% of all study participants experienced fatigue and/or headaches, and more than 40% in all arms experienced depression of anxiety. Suicidal behavior was recorded in 2% of individuals, with three suicides occurring during the study: two in the high-dose peginterferon arm and one in the standard interferon arm. Virology data from the Roche combination therapy study look similar to that of Schering.

Presented at DDW last May, results from Roche's NV15801 study documented that 30% of the patients in the monotherapy arm achieved a sustained viral response compared to 45% in the interferon+ribavirin arm and 56% in the PEG-interferon+ribavirin arm for all comparisons). In genotype 1 patients, the sustained viral response rates were 21%, 37%, and 46%, respectively. And, in genotype 2/3 patients, the sustained viral response rates for the three arms were 45%, 61%, and 76%, respectively.

Results from the viral kinetics substudy have also become available. The study found that individuals who have either a 2 log drop in HCV RNA or become HCV RNA undetectable by week 12 have a 65% chance of remaining undetectable for 72 weeks (considered cured by some people). Conversely, for individuals who did not achieve a 2 log drop in HCV RNA or become HCV RNA undetectable after 12 weeks of treatment, there is a 97% chance that they never will. These kinetic data are similar to those presented by Schering in its Lancet paper. This indicates that checking one's HCV RNA at 12 weeks may help to determine if therapy should continue for a year or be discontinued.

Pegylated interferon, while markedly more convenient than and equally effective as standard interferon alone, is turning out to be neither kinder nor gentler. Nor is it more effective than standard interferon+ribavirin (Schering's Rebetron) for poor prognostic factor patients, individuals with a baseline HCV viral load >2 million copies/mL and an HCV genotype 1.

This, however, is not public knowledge. It appears nowhere in the Lancet paper. One has to look into the FDA label (page 6, section 2.0) in order to see that the response rates for individuals with poor prognostic factors were virtually indistinguishable between the two treatments: 30% for high-dose peginterferon+ribavirin and 29% for standard interferon+ribavirin in the Schering trial. This crucial piece of evidence means that while peginterferon is more convenient than standard interferon+ribavirin, it is not virologically superior in fully half the people with HCV.

Like Schering, Roche appears to be hush-hush about the comparative results in poor prognostic patients. The data were not presented at DDW and are not scheduled to be presented in a peer-reviewed oral or abstract presentation at the upcoming AASLD meeting. Sources say it's doubtful they will appear in the manuscript.

Officials at Hoffmann-La Roche recently notified the FDA that a serious adverse event (hepatic decompensation) has occurred in seven HCV/HIV co-infected individuals enrolled in its NR15961 study. Five of these cases occurred among study participants in the PEG-Intron+ribavirin study group, and two of the cases occurred in those receiving standard interferon (Intron) plus ribavirin. Five of these study volunteers didn't recover. According to the Roche letter:

All seven of these patients had cirrhosis and were receiving concomitant HAART therapy. 5 of 7 were on stavudine, 4 of these 5 patients were also on didanosine. All seven of these cases of hepatic decompensation occurred during the first 4 months of therapy. In five of the seven cases, the patients subsequently died while off study drug. Among the seven patients, three patients were enrolled by investigators even though they violated the protocol entry criteria; two patients had Child's class B and one had previous splenectomy...All three of these patients who violated entry criteria had further progression of hepatic decompensation and later died. The other four patients fulfilled all protocol entry criteria and had no evidence of pre-existing hepatic decompensation. Two of these patients died.

Roche says that "a thorough evaluation of the safety data from all other on-going trials with patients co-infected with HCV/HIV has not identified any additional cases of hepatic decompensation." The study will continue, but Roche has requested all investigators ensure that:

Study personnel should be educated on the importance of careful assessment for evidence of hepatic decompensation in co-infected patients with cirrhosis who are being treated with antiretroviral therapy, especially at baseline, but also throughout therapy, particularly within the first 16 weeks.
Patients with evidence of hepatic decompensation should be withdrawn from therapy immediately and carefully followed until they recover completely.

It will take some time to understand why these patents decompensated so quickly after study entry. It may be a combination of several things, including: 1) the natural history of HIV/HCV co-infection in patients with cirrhosis; 2) HAART hepatotoxicity; and/or 3) interferon-based therapy in late-stage cirrhotics. To determine if this deleterious interaction between HAART and interferon in cirrhotic patients has occurred before, the FDA must gain access to Schering and Amgen's databases of co-infected patients--before Schering's marketing division figures out a way to use this as PR propaganda against Roche.

http://www.aegis.com/pubs/tag/2001/TG011002.html

011010
TG011002

Injection Drug Users Continue Risky Habits Even After Testing Positive for Hepatitis C Virus

Young injection drug users continued to share syringes, needles and other paraphernalia even after they found out that they had tested positive for the hepatitis C virus (HCV), according to a study reported in the October 1 issue of the journal Clinical Infectious Diseases.

Researchers said their findings suggest that young injection drug users may not be aware of the risk of hepatitis C infection. They also noted that the study highlights the urgent need for post hepatitis C test guidelines and intervention to reduce such high-risk behavior that perpetuates the risk of transmission.

