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HCV Advocate Newsletter

back to 2003 Newsletters

May 2003 HCV Advocate

A Simple Guide to Understanding the Cost of HCV Medications
Alan Franciscus,
Editor-in-Chief, HCV Advocate


Calculating the cost of treatment is not as simple as it should be. Even doctors and pharmacists have problems getting it right. Making it through treatment may be as simple as being able to afford it. This guide will help you figure out how much treatment might cost you and help you to plan accordingly. Read more here.

Drugs and the Liver
Liz Highleyman

Many drugs—estimated at nearly 1,000—can harm the liver. These include prescription and over-the-counter medications, illicit recreational drugs, and herbal remedies. In the worst cases drug toxicity can cause acute liver failure, necessitating a liver transplant or causing death. In fact, drug toxicity is the leading cause of acute liver failure, and liver toxicity (hepatotoxicity) is the most common reason drugs are withdrawn from the market. Although severe drug-related liver injury is rare, the risk is higher in people with chronic hepatitis B or C. Read more here.

Understanding Your Liver Biopsy
Kara Wright, PA-C

Many patients diagnosed with hepatitis C will need to undergo a liver biopsy. A liver biopsy is an outpatient procedure which involves obtaining a small piece of liver tissue to be analyzed by a pathologist. Biopsies are done to determine the severity of injury to the liver from the hepatitis C virus. This excellent article covers it all: what to expect, methods, complications, liver anatomy and histology (great stuff!), and understanding your results including an explanation of the Metavir and the Knodell scoring systems. Read more here.

HealthWise – Navigating Illness—Suggestions for Patients, Family, Friends, and Coworkers
Lucinda Porter, RN

Patients have many responses and approaches to illness and health. Some use denial in order to cope. Others respond by feeling scared or overwhelmed. Anger and resentment are common reactions. Acting tough and invincible is another way of handling illness. There are inherent strengths and weaknesses in all of these coping mechanisms. These approaches all work, but there are limits to them. Read more here.

The Future Burden of HCV
Alan Franciscus,
Editor-in-Chief, HCV Advocate


Taking into account the current number of chronic HCV infections in the US today, it is expected that in the future a dramatic increase in medical costs will be associated with HCV and the consequences of HCV-related medical conditions. Read more here.

Hepatitis C Viral Load: International Units versus Copies/ml – What Are the Differences?
Alan Franciscus,
Editor-in-Chief, HCV Advocate


There are four virological markers of hepatitis C virus (HCV) infection that are used clinically for the management of patients with hepatitis C. These virological markers are the HCV genotype, HCV RNA, HCV core antigen, and antibody to HCV (anti-HCV). Recently the measurement tools have become standardized and this has resulted in some confusion. This article should sort you out.

Bayer Receives Viral Load Test Approval
Alan Franciscus,
Editor-in-Chief, HCV Advocate


On April 03, 2003, Bayer HealthCare Diagnostic received pre-market approval of their VERSANT® HCV RNA 3.0 Assay (bDNA)—a quantitative viral load test that directly measures the amount of hepatitis C RNA in the blood, and can help predict treatment outcomes. Read more here.

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A Simple Guide to Understanding the Cost of HCV Medications
Alan Franciscus
Editor-in-Chief, HCV Advocate


The standard of care for treating chronically infected individuals with hepatitis C is the combination of pegylated interferon plus ribavirin. There are currently two branded combinations of pegylated interferon plus ribavirin approved by the FDA to treat hepatitis C—Schering’s PEG-Intron plus Rebetol (branded ribavirin in capsule formulation) and Roche’s Pegasys plus Copegus (branded ribavirin in tablet formulation). Neither of the combination products come in combination prescriptions, unlike Rebetron in the past which was combination packaging of Schering’s alfa interferon 2b (Intron-A) plus Schering’s ribavirin. Since Schering was the only company that manufactured branded ribavirin at that time it prevented competition from the other alfa interferon 2a (Roferon-A) or consensus interferon (Infergen) products on the market as physicians and patients did not have access to ribavirin without seeking out compounded sources.

The recent FDA approval of Pegasys plus Copegus was welcomed by many medical providers and patient advocates since it would provide another treatment option for people with hepatitis C and competition in the market place would hopefully make the pricing of hepatitis C treatment a viable option. Last year, Roche announced the pricing of Pegasys which was priced a little lower than Peg-Intron but still not enough to satisfy the majority of patient advocates or to reduce the burden of treatment costs. However, due in part to community pressure, at the beginning of 2003 when Copegus became available for distribution, Roche priced their branded ribavirin significantly lower than their competition, Rebetol—over 40% lower in fact. The Roche pricing of Pegasys in combination with Copegus has the potential to now considerably reduce the cost of pegylated interferon plus ribavirin therapy for patients with hepatitis C who need to be treated. Hopefully, the reduced cost of Copegus will be passed on to patients and the difference in costs between Copegus and Rebetol will not be gobbled up by the Managed Care Organizations in the form of a direct profit with the same copay to the patient.