The study evaluated the change in behavior among a group of young injection drug users after disclosure of a positive hepatitis C virus antibody test result among a group young injection drug users.

The researchers detected no significant differences in the sharing of syringes and needles of the 46 injection drug users who had a positive hepatitis C test result and 60 injection drug users who did not have a positive HCV test result or who were unaware of their test result.

Other sources: Clinical Infectious Diseases

Acetaminophen (Tylenol) Liver Damage "Is it safe for me to take Tylenol?"

Do the recommended doses of Tylenol cause any liver damage?
Why should we know that the generic name of Tylenol is acetaminophen?
Just how much acetaminophen is safe to take?
How is acetaminophen processed (metabolized) in the body?
How does an overdose of acetaminophen cause liver injury?
Is overdose with acetaminophen usually accidental or intentional?
How can accidental overdose be avoided in adults?
How can overdose be avoided in children?
What happens to a person with acetaminophen-induced liver damage?
What should be done if acetaminophen toxicity is suspected?
Acetaminophen (Tylenol) Liver Damage At A Glance
"Is it safe for me to take Tylenol?"

Tylenol is currently the most popular painkiller in the United States. Americans take over 8 billion pills (tablets or capsules) of Tylenol each year. Acetaminophen is the general (generic) name for Tylenol, which is a brand name. Although acetaminophen is contained in over 200 medications, most of them do not have the name “Tylenol” on their labels. Moreover, just about every patient with liver disease in my practice invariably asks: “Is it safe for me to take Tylenol?” or “How much Tylenol can I take?” These questions highlight the public’s awareness of the potential for acetaminophen to cause liver damage or injury.

Tylenol is a very effective pain-killing (analgesic) and fever-reducing (anti-pyretic) agent. It is also a very safe drug as long as the recommended dosage is not exceeded. In fact, the use of Tylenol instead of aspirin to treat fevers in infants has greatly reduced the occurrence of Reyes syndrome, an often fatal form of liver failure. Ironically, however, taking too much Tylenol (an overdose) can also cause liver failure, although by a different process (mechanism), as discussed below.

Do the recommended doses of Tylenol cause any liver damage?

Some early reports did describe the occurrence of chronic liver disease that was associated with the long-term use of Tylenol in the recommended doses. These studies were published in the 1970s, however, and I suspect that many of these patients may have had unrecognized chronic hepatitis C infection. Anyway, today, the consensus is that the usual doses of Tylenol cause significant liver damage only rarely or not at all in people with normal livers.

Likewise, a person with liver disease does not appear to be at an increased risk of developing additional liver injury from taking Tylenol. This is so regardless of the cause of the liver disease and provided the patient does not drink alcohol regularly. Thus, Tylenol is quite safe to use in the usual dose in patients with acute (brief duration) or chronic (long duration) hepatitis. For example, Tylenol is routinely prescribed to treat the flu-like symptoms that can be caused by interferon treatments for patients with chronic hepatitis. Keep in mind, however, that all drugs, including Tylenol, should be used with caution, if at all, in patients with severe liver disease, such as advanced cirrhosis (scarring of the liver) or liver failure.

Why should we know that the generic name of Tylenol is acetaminophen?

For the remainder of this discussion, I will refer to the generic name acetaminophen, rather than to the brand name Tylenol. I decided to do this to emphasize the need for people to read the labels of medicine bottles carefully. As mentioned above, the labels usually will say acetaminophen rather than Tylenol. For example, each tablespoon of the common nighttime cold remedy, Nyquil, contains 500 milligrams (mg) of acetaminophen. Similarly, each tablet of Vicodin, a popular, potent painkiller that contains a narcotic, has also either 500, 650, or 750 mg of acetaminophen, depending on the formulation.

As already mentioned, an overdose of acetaminophen can cause liver damage. This damage occurs in a dose-related manner. (Some other medications can cause liver injury in an unpredictable fashion that is unrelated to the dose.) In other words, liver injury from acetaminophen occurs only when someone takes more than a certain amount of the drug. Likewise, the higher the dose, the greater is the likelihood of the damage. What is more, this liver injury from an overdose of acetaminophen is a serious matter because the damage can be severe and result in liver failure and death. In fact, acetaminophen overdose is the leading cause of acute (rapid onset) liver failure in the U.S. and the United Kingdom.

Just how much acetaminophen is safe to take?

For the average healthy adult, the recommended maximum dose of acetaminophen over a 24 hour period is four grams (4000 mg) or eight extra-strength pills. (Each extra-strength pill contains 500 mg and each regular strength pill contains 325 mg.) A person who drinks more than two alcoholic beverages per day, however, should not take more than two grams of acetaminophen over 24 hours, as discussed below. For children, the dose is based on their weight and age, and explicit instructions are given in the package insert. If these guidelines for adults and children are followed, acetaminophen is safe and carries essentially no risk of liver injury.

On the other hand, a single dose of 7 to 10 grams of acetaminophen (14 to 20 extra-strength tablets) can cause liver injury in the average healthy adult. Note that this amount is about twice the recommended maximum dose for a 24 hour period. In children, a single dose of 140 mg/kg (body weight) of acetaminophen can result in liver injury. Amounts of acetaminophen, however, as low as 3 to 4 grams in a single dose or 4 to 6 grams over 24 hours have been reported to cause severe liver injury in some people, sometimes even resulting in death. It seems that certain individuals, for example, those who regularly drink alcohol, are more prone than others to developing acetaminophen-induced liver damage. To understand this increased susceptibility in some people, it is useful to know how acetaminophen is processed (metabolized) in the liver and how the drug causes liver injury.

How is acetaminophen processed (metabolized) in the body?

The liver is the primary site in the body where acetaminophen is metabolized. In the liver, acetaminophen first undergoes sulphation (binding to a sulphate molecule) and glucuronidation (binding to a glucuronide molecule) before being eliminated from the body by the liver. The parent compound, acetaminophen, and its sulphate and glucuronide compounds (metabolites) are themselves actually not harmful. An excessive amount of acetaminophen in the liver, however, can overwhelm (saturate) the sulphation and glucuronidation pathways. When this happens, the acetaminophen is processed through another pathway, the cytochrome P-450 system. From acetaminophen, the P-450 system forms an intermediate metabolite referred to as NAPQI, which turns out to be a toxic compound. Ordinarily, however, this toxic metabolite is rendered harmless (detoxified) by another pathway, the glutathione system.

Tylenol Liver Damage

How does an overdose of acetaminophen cause liver injury?

The answer is that liver damage from acetaminophen occurs when the glutathione pathway is overwhelmed by too much of acetaminophen’s metabolite, NAPQI. Then, this toxic compound accumulates in the liver and causes the damage. Furthermore, alcohol and certain medications such as phenobarbital, phenytoin, or carbamezepine (anti-seizure medications) or isoniazid (anti-TB drug) can significantly increase the damage. They do this by making the cytochrome P-450 system in the liver more active. This increased P-450 activity, as you might expect, results in an increased formation of NAPQI from the acetaminophen. Additionally, chronic alcohol use, as well as the fasting state or poor nutrition, can each deplete the liver’s glutathione. So, alcohol both increases the toxic compound and decreases the detoxifying material. Accordingly, the bottom line in an acetaminophen overdose is that when the amount of NAPQI is too much for the available glutathione to detoxify, liver damage occurs.

Is overdose with acetaminophen usually accidental or intentional?

In the U.S., suicide attempts account for over two thirds of acetaminophen-related liver injury, whereas accidental overdose accounts for only one third of the cases. In young children, accidental overdose accounts, surprisingly, for an even lower percent of the cases. That is, among these often-curious toddlers, accidental overdose is responsible for less than 10% of the instances of acetaminophen toxicity. Moreover, the vast majority of these accidental overdoses were due to unintentional overdoses given by the caregivers of the children.

How can accidental overdose be avoided in adults?

To avoid unintentional overdoses among adults, I offer the following suggestions. Read the labels of the medication bottles carefully and determine the amount or strength of acetaminophen in each pill or spoonful.

Become familiar with all of the other medications that you are taking. Remember that over 200 drugs contain acetaminophen as one of the ingredients and that certain drugs, such as phenobarbital, can significantly increase liver damage.

Before you take the medication, write down (record) the maximum safe number of pills or spoonfuls that you can ingest over 24 hours. Stick to that quantity and do not deviate. If, however, you are unsure of the safe number of doses or think that you need to take more than you should, call your doctor or pharmacist.

When you receive a prescription for a new medication, ask your doctor or pharmacist whether it affects the body’s metabolism (processing) of the other medications that you are taking, including acetaminophen.

If you have been drinking alcohol regularly, do not exceed taking 2 grams of acetaminophen over 24 hours. Be honest with yourself about the ingestion of alcohol.

Record the number of pills or spoonfuls of acetaminophen and the time that you take them.

Tylenol Liver Damage

How can overdose be avoided in children?

The dosing of acetaminophen for children, as previously mentioned, depends on their weight and age. To avoid overdose in children, follow the same procedures for them as suggested above for adults. Beyond that, two adults should independently determine the dose of acetaminophen for a child. If there is disagreement about the recommended dose, consult a pharmacist or physician. These precautions are not excessive when you consider that in one experimental mock situation, only 30% of adults correctly calculated the dose of acetaminophen for their child. If a baby-sitter is caring for a sick child, parents should carefully write out the dose and schedule for the administration of the drug. The fact is that each year, in children with high fevers who were given repetitive doses of acetaminophen, deaths have occurred due to accidental overdose and the resulting liver damage.

What happens to a person with acetaminophen-induced liver damage?

Three clinical stages (phases) of acetaminophen-induced liver injury have been described. During the first phase, that is, the initial 12 to 24 hours or so after ingestion, the patient experiences nausea and vomiting. For the next perhaps 12 to 24 hours, which is the second phase or the so-called inactive (latent) phase, the patient feels well. In the third phase, which begins about 48 to as late as 72 hours after the ingestion of acetaminophen, liver blood test abnormalities begin to appear. Most notably, extremely high (abnormal) levels of the liver blood tests, AST and ALT, are common with this type of liver injury. The outcome (prognosis) of the liver injury can be predicted fairly accurately on the basis of the patient’s clinical exam and blood tests. For example, at one extreme, if the patient develops severe acid buildup in the blood, kidney failure, bleeding disorders, or coma, then death is almost certain. Only a liver transplant can possibly save such a patient.