Schering’s brand of pegylated interferon—PEG-Intron—comes in a white to off-white powdered form that requires mixing with a liquid solution (reconstituting) before injection and needs to be dosed by body weight (with the exception that any patient >85kg gets 150 µg). Doses are 50 µg, 80 µg, 120 µg and 150 µg. Schering’s brand of ribavirin—Rebetol—comes in a 200 mg capsule form taken twice daily. Schering’s combination therapy is FDA approved for all genotypes for a period of 48 weeks and for 800mg of Rebetol.

Roche’s brand of pegylated interferon by injection—Pegasys—comes in a ready made solution that does not require reconstitution and by design was developed to be dosed at 180 µg for all patients regardless of weight. Roche’s brand of ribavirin —Copegus—comes in a 200 mg tablet form to be taken twice daily. The FDA indication for Roche’s combination treatment for genotype 1 is 48 weeks with 1000/1200mg Copegus and 24 weeks for genotype 2 & 3 with 800mg Copegus.

Even though Peg Intron in combination with Rebetol is only indicated for 800mg of Rebetol by the FDA and post-marketing trials are still trying to determine the correct dosage of ribavirin for the combination of Peg Intron and Rebetol, medical providers continue to follow one of two schools of thought. The two schools of thought are either 10.6mg/kg of ribavirin or 1000mg ribavirin for patients 75kg or less, and 1200mg for patients greater than 75kg.

For simplicity we will use one dose for Peg-Intron (150 µg), since the average patient with hepatitis C in the United States weighs between 86-105 Kg (188-231 lbs) and 150 µg is the recommended dose for this weight range, plus a fixed dose of Rebetol (1200 mg daily). For Pegasys the amount will be 180 µg (all body weights) and for Copegus, 1200 mg daily, for a treatment period of one year, in order to compare the costs of these two combinations.

According to Wholesale Acquisition Cost (WAC), as of 4/18/2003 the price for 48 weeks of therapy for Peg-Intron (the standard period of time for treating genotype 1 patients, which is the majority of people with HCV in the United States), is $14,604 and for Pegasys the WAC price is $13,968. Using WAC quotes also, the cost of 48 weeks of ribavirin therapy by brand is $17,801 for Rebetol (1200 mg daily) and $10,208 for Copegus (1200 mg daily).

Putting it all together the cost of a 48 week treatment period for Peg-Intron plus Rebetol is $32,405 versus $24,176 for Pegasys plus Copegus.

It should be noted that WAC does not include any negotiated discounts that a retailer may receive, which could potentially lower the cost of the drugs. For a more comprehensive breakdown of costs, please visit our web site www.hcvadvocate.org.

Copyright May 2003 – Hepatitis C Support Project – All Rights Reserved. Permission to reprint is granted and encouraged with credit to the Hepatitis C Support Project

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Drugs and the Liver
Liz Highleyman

Many drugs—estimated at nearly 1,000—can harm the liver. These include prescription and over-the-counter medications, illicit recreational drugs, and herbal remedies. In the worst cases drug toxicity can cause acute liver failure, necessitating a liver transplant or causing death. In fact, drug toxicity is the leading cause of acute liver failure, and liver toxicity (hepatotoxicity) is the most common reason drugs are withdrawn from the market. Although severe drug-related liver injury is rare, the risk is higher in people with chronic hepatitis B or C.

How Drugs Damage the Liver

After most oral medications are ingested, they are carried in the bloodstream from the intestines to the liver, where they are metabolized, or broken down into active chemical components and byproducts (metabolites). Some of these metabolites are toxic to the liver. Eventually the byproducts are excreted in the bile (which is eliminated in the feces) or the urine. The chemical changes are carried out by enzymes in the liver (not to be confused with the liver enzymes—such as ALT and AST—measured in liver function tests). A family of enzymes called the cytochrome P450 (CYP450) system plays a major role in drug metabolism; a few of these enzymes—CYP3A4, CYP2D6, and CYP2C9/10—process most common prescription drugs.

Interactions can occur when one drug (or herb, or even food product such as grapefruit juice) speeds up or slows down the metabolism of another. If a substance inhibits CYP450 enzymes, drug processing is slowed and drug levels in the body may rise too high, causing intensified toxicities and side effects. If it induces CYP450 enzymes, drug metabolism is accelerated and drugs may be eliminated too quickly, causing concentrations to fall to ineffective levels. If multiple drugs are metabolized by a shared processing pathway, there may be a "bottleneck" as they compete for the same CYP450 enzymes.