What should be done if acetaminophen toxicity is suspected?

A physician should evaluate the individual immediately. Remember that bringing the bottles of acetaminophen and all of the person’s other medications to the emergency room is always useful. The risk that an acetaminophen overdose will cause liver injury correlates with the blood level of acetaminophen relative to the time the drug was taken. Physicians, therefore, are able to estimate the patient’s probability of developing liver injury after an overdose. To make this determination, they obtain the patient’s history of acetaminophen ingestion and measure the blood level of the drug. With this information, the doctor then can refer to a table (nomogram) that provides an estimate of the risk of developing liver injury. The accuracy of this estimate, however, depends on the reliability of the time of ingestion and whether the acetaminophen was taken over a period of time or all at once.

Tylenol Liver Damage

With suspected acetaminophen overdose, the doctors usually will pump (gavage) the patient’s stomach to remove pill fragments. In reality, many individuals who overdose with acetaminophen in a suicide attempt will have taken other pills in addition. Some doctors, therefore, will consider treating the patient with activated charcoal, which binds (and thereby inactivates) many medications. However, this treatment is controversial because of a concern that the activated charcoal may also bind the antidote for acetaminophen overdose.

Patients who are thought to be at a high-risk or even only at a possible risk of developing acetaminophen liver injury should be given the antidote, N-acetyl cystiene (Mucomyst) orally (or intravenously in Europe). This drug works by indirectly replenishing glutathione. The glutathione, as you recall, detoxifies the toxic metabolite of the acetaminophen. The N-acetyl cystiene is most effective when administered within 12 to 16 hours after the acetaminophen was taken. Most physicians however, will administer N-acetyl cystiene even if the patient is first seen beyond this 16 hour period. Thus, a British study showed that patients already with liver failure who then received the N-acetyl cystiene were more likely to survive than patients who did not receive the antidote. Moreover, the survival occurred in these patients regardless of the time of initial administration of N-acetyl cystiene. Finally, people who recover from acetaminophen-induced liver damage are left, fortunately, with no residual or ongoing (chronic) liver disease.

Acetaminophen (Tylenol) Liver Damage At A Glance

Acetaminophen is a very safe drug when taken as directed, even for people with liver disease. Nevertheless, every drug carries risks.

Liver damage from acetaminophen, which can be severe, can result either from an overdose or from regular doses that are taken while drinking alcohol.

Most cases of acetaminophen-induced liver injury are caused by an intentional or suicidal overdose.

Unintentional or accidental overdose of acetaminophen can usually be avoided with care and attention to the dosing.

Physicians can estimate a patient's probability of developing liver injury based on the timing of the overdose and the blood level of the drug.

In patients with acetaminophen liver damage, the usual clinical sequence is nausea and vomiting for the first 12-24 hours, then the patient seems well for the next 12-24 hours, after which abnormal liver blood tests develop.

An antidote, N-acetyl cystiene, is available and should be given to the patient as soon as possible, preferably within 16 hours after the acetaminophen was taken.

Medical Author: Tse-Ling Fong, M.D.
Medical Editor: Leslie J. Schoenfield, M.D., Ph.D.

VIRACEPT(R)

Appears to be Generally Well Tolerated In Hepatitis-C Co-Infected Patients

Monday September 30, 8:32 am ET

SAN DIEGO, Sept. 30 /PRNewswire-FirstCall/ -- Data presented today at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy in San Diego reveal that for patients co-infected with Hepatitis-C (HCV) and HIV, VIRACEPT® (nelfinavir mesylate) is generally well tolerated. The retrospective analysis, conducted by Agouron Pharmaceuticals, Inc., a Pfizer Company (NYSE: PFE - News), examined the responses of 1,055 HCV/HIV co-infected individuals treated with more than three months of protease inhibitor (PI) therapy and compared responses of patients on VIRACEPT, indinavir, saquinavir, ritonavir and amprenavir based upon comparisons of grade three and grade four elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT). AST and ALT are liver enzymes that play a role in protein metabolism; elevated serum levels of AST and ALT can be indicators of liver damage.

"Hep-C/HIV co-infection is a huge problem: the prevalence of co-infection among all people living with HIV ranges from 30 to 50 percent. Treating these co-infected patients is becoming increasingly important. What we discovered in this study indicates that nelfinavir appears to result in less grade three and four liver elevations for those patients taking a HAART regimen that includes a protease inhibitor," observed lead investigator Douglas T. Dieterich, M.D., Mt. Sinai Medical Center.

This retrospective study collected safety data, viral load, CD4 cell count and treatment history (both HIV and HCV) from co-infected patients receiving PI therapy for at least three months, though the mean time on PI-inclusive highly active antiretroviral therapy was 27.6 months. Of the 1,055 cases reviewed, 77 percent were male; the median baseline CD4 cell count was 240, and median viral load was 4.11 log10. VIRACEPT patients numbered 426, while 365 were on indinavir, 181 on saquinavir, 148 on ritonavir and 8 on amprenavir. Of the total 1,055 subjects, 106 were on dual PIs.

In evaluating liver toxicity, four percent of patients on VIRACEPT had grade three or four elevation in AST, in contrast to seven percent of indinavir patients, eight percent of ritonavir patients, and eleven percent of saquinavir patients. In addition, three percent of VIRACEPT patients had a grade three or four elevation in ALT compared to seven percent of indinavir patients, three percent of ritonavir patients, and seven percent of saquinavir patients.

Throughout the course of the study, patients had a mean CD4 cell count increase of 136 and a decrease in viral load of 1.09 log10, with 56 percent having a viral load of less than 400 copies/mL. Mean viral load changes for patients with a baseline CD4 cell count of less than 50, 50 to 200, and greater than 200, were, respectively, -1.48 log10 (45 percent with less than 400 copies/mL), -1.23 log10 (56 percent with less than 400 copies/mL) and - .921 log10 (61 percent with less than 400 copies/mL). For VIRACEPT patients at these same baseline CD4 cell counts, the following viral load decreases were noted: -1.72 log10 (44 percent with less than 400 copies/mL), -1.54 log10 (52 percent with less than 400 copies/mL) and -1.04 log10 (63 percent with less than 400 copies/mL). For patients with a baseline CD4 cell count of less than 50, 50 to 200, and greater than 200, mean CD4 increases were respectively 179, 154, and 116. For VIRACEPT patients at these same baseline CD4 cell counts, the following increases were noted: 177, 136, and 93.

VIRACEPT, in combination with other anti-retroviral agents, is indicated for the treatment of HIV infection. The recommended dosage for VIRACEPT is 1,250 mg (five 250 mg tablets) twice a day or 750 mg (three 250 mg tablets) three times daily. VIRACEPT has been shown to be generally well-tolerated. The most commonly reported side effect attributable to VIRACEPT is diarrhea.

VIRACEPT is metabolized primarily by the liver. Therefore, caution should be exercised when administering VIRACEPT tablets to patients with impaired hepatic function. Redistribution or accumulation of body fat may occur in patients receiving anti-retroviral therapy. The cause and long-term health effects of these conditions are not known at this time. Increased bleeding in patients with hemophilia, as well as diabetes mellitus and hyperglycemia, have been reported with protease inhibitors.

VIRACEPT should not be used with certain medications. Taking certain other prescription and nonprescription drugs and supplements with VIRACEPT could create the potential for serious side effects that could be life-threatening. In addition, some drugs may markedly reduce VIRACEPT plasma concentrations, resulting in suboptimal antiviral activity and subsequent emergence of drug resistance. Patients should always talk to their physician or healthcare provider before starting new medicines. HIV drugs do not cure HIV infection or prevent individuals from spreading the virus.

Agouron Pharmaceuticals, Inc. became a wholly owned subsidiary of Pfizer Inc in 2000. Pfizer Inc discovers, develops, manufactures and markets leading prescription medicines, for humans and animals, and many of the world's best known over-the-counter consumer brands.

For more information, dial toll free 1-888-VIRACEPT (847-2237).

VIRACEPT® and Agouron® are registered trademarks of Agouron Pharmaceuticals, Inc.

Source: Agouron Pharmaceuticals, Inc.

Tuesday, 1 October, 2002, 23:14 GMT 00:14 UK

Herbal hope for liver disease

http://news.bbc.co.uk/2/hi/health/2289647.stm

A toad extract - bufotoxin - has the 'best potential'

Taking herbal medicine as well as conventional drugs may help long-term hepatitis B sufferers, say researchers in California.

A study suggests Chinese herbal medicine on top of the standard treatment - interferon alfa - is better than interferon alone.

The analysis of 27 clinical trials - by a University of California, Berkeley, team - is published in the American Journal of Public Health.

"The results are encouraging enough that, if I had chronic hepatitis B and had previously failed interferon alfa treatment, I would talk to my doctor about combining interferon alfa with Chinese herbal medicine," says lead author Michael McCulloch.

Chronic infection

Hepatitis B is a type of liver disease caused by the hepatitis B virus.

If the infection lasts for more than six months, it is known as chronic hepatitis.

In this study, all the patients had the chronic form of the disease. Many were taking a variety of Chinese herbal medicines - including root, plant and toad extracts.

Some were also taking the standard treatment - interferon alpha, which can cause side effects like fatigue, depression and flu-like symptoms.

Overall, Chinese herbal medicine combined with interferon alpha was one-and-a-half to two times as effective as interferon alpha alone, says the Berkeley team.

But the researchers say they cannot make firm conclusions about the use of Chinese herbal medicines based upon the results from these clinical trials.

Risks and benefits

There is anecdotal evidence that herbs are useful in hepatitis either to improve general wellbeing or help with side effects, says Nigel Hughes, chief executive of UK charity the British Liver Trust.

But he says - like all treatments - herbal medicine has risks and benefits. He sees a need for more research, especially because small scale studies of Chinese herbal medicine have produced conflicting results.