Some drugs (such as acetaminophen, or Tylenol) are harmful to the liver at predictable doses. Most others (such as isoniazid, used to treat tuberculosis) are more unpredictable or "idiosyncratic," and cause liver damage only occasionally in susceptible people. Some drugs kill liver cells (hepatocellular necrosis) and cause acute liver injury. Several others (such as erythromycin and certain steroid hormones) can cause impaired bile flow, or cholestasis. Still others can cause chronic liver damage, cirrhosis, allergic or hypersensitivity reactions, fat buildup in the liver (steatosis), immune reactions, or damage to hepatic blood vessels. Some may even cause liver tumors.

Who is at Risk for Hepatotoxicity?

Different individuals process drugs at varying rates: some are slow metabolizers, while others are rapid metabolizers. These differences are largely genetic; for example, some people have less CYP450 enzymes than others. Pharmacogenetic tests that determine how well specific people can metabolize drugs may soon be widely available. Other factors—such as smoking cigarettes, drinking alcohol, and eating certain foods—can also affect drug metabolism. Research suggests that women are more likely to experience drug-related hepatotoxicity, perhaps because they have a lower average body weight. Also, children and elderly people tend to metabolize drugs more slowly. Because of these variations, a drug dose that is appropriate for one person may be too high or too low for another.

People with existing liver disease—for example, due to hepatitis B or C or heavy alcohol consumption—are more likely to experience drug-related liver toxicity. People with damaged livers may have inadequate levels of CYP450 enzymes, and those with impaired blood flow through the liver may break down drugs less efficiently. For this reason, people with liver disease sometimes need lower than normal medication doses.

What are the Symptoms of Liver Toxicity?

Severe liver toxicity can result in rapid, acute liver failure, which may lead to encephalopathy (brain dysfunction), impaired blood clotting, coma, and death. But most cases of liver toxicity are less serious. The most common symptom of hepatotoxicity is elevated levels of liver enzymes, including ALT and AST, which leak into the bloodstream when liver cells are damaged. People who take drugs that are processed by the liver often have slightly elevated liver enzymes, but levels two or more times the upper limit of the normal range (0-48 IU/L for men and 0-42 IU/L for women) are cause for concern. Levels five times or more the upper limit of normal (grade 3 toxicity) indicate severe liver toxicity. However, liver enzyme levels are not a foolproof indictor of hepatotoxicity, since some people can experience drug-induced liver damage without having dramatically increased ALT or AST levels.

Mild-to-moderate hepatotoxicity is often asymptomatic, but some people may experience nausea, diarrhea, loss of appetite, fatigue, itching (pruritus), muscle and joint aches, or abdominal pain. Drug toxicity that causes cholestasis can lead to elevated levels of bilirubin, a pigment released when the liver breaks down red blood cells. This can cause jaundice (yellowing of the skin and whites of the eyes), dark urine, and pale stools. Often it can be hard to distinguish drug-related liver toxicity from other types of liver damage, since the symptoms and diagnostic test results may be so similar.

In order to diagnose drug-induced hepatotoxicity, it is important to consider when liver enzyme elevations or other symptoms occur relative to when a drug is started. Symptoms typically appear within days or weeks after starting a new drug and often stabilize over time. But in some cases (for example, with isoniazid and certain antibiotics) liver toxicity can develop after a longer period—up to several months—on a medication. The surest way to determine if a drug is the cause of liver-related symptoms is if the symptoms subside when the drug is stopped and worsen again if it is restarted.

What Drugs and Herbs Cause Hepatotoxicity?

Many different drugs are known to cause liver toxicity. Acetaminophen is the one of the leading causes of acute liver failure, responsible for more than 50,000 emergency room visits and some 100 deaths in the U.S. each year. Liver cell death occurs when the liver’s normal drug-processing pathway is overwhelmed and a toxic byproduct called NAPQ1is produced. Usually severe hepatotoxicity occurs when people take twice the normal dose or more, but some individuals are susceptible to liver damage at lower doses; liver toxicity is especially likely when the drug is used with alcohol. N-acetylcysteine, which replenishes a natural protein called glutathione, is an antidote to acetaminophen poisoning.