"We need to know the mechanism of which herbs work and why," Mr Hughes told BBC News Online.

"We need large scale independent clinical trials of herbal treatments."

The World Health Organization estimates that two billion people around the world are infected with hepatitis B. About 350 million of these have the chronic form of the disease.

Chronic or Primary HCV Infection ?

NEW YORK (Reuters Health) Sept 24 - An assay for IgG avidity in hepatitis C virus (HCV) infection may be useful in distinguishing primary infection from chronic disease, Japanese researchers report in the October issue of the Journal of Medical Virology. Dr. Atsushi Kanno of Tohoku Koseinenkin Hospital, Sendai, and Dr. Yukumasa Kazuyama of Kitasato-Otsuka Biomedical Assay Laboratories, Sagamihara, note that in HCV it is "important to distinguish acute infection and chronic infection when considering treatment." However, "seroconversion of antibody to HCV (anti-HCV) is currently the only reliable marker to identify primary HCV infection," they write. To determine whether an enzyme immunoassay for anti-HCV IgG avidity might also be useful in this regard, the researchers tested the avidity assay in 36 anti-HCV-positive immunocompetent patients. The investigators found that the avidity assay gave a mean avidity index of 7.7 in patients with primary HCV infection, a figure significantly lower than that in patients with histologically confirmed chronic HCV infection (77.0; p < 0.0001) or in patients who had previously had HCV infection (44.5; p < 0.0001). Examination of a subset of 6 patients with primary HCV infection showed that the avidity index was low in the acute phase of the infection, but increased over time. "The avidity assay for IgG anti-HCV is a useful tool to discriminate...primary HCV infection from chronic or past HCV infection," the researchers conclude. J Med Virol 2002;68:229-233.

Risk of GI symptoms with over-the-counter nonsteroidal anti-inflammatory drugs

SourceURL:http://www.gastrohep.com/news/news.asp?id=1599 Risk of GI symptoms with over-the-counter nonsteroidal anti-inflammatory drugs Over-the-counter NSAIDs are not a benign medication even at low dosage, with NSAID users twice as likely as nonusers to report GI symptoms, finds a study in the September issue of the American Journal of Gastroenterology. In this study, researchers sought to determine the use of over-the-counter (OTC) nonsteroidal anti-inflammatory drugs (NSAIDs), their GI side effects, as well as to identify any professional or self-care for these side effects. The team, from the United States, surveyed an age-stratified random sample of over 1500 people using a telephone survey. All subjects were 40 years of age or over. Subjects were divided into 2 groups, the first, contained 535 people who had used OTC NSAIDs for 4 of the previous 7 days. The second, 1068 people who had not used any NSAIDs within the previous 30 days. The team measured each individual's current use of OTC NSAIDs, any GI symptoms, plus diagnoses and their treatment. They also measured any use of prescription or OTC GI medications. The researchers identified the most commonly used OTC NSAID as aspirin, either alone or in combination compounds. GI symptoms twice as likely in over-the-counter NSAID users. It was discovered that the majority of NSAIDs taken were for the prevention of myocardial infarction or stroke (43%). This was followed by pain relief and relief of arthritis symptoms. The team also found that NSAID users (20%) were twice as likely as nonusers (10%) to report GI side effects. When experiencing GI symptoms, they were more than twice as likely to use an OTC GI medication (47% compared to 21%). Dr Joseph Thomas' team concluded, "OTC NSAIDs are not a benign medication even at low dosages". In addition, "Physicians may be unaware that patients self-medicate with OTC NSAIDs or with OTC GI medications". In an editorial in the same publication, Drs Scheiman and Fendrick comment that, "Most regular NSAID users lack awareness of their potential side effects". "The sheer numbers of individuals exposed to OTC agents raise concern regarding their appropriate use", they state. Am J Gastroenterol 2002; 97 (9): 2215-9, 2159-61 04 October 2002

FDA Meeting May Mean Roadblock for Roche

By Adam Feuerstein
Senior Writer
10/07/2002 06:00 PM EDT
Click here for more stories by Adam Feuerstein

The Food and Drug Administration is asking Swiss drugmaker Roche to take its experimental hepatitis C therapy to an advisory panel -- an unexpected decision that could benefit Enzon (ENZN:Nasdaq - news - commentary - research - analysis) and Schering-Plough (SGP:NYSE - news - commentary - research - analysis), which already market a competing treatment.

Friday, the FDA announced that its Antiviral Drugs Advisory Committee would convene Nov. 14, to discuss Roche's two-drug cocktail aimed at treating the serious liver disease. Roche's experimental therapy combines Pegasys, a longer-acting version of the immune-boosting drug interferon with the antiviral medicine ribavirin. Roche manufactures both drugs.

The only problem with this meeting is that Roche, in its guidance to analysts, has never mentioned the need for an advisory panel meeting, forecasting instead, an FDA approval of the Pegasys therapy in December. Sometimes, the FDA schedules advisory panels because it has clinical concerns with drugs -- it could be about a drug's safety or efficacy -- and it wants to gather outside opinions. If that's the case with Pegasys, it could signal a potential delay in the drug's approval.