Many anti-HIV drugs are associated with liver toxicity—a cause for concern among people coinfected with HIV and hepatitis B or C. All classes of anti-HIV drugs have been linked with liver toxicity. The non-nucleoside reverse transcriptase inhibitor nevirapine (Viramune) can cause liver inflammation and elevated liver enzyme levels. One South African trial found that women taking nevirapine were twice as likely as men to experience liver-related side effects; two women in the study died due to liver failure. Protease inhibitor drugs are most often associated with liver problems, especially ritonavir (Norvir). A study by researchers at Johns Hopkins University found that the risk of liver toxicity was five times greater in people taking this drug. Ritonavir plays a major role in drug interactions. Because it induces certain CYP450 enzymes, it can cause rapid metabolism and low levels of many other drugs. On the other hand, because it has a high affinity for the CYP3A4 enzyme, ritonavir can cause elevated levels of other drugs that also compete for processing by this same enzyme. But this effect is not always bad: small amounts of ritonavir are now often added to other protease inhibitors to raise their blood levels and allow lower doses to be used. Careful drug selection can help prevent hepatotoxicity. The newer protease inhibitors nelfinavir (Viracept) and atazanavir (Reyataz, not yet approved) may be the best options for coinfected people. Importantly, most people—including those coinfected with HBV or HCV—do not experience serious liver problems due to anti-HIV drugs. With an increasing number of antiretroviral medications available, most coinfected people can be successfully treated for both HIV and viral hepatitis.

For many other conditions as well, there are a variety of drugs to choose from and the most hepatotoxic ones can often be avoided. For example, the anti-diabetes drug troglitazone (Rezulin) was taken off the market in March 2000 due to severe liver toxicity, including nearly 90 reported cases of liver failure and 60 deaths; two newer drugs for type 2 diabetes—rosiglitazone (Avandia) and pioglitazone (Actos)—are safer for the liver. Other drugs pulled from the market by the FDA due to concerns about liver toxicity include the pain medication bromfenac (Duract), the diuretic ticrynafen (Selacryn), and the arthritis drug benoxaprofen (Oraflex). The antidepressant nefazodone (Serzone)—associated with more than 50 reports of liver injury, including 11 deaths—has been withdrawn in Europe and consumer advocates have asked the FDA to ban it in the U.S. as well, saying it is no more effective than other similar drugs. Advocates have also asked the FDA to withdraw the arthritis drug leflunomide (Arava).

But some drugs, even though they cause liver toxicity, remain on the market because they have important benefits and there are no equally effective safer medications. The antibiotic trovafloxacin (Trovan) is still available—despite several cases of acute liver injury leading to transplants or deaths—for people with life-threatening bacterial infections. Isoniazid is one of the drugs most often associated with liver toxicity, but it is still used to prevent and treat tuberculosis. For some conditions—such as seizures—many of the effective drugs can cause hepatotoxicity.

In addition to drugs, some nutritional supplements can cause liver toxicity, as can many herbs, herbal teas, and patented traditional Chinese herbal formulas. Although some herbs are beneficial to the liver, others are highly toxic. There have been numerous reported cases of liver failure and death associated with certain herbs. For example, in March 2002 the FDA issued a warning about kava kava, and sale of the herb is banned in France, Germany, and Switzerland. People interested in using herbs—especially if they have liver disease—should consult a knowledgeable practitioner.

Some Other Drugs Associated with Liver Toxicity:

  • amiodarone (Cordarone), heart arrhythmia
  • azathioprine (Imuran), rheumatoid arthritis
  • carbamazapine (Tegretol), seizures
  • chlorpromazine (Thorazine), antipsychotic
  • cyclophosphamide (Cytoxan), cancer chemo therapy
  • diclofenac (Voltaren), arthritis
  • diltiazem (Cardizem), angina and high blood pressure
  • felbamate (Felbatol), seizures
  • ketoconazole (Nizoral), fungal infections
  • methotrexate (Rheumatrex), arthritis, cancer chemotherapy
  • methyldopa (Aldomet), high blood pressure
  • nitrofurantoin (Macrodantin), urinary tract infections
  • pemoline (Cylert), attention deficit disorder
  • phenytoin (Dilantin), seizures
  • tacrine (Cognex), Alzheimer’s disease
  • ticlopidine (Ticlid), reduce blood clotting, prevent strokes
  • tolcapone (Tasmar), Parkinson’s disease
  • valproic acid, seizures
  • zafirlukast (Accolate), asthma
  • zileuton (Zyflo), asthma
Some Supplements Associated with Liver Toxicity:
  • iron
  • niacin in high doses
  • vitamin A in high doses
Some Herbs Associated with Liver Toxicity:
  • bush tea
  • chaparral
  • coltsfoot
  • comfrey
  • Crotalaria species
  • ephedra (Ma Huang)
  • germander
  • Gordolobo yerba tea
  • groundsel
  • Heliotropium species
  • Jin Bu Huan
  • kava kava
  • Mate tea
  • mistletoe
  • pennyroyal oil
  • pyrrolizidine alkaloids
  • sassafras
  • Senecio species
  • senna
  • skullcap
  • valerian
Preventing Liver Toxicity

Ideally, drug-related liver problems should be discovered when drug candidates are tested. However, because animals and humans metabolize drugs differently, sometimes liver toxicity is not seen in animal studies. Drug candidates are often withdrawn from consideration due to hepatotoxicity in early human clinical trials. But in other cases, severe liver toxicity is so rare that it does not show up in clinical trials. For example, no cases of liver failure were reported in trials of trovafloxacin that included some 7,000 participants. Liver toxicity may only become apparent after a drug is approved and used by larger numbers of people.

If possible, people with chronic hepatitis B or C should avoid taking drugs associated with liver toxicity. Often effective alternative medications are available that can be used instead. In some cases, it may be possible to reduce the risk of liver problems by using lower drug doses. But sometimes people need a medication known to cause hepatotoxicity. Individuals taking such drugs—especially if they have existing liver disease—should have their liver function (including ALT, AST, and bilirubin levels) monitored regularly. This is especially important when starting a new medication. Because alcohol can increase the risk of drug-related liver injury, avoid or reduce alcohol consumption. Finally, it is important to tell your doctor and all other healthcare providers about any prescription drugs, over-the-counter medications, recreational drugs, herbs, or nutritional supplements you are using. If hepatotoxicity is discovered early, liver damage usually can be halted and the liver can recover.

Copyright May 2003 – Hepatitis C Support Project – All Rights Reserved. Permission to reprint is granted and encouraged with credit to the Hepatitis C Support Project

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Understanding Your Liver Biopsy
Kara Wright, PA-C

Many patients diagnosed with hepatitis C will need to undergo a liver biopsy. A liver biopsy is an outpatient procedure which involves obtaining a small piece of liver tissue to be analyzed by a pathologist. Biopsies are done to determine the severity of injury to the liver from the hepatitis C virus.

What to expect

Prior to the liver biopsy, patients will undergo blood work to determine how well the blood clots. This blood work usually consists of a prothrombin time (PT), partial thromboplastin time (PTT), and platelet count. The liver contains numerous blood vessels, so it is important that the blood clot effectively to prevent hemorrhage. Patients are advised to stop all medications that increase the risk of bleeding, such as aspirin, ibuprofen (Motrin, Advil), naproxen (Aleve), and blood thinners such as warfarin (Coumadin) and heparin. A provider will indicate how long patients must be off these medications prior to and after the procedure.

Once a patient arrives for the biopsy, the medical history is reviewed. Patients may get an intravenous line (needle in a vein in the arm) so medication can be administered as needed. Often patients are given analgesic and sedative medication to minimize discomfort and anxiety. Some practitioners may not offer this, as it is important to have full cooperation from the patient during the procedure.

Patients lie on their back with the right arm under the head. The physician locates the appropriate site on the right side of the rib cage, and the skin is cleansed and draped with sterile towels. A local anesthetic is injected into the skin to numb the area. The biopsy is done at end-expiration (when you have completely breathed out) to ensure the lung is smaller and the liver is closer to the chest wall. A needle is quickly passed through the skin to the liver, and a small cylindrical sample of tissue is extracted.

After the biopsy, patients are asked to lie on the right side for several hours. The blood pressure and pulse are checked frequently, and the patient is monitored for 4-8 hours after the procedure. Patients will need to be driven home if they are given any type of sedating medication.

Methods

There are several methods available to obtain liver tissue. Most liver biopsies are performed using the percutaneous (through the skin) technique. The physician may percuss (tap) on the right side of your chest to locate the liver and pass the needle through the ribs once he/she has located an appropriate site. This is called a blind biopsy because no mechanism to view the liver is used.

Many providers use the assistance of an ultrasound machine prior to the biopsy in order to locate the optimal site for biopsy. In some cases, a CAT scan may be performed to locate a precise site as well. These devices also help to define the anatomy of the liver and the relative positions of the lungs, kidney and gallbladder.

Some patients may need to undergo a transjugluar biopsy. This is performed by threading a needle with a catheter into a vein in the neck (the jugular vein), which extends to the liver. A special x-ray called fluoroscopy is used to visualize the veins. The biopsy is taken through the vein, and the procedure takes 30-60 minutes. These are usually performed in special cases where the patient’s blood is not clotting efficiently.

Complications

Liver biopsies are very safe with only 2-3% of patients experiencing complications requiring hospitalization. Mortality (death) occurs in 1:10,000 to 1:12,000 patients. The most common effect is discomfort, experienced by up to 25% of patients. The discomfort is felt at the biopsy site or in the right shoulder. This typically resolves after 24 hours and responds well to Tylenol.

Some patients may experience low blood pressure immediately after the procedure. Patients may feel as if they will faint, but this is usually transient and responds well to IV fluids. Bleeding occurs in 0.3% of patients and may become apparent 3-4 hours after the procedure. Bleeding often stops spontaneously, and a blood transfusion is rarely required.