That would be welcome news for Schering-Plough and Enzon, which generated sales of $1.4 billion in 2001 for its competing PEG-Intron/Rebetol combination therapy for hepatitis C. (Schering-Plough records sales on its books, paying a royalty revenue to Enzon.) Looming competition from Roche has been a big concern for Schering-Plough and contributed, in part, to the drugmaker's profit warning last week.

"The scheduling of a panel meeting at such a late date is unusual, and if there's a delay in Pegasys' approval, it would be helpful to Schering-Plough and Enzon," says Legg Mason biotech analyst Stefan Loren. By his reckoning, even if the panel meeting goes extremely well for Roche, it still could push back FDA action into January. He rates Enzon buy, and his firm has a banking relationship with the company.

Warning Issued on Reuse of Needles

Oct 10, 12:45 AM (ET)
By NICK TROUGAKOS

OKLAHOMA CITY (AP) - A hepatitis C outbreak that has infected 52 people in Oklahoma has led to a national warning to nurse anesthetists against reusing needles in intravenous tubes.

James C. Hill, a nurse anesthetist in Oklahoma City, told health officials he reused needles and syringes up to 25 times a day to inject pain medication through intravenous tubes at a pain management clinic in Norman and two surgical centers in Oklahoma City. Such reuse of needles can spread the disease, which can lead to serious liver damage, cancer and even death. Hill is under investigation by the state Department of Health and the Oklahoma Board of Nursing.

Health officials have sent letters to 1,220 patients treated by Hill, telling them to get tested for hepatitis C, and 52 of the patients have tested positive since late August.

Last year, 19 patients of a Brooklyn, N.Y., clinic contracted hepatitis C when an anesthesiologist reused needles and a vial of medication. The American Association of Nurse Anesthetists has sent 33,000 letters to hospital administrators, nurse anesthetists and nursing students nationwide, citing the Oklahoma outbreak and telling them not to reuse needles. Experts say some health practitioners may not be aware that reusing needles is dangerous because the needles are inserted into tubes rather than under the skin.

"After discussion with infection control experts, we have concerns there may be a widespread misunderstanding by health care practitioners of the dangers associated with the reuse of needles and syringes," the letter said.

Dr. Elliot Greene, associate professor of anesthesiology at Albany Medical College in Albany, N.Y., said studies done in the 1990s documented that health care professionals sometimes reused needles when injecting drugs into intravenous tubes.

"It was a shocking thing to see," said Greene, who serves on the task force for infection control in the American Society of Anesthesiologists. He said the problem has to do with a lack of education.

"There are a lot of people who started their practice before this was an issue," Greene said. "They got into certain practice patterns that are now considered bad technique."

Jeff Beutler, executive director of the nurse anesthetists association, said that when a shot is given into an intravenous line, a needle can easily come into contact with a patient's blood. Blood-to-blood contact spreads hepatitis C.

Beth Bell, chief of the epidemiology branch in the division of viral hepatitis at the Centers for Disease Control and Prevention, said research clearly shows the danger of reusing needles.

"The way that these kind of intravenous tubes are placed, what often occurs is that there is a back-flow of blood into the intravenous tube," she said. State Epidemiologist Dr. Mike Crutcher said Hill believed he was practicing safe medicine.

"He didn't think it was abnormal procedure," Crutcher said. "It's hard to imagine that he would think it was normal." Messages left on Hill's telephone answering machine were not returned.

InterMune, Inhale to develop hepatitis C drug

Tuesday October 8, 8:36 am ET

BRISBANE, Calif., Oct 8 (Reuters) - InterMune Inc. (NasdaqNM:ITMN - News) and Inhale Therapeutic Systems Inc. (NasdaqNM:INHL - News) on Tuesday said they have agreed to develop an extended release treatment for hepatitis C.

InterMune currently markets a hepatitis C medicine called Infergen. It will develop Infergen using Inhale's PEGylation technology, which helps prolong or improve the effectiveness of a drug, into a new medicine called PEG-Infergen.

The new drug, if approved, would compete with Schering-Plough Corp.'s (NYSE:SGP - News) big-seller, Peg-Intron, and a new hepatitis C drug from Roche Holding AG (ROCZg.VX) called Pegasys. Roche's drug is expected to gain U.S. approval by the end of the year.

"We believe PEG-Infergen will build on the success we are having with Infergen in this market," said Scott Harkonen, president and CEO of InterMune. "We expect this market will grow to $3 to $4 billion over the next five years."

Harkonen added that the firms plan to initiate clinical trials with this compound in the first quarter of 2003.

'Invisible Condom' May Prevent HIV and Herpes
By Melissa Schorr

NEW YORK, September 21, 2001 (Reuters Health) - A heat-activated, 
antimicrobial gel under development, known as the "invisible condom," was 
able to prevent the transmission of HIV and herpes when tested on cells in 
the laboratory, Canadian researchers report.

"This gel acts as a barrier," said study co-author Dr. Jocelyne Piret, 
leader of the project and a researcher at Laval University in Quebec City, 
Canada. "We have data that it is effective against herpes, it is also 
effective against HIV."