Another risk is bile peritonitis. Bile is a substance which helps digest food and is contained in the ducts of the liver. If it leaks out, it can cause irritation of the lining of the abdomen. This typically resolves spontaneously but may require removal of the gallbladder. As with most procedures, infection is a small risk due to bacteria being released into the blood. However, this is not likely, due to the sterile technique the provider will follow. If it occurs, it may be treated with antibiotics as necessary.

Perforation may occur if the needle pierces an adjacent organ. These include lungs, kidney, small intestine, and gallbladder. This is an infrequent complication, which may require surgical correction.

Liver anatomy and histology

The liver is the largest organ in the body. It weighs 3.5 to 4 pounds and is completely covered by a fibrous sheath called Glisson’s capsule. The liver is composed of thousands of liver lobules. A lobule is hexagonal (six-sided) and consists of many liver cells. In the center of the hexagon is a central vein which carries blood away from the liver. At each corner of the hexagon is a portal triad, also called a portal tract. The portal triad consists of an artery, a vein, and a bile duct (which carries bile away from the lobule).

The hepatitis C virus enters the body through the bloodstream. It is carried to the liver and invades and infects liver cells. HCV is able to reproduce itself in liver cells, blood cells, and bone marrow. Hepatitis C causes liver damage in stages. It first causes inflammation. Liver inflammation refers to the presence of special cells called inflammatory cells in the liver. Inflammation leads to changes in liver structure, slowed blood circulation, and the death of liver cells (necrosis). Chronic inflammation eventually causes scar tissue to form, a condition known as fibrosis. If the disease goes untreated, fibrosis (scarring) will occur which will then lead to cirrhosis. When fibrosis occurs, it begins around the portal triad and is called periportal fibrosis. As the fibrosis extends, it typically extends like spokes from the center of a wheel. The spokes are called fibrous septae. Bridging fibrosis occurs when the fibrous spokes from one wheel meet with the fibrous spokes from another wheel. Cirrhosis is severe scarring surrounding the lobules which disturbs the architecture of the liver. This may interfere with normal functioning of the liver.

Understanding your results

Liver biopsies have been performed since the 1950’s and the wording and classification has changed significantly over time. There are several different mechanisms for scoring liver biopsies, and there are a few limitations to any biopsy specimen. It is important to realize that the quality of each tissue sample can vary. Liver disease does not always affect the liver in a uniform pattern; so one sample may not reflect the overall disease activity. All liver biopsies are subject to variability in interpretation by different observers.

Metavir

The Metavir score for interpreting liver biopsies was specifically designed for patients with hepatitis C. The score consists of a grade and a stage. The grade gives an indication of the activity (amount of inflammation) and the stage indicates the amount of fibrosis (scarring). The grade, or activity score, is assigned a number based on the intensity of inflammatory lesions. These inflammatory lesions cause cell injury leading to cell degeneration or cell death. On a scale of 0-3 or 4 (depending on the pathologist), 0 is no activity and 3 or 4 is severe activity. This is important because inflammatory changes are precursors to fibrosis. If the activity score is high, there is a significant amount of inflammation occurring in the liver which progresses to scarring.

The fibrosis score is also assigned a number from 0-4. 0=no scarring, 1=portal fibrosis without septa (scarring around the portal triad), 2=few septa (few spokes coming out from the wheel of the portal triad), 3=numerous septa with cirrhosis, 4=cirrhosis (severe scarring surrounding the lobule). Scarring of the liver leads to distortion of the architecture of the liver. As this progresses to cirrhosis, the liver may be unable to perform its needed functions.

Knodell

The Knodell score is commonly used as well. It is also known as the histologic activity index (HAI) and is composed of four individually assigned numbers making up one single score. The first component is scored 0-10 and the remaining are scored 0-4 with total Knodell scores ranging from 0-22. The first three scores (periportal and/or bridging necrosis, intralobular degeneration and focal necrosis, and portal inflammation) compose the inflammatory portion of the score and are indications of how much inflammation is occurring in the liver. The inflammatory score can range from 0-18. A score of 0 indicates no inflammation, 1-4 indicates minimal inflammation, 5-8 shows mild inflammation, 9-12 reveals moderate amounts of inflammation, and 13-18 indicates marked amounts of inflammation in the liver. The fourth component (fibrosis) indicates the amount of scarring in the liver and is scored from 0 (no scarring) to 4 (cirrhosis).

Conclusion

The results of a liver biopsy can provide invaluable information. First, biopsies give the patient and provider an idea of the extent of liver damage. Second, the amount of fibrosis in the liver can be used as a way of evaluating how quickly the disease appears to be progressing. Having knowledge of approximately when a patient was initially infected with HCV can help determine the rate of disease progression. For example, if Mr. Smith had a blood transfusion in 1970 and has no other risk factors, he can assume he has had the disease for 33 years. If his biopsy shows minimal scarring, he can assume that the disease is progressing very slowly, and this may help him make a better decision regarding treatment.

The liver biopsy is an important tool for patients and health care providers. Although it is not mandatory prior to treatment, most experts recommend liver biopsies. It is important to understand your biopsy results, and individual findings should be discussed with a practitioner.

Copyright May 2003 – Hepatitis C Support Project – All Rights Reserved. Permission to reprint is granted and encouraged with credit to the Hepatitis C Support Project

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Healthwise: Navigating Illness—Suggestions for Patients, Family, Friends, and Coworkers
By Lucinda K. Porter, RN, BA, CCRC

Recently a patient said to me, "Illness is a way to health." This is a simple but profound concept. Patients have many responses and approaches to illness and health. Some use denial in order to cope. Others respond by feeling scared or overwhelmed. Anger and resentment are common reactions. Acting tough and invincible is another way of handling illness. My personal favorite is to see illness as an opportunity for growth. It is a version of "remaining positive."

There are inherent strengths and weaknesses in all of these coping mechanisms. These approaches all work, but there are limits to them. Being strong is fine when one feels strong, but what about those times when one feels tapped out of reserves? Denial can be effective in the short run but is difficult to maintain when the symptoms cannot be ignored. As for always trying to look at the brighter side, that can be challenging on those days when nothing seems positive.

Coping mechanisms serve a purpose; they can help us survive. But sometimes coping measures lose effectiveness and become a burden. Moreover, chronic illness can be exhausting. "Keeping up appearances" during illness consumes further energy. This is true for the patient as well as for those in the patient’s life. This article offers some illness navigation tips for patients as well as their family, friends, and coworkers.

Patients: Allow others to help you. Ask for help, even for those things you know you can do for yourself. Accepting the kindness of others is a brave and generous act. Be clear about what you need.

Caregivers: Respect the patient’s autonomy. Ask if there are ways in which you can help. Be clear about what you can or cannot give. Do not give more than what is asked for or do more than a patient wants. Respect the patient’s boundaries.

Patients and Caregivers: Find support. This is important whether you are a patient or a caregiver. Support groups can provide valuable information and insight. Some support groups are open to families and friends of HCV patients.

Listen—really listen. Never assume that people act the same way in all situations. People act in a variety of ways when it comes to being cared for or when offering care to others.

Be respectful of self and others. Do not negate or discount the feelings of another.

Be honest, but compassionate. Be authentic—do not try to force yourself to be anything else than what you are. Talk about the illness and its impact on you. Feel free to not talk about the illness. It is perfectly appropriate to talk about the ordinary side of life. Sitting in silence is another wonderful alternative.

Keep life simple. Let go of perfection. Perfectionism can be harmful, for the healthy as well as for those with chronic health issues. Know that there are many paths to health. This is not a test and you cannot fail. It is acceptable to cry, be angry, to feel alone, or to feel numb. It is also appropriate to laugh. Just remember, whether you are a patient or part of the patient’s community, you do not have to do this alone.
Resources:

For more info regarding disclosure of hepatitis C, see the hcspFACT sheet: Hepatitis C Disclosure by Alan Franciscus www.hcvadvocate.org

Support Group Resources:

Ask your care provider to recommend a local support group.

American Liver Foundation: www.liverfoundation.org
800.GO.Liver (465-4837) toll-free
888.4HEP.USA (443-7872) toll-free


HCV Advocate: www.hcvadvocate.org

Hepatitis Foundation International: www.hepfi.org 800-891-0707 toll-free

Lucinda K. Porter, RN is a research nurse and patient educator at Stanford in the area of hepatology. She co-facilitates a support group and is active in many aspects of hepatitis C education. In addition to being HCV positive, she has a life which includes her husband and daughter.

Copyright, May 2003 Lucinda Porter, RN, and Hepatitis C Support Project / HCV Advocate www.hcvadvocate.org – All Rights Reserved.

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The Future Burden of HCV
Alan Franciscus
Editor-in-Chief, HCV Advocate


The National Institutes of Health (NIH) conservatively estimates that up to 4 million Americans have been exposed to hepatitis C. New infections have dropped dramatically in the last 10 years, but the majority of those chronically infected with HCV will not seek medical care because they are unaware of their infection. Taking into account the current number of chronic HCV infections in the US today, it is expected that in the future a dramatic increase in medical costs will be associated with HCV and the consequences of HCV-related medical conditions. Researchers found that cirrhosis will increase from 16% -32% by the year 2020 in an untreated population because as the duration of infection increases, the rate of liver disease progression climbs—complications of cirrhosis will increase by 106%, liver cancer will increase by 81%, and liver-related deaths will increase by 180%. As well, the estimated increase in the number of persons progressing on to serious liver disease brings with it a concomitant increase in costs for treating the conditions associated with advanced liver disease.