In their report, published in the August issue of the journal Sexually 
Transmitted Diseases, the investigators explain that the gel successfully 
acted as a physical barrier blocking HIV-1 and the herpes simplex virus 
from infecting other cells.

The gel would contain microbicides such as sodium lauryl sulfate, which 
would further destroy the microbes. In addition to preventing the 
transmission of disease, the product would also act as a contraceptive, 
Piret said.

The researchers hope their gel may be less toxic than other spermicides 
currently on the market, such as nonoxynol-9, which the report indicates 
has been found to irritate the vaginal lining with frequent use and may 
actually foster the transmission of sexually transmitted diseases.
The gel is entering a Phase I clinical trial on female patients and could 
be on the market as soon as next year, Piret noted.

The gel would be applied in liquid form to the vaginal area with an 
applicator and turn to a gel formation upon encountering body heat. Because 
it begins in this fluid state, the gel seems to be able to spread into all 
crevices of the vaginal area. In the lab, the gel remained effective for as 
long as 6 hours, Piret added.

SOURCE: Sexually Transmitted Diseases 2001;28:484-491.

Device extends liver cancer patients' lives-study

Last Updated: 2002-10-10 10:02:10 -0400 (Reuters Health)

By Deena Beasley

LOS ANGELES (Reuters) - Use of a radiofrequency device that kills tumors
with heat significantly extends survival in liver cancer patients not
eligible for surgery, researchers said on Wednesday.

"The logic is that if I can go in there and debulk or ablate the tumor, the
patient will live longer. This is the first opportunity where we have had
enough patients to gather the data," said Dr. Allan Siperstein of the
Cleveland Clinic Foundation in Cleveland, the study's lead investigator.

The retrospective study compared the survival outcomes of 225 patients
treated between 1996 and 2000 with an electrosurgical device made by RITA
Medical Systems Inc. to historical survival rates for a similar group of
patients treated with chemotherapy alone.

Three years after being treated with the device, often in combination with
chemotherapy, 38% of patients with primary liver cancer and 60% of patients
whose cancer had spread from the colon to the liver were still alive
compared to 10% on chemotherapy alone, the study found.

Complications of the treatment--which involves thin electrodes that heat
and destroy, or ablate, the targeted tissue--can include wound infection
and the need for blood transfusions, the investigator said.

Only one out of 10 people who develop liver cancer are considered
candidates for removal of their tumor with traditional surgery, Siperstein
said. He said that chemotherapy is most often these patients' best choice,
but it works very poorly in most liver cancer cases.

Results of the study were presented in San Francisco at a meeting of the
American College of Surgeons.

"Doctors are conservative. We want to see the advantage of a treatment
before recommending it to patients," Siperstein said.

Copyright © 2002 Reuters Limited.

FDA OKs Another Hepatitis C Therapy
Wed Oct 16, 9:28 PM ET

WASHINGTON (AP) - Hepatitis C patients won another option to treat the dangerous liver disease Wednesday: Hoffman-La Roche Inc. announced the government has approved its once-a-week injection called Pegasys.

Pegasys is a longer-acting version of the longtime hepatitis treatment interferon-alpha. But it's not the first. Competitor Schering-Plough Corp. won Food and Drug Administration (news - web sites) approval to sell its once-a-week hepatitis shot, Peg-Intron, almost two years ago.

Roche plans to debut Pegasys with a twist: The first 15,000 patients whose doctors prescribe Pegasys before the end of the year will get a three-month free trial of the shots. Roche says by the end of three months, doctors can tell which patients are likely to benefit from Pegasys and thus should continue taking it, and which should stop.

Roche didn't reveal what it will charge for Pegasys, but other leading hepatitis treatments cost from $500 to $1,500 a month.

Spontaneous Recovery from Hepatitis C Infection Higher Than Thought

The percentage of patients who spontaneously recover from being infected with the hepatitis C virus is much higher than previously thought, according to a study reported in the October issue of the journal Hepatology.

Harvey Alter, an editor of the journal who wrote a commentary to the study, said the classic thinking in the field is that only 15 percent of such patients spontaneously clear the virus. "Data are now accumulating to indicate that spontaneous recovery rates are much higher, particularly in younger individuals," he observed.

This particular study found that 57 percent of the 14 participants infected with the virus eventually had a spontaneous recovery. Levels of HCV RNA became undetectable four to five months after the presumed time of infection in five of the patients and by eight, 13 and 24 months, respectively, in the other three patients who recovered. The remaining six study participants developed chronic infection.

"Based on this and other studies, spontaneous recovery rates appear sufficiently high that it seems safe and reasonable to wait at least six months before initiating treatment for acute hepatitis C," said Alter.

In another commentary on the study, Dr. David Oldach, of the University of Maryland School of Medicine, said uncertainty would remain over just how long therapy can be delayed, while hoping for a spontaneous cure.

Oldach said the study suggests that three months from the time of infection is clearly reasonable and up to six months is justifiable on a case-by-case basis. "Doctors and patients will have to continue grappling with this difficult issue and should make the decision jointly," he added.