The authors concluded that "the prevalence of cirrhosis and the incidence of its complications will increase over the next 10 to 20 years as the duration of infection increases among those with chronic hepatitis C." The study also emphasizes the need for greater access to transplantation by expansion of the donor pool, increased use of split livers and living donors, and novel options such as xenotransplantion. Furthermore, some experts believe that many more patients need to be identified and treated as there is much evidence that treatment slows down disease progression even in the absence of virologic response. These interventions are critical if there is to be hope in reducing the future disease burden of hepatitis C.

Copyright May 2003 – Hepatitis C Support Project – All Rights Reserved. Permission to reprint is granted and encouraged with credit to the Hepatitis C Support Project

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Hepatitis C Viral Load: International Units versus Copies/ml – What Are the Differences?
Alan Franciscus
Editor-in-Chief, HCV Advocate


There are four virological markers of hepatitis C virus (HCV) infection that are used clinically for the management of patients with hepatitis C. These virological markers are the HCV genotype, HCV RNA, HCV core antigen, and antibody to HCV (anti-HCV).

The diagnosis of acute and chronic hepatitis C is based on both anti-HCV detection using enzyme immunoassays (EIA) and HCV RNA detection using a sensitive molecular biology-based technique known as PCR – Polymerase Chain Reaction. HCV genotype determination and HCV RNA quantification are now used to tailor treatment to the individual patient and to determine the likeliness of treatment efficacy.

Hepatitis C patients are becoming more and more involved with the tools which measure their response to treatment, but the laboratory results can be confusing, especially as they relate to HCV RNA, which is also referred to as viral load. Based upon recommendations from the World Health Organization, HCV RNA is now being measured in International Units (IUs) rather than copies/ml, which have traditionally been used and are still being referred to in many clinical trials. The conversion from copies/ml to IU/mL varies from each quantitative test. Below is a conversion table based upon assay.

Assay Conversion Factor
Amplicor HCV Monitor v2.0
(manual procedure)
1 IU/mL = 0.9 copies/ml
Cobas Amplicor HCV Monitor v2.0
(semi-automated procedure)
1 IU/mL = 2.7 copies/ml
Versant HCV RNA 3.0 Quantitative Assay 1 IU/mL = 5.2 copies/ml
LCx HCV RNA Quantitative Assay 1 IU/mL = 3.8 copies/ml
SuperQuant 1 IU/mL = 3.4 copies/ml
Copyright May 2003 – Hepatitis C Support Project – All Rights Reserved. Permission to reprint is granted and encouraged with credit to the Hepatitis C Support Project

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Bayer Receives Viral Load Test Approval
Alan Franciscus
Editor-in-Chief, HCV Advocate


On April 03, 2003, Bayer HealthCare Diagnostic received pre-market approval of their VERSANT® HCV RNA 3.0 Assay (bDNA)—a quantitative viral load test that directly measures the amount of hepatitis C RNA in the blood.

Quantitative viral load test measures the amount of virus in one milliliter of blood. This test can help predict whether treatment is likely to work and can show whether HCV medications are working once treatment is initiated. Bayer’s test measures HCV levels in the range of 615 to 7.7 million HCV RNA IU/mL and has been authenticated in the six major HCV genotypes (1-6).

Quantitative HCV viral load is usually expressed as low (below 800,000 IU/mL) or high (over 800,000 IU/mL). A low viral load prior to treatment is more predictive of a successful treatment response to HCV medications. In addition, a 2 log drop or elimination of HCV RNA by week 12 is a strong negative predictor of response. Those patients who do not achieve either a 2 log drop in HCV RNA or are virus-negative at 12 weeks are unlikely to achieve a sustained virological response, which is the elimination of virus 6 months post treatment. It should be noted that an association between the amount of HCV RNA or viral load and HCV disease progression has not been shown, but some experts believe that the amount of virus may be associated with a greater risk of HCV transmission, particularly mother-to-infant transmission. Viral load has not been widely correlated with risk of sexual transmission even though there have been small studies showing such correlation.

In November 2002, Bayer received FDA marketing approval for their qualitative viral load test—VERSANT® HCV RNA Assay Transcription-Mediated Amplification (TMA) which is the most sensitive test for HCV RNA (measures less than 10 IU/mL). The qualitative viral load test only measures the presence of the virus and is used to confirm active HCV infection. In addition, Bayer also markets VERSANT ® HCV genotype assay (LiPA) which identifies the genotypes.

Copyright May 2003 – Hepatitis C Support Project – All Rights Reserved. Permission to reprint is granted and encouraged with credit to the Hepatitis C Support Project

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