Hepatitis C

Hepatitis virus. PHIL

Author: Dr Norah Terrault University of California San Francisco 2008-07-23
Hepatitis C is a common cause of chronic liver disease both worldwide and in the U.S. Hepatitis C virus is transmitted through blood or blood-contaminated objects. Many individuals do not know they are infected. Most persons with chronic hepatitis C will be without any symptoms. Acute infection is followed by a chronic disease is the majority of those infected. Hepatitis C infection can lead to cirrhosis and liver cancer after several decades of infection. Effective treatments are available.

Hepatitis C virus (HCV) is a separate genus of the Flaviviridae family of viruses. Prior to 1989, this form of hepatitis was known as non-A, non-B hepatitis, but was renamed hepatitis C once the virus was discovered. HCV is a small, spherical, enveloped virus and the genome is a single strand of RNA. One of the hallmarks of HCV is the high degree of variability in the genetic make-up of the virus and the propensity of the virus to mutate or change over time. This is one of the reasons why it has been difficult to design a vaccine that can protect against HCV infection. Thus, unlike hepatitis A virus and hepatitis B virus, which can be prevented by vaccination, there is no vaccine available to protect individuals from HCV. 

HOW DOES HCV CAUSE HEPATITIS?

HCV is an hepatotrophic virus, meaning that the virus replicates only within the liver. The virus gains access to the liver through blood. Once in the liver, HCV multiplies, and new viruses are exported from the liver cells back into the blood. The immune system mounts an attack on the virus, replicating in the liver, working to eliminate the virus. This immune response results in inflammation and liver cell injury, which is termed “hepatitis.” If the immune response against HCV is successful, the virus will be eliminated and the person will recover from the acute hepatitis and have no residual negative effects to the liver. 

During the infection, antibody against HCV is made, but this antibody is insufficient to protect an individual against future HCV infection. In this regard, HCV differs from hepatitis B virus and hepatitis A virus. Persons infected with hepatitis A or B who recover have an antibody that protects them for life against repeat infection. Persons infected with HCV who recover can get infected again if repeat exposure to HCV occurs.

Unfortunately, in the majority of individuals infected with HCV, the immune attack against the virus is unsuccessful and the infection persists. These individuals have chronic infection and ongoing damage to the liver.  After several decades of infection and liver injury, some individuals with chronic HCV infection will develop cirrhosis, liver failure, and/or liver cancer.

HOW FREQUENTLY IS HCV INFECTION SEEN IN THE GENERAL POPULATION?
A total of 120 million individuals worldwide have hepatitis C. At least 4 million Americans have been infected and it is estimated that 80% have chronic infection. There is substantial variation in the prevalence of HCV in the different populations in the world, with the highest rate of infection in Egypt [1]. In the U.S. population, HCV infection occurs twice as frequently in men as women, and the most common age group with chronic infection is aged 30-49 years [2]. Most people with chronic HCV were infected 20-40 years ago. There are also racial differences in the incidence of infection in the U.S. population, with African-Americans over the age of 40 years approximately 3 times more likely to have chronic HCV than Non-Hispanic Whites.

WHAT ARE THE RISKS FOR GETTING HEPATITIS C INFECTION?
Hepatitis C virus is transmitted through blood or blood-contaminated objects. The persons at highest risk for acquiring HCV are those exposed to large quantities of infected blood, through transfusions or organ transplant, or those repeatedly exposed to infected blood, such as injection drug users. The risk is less among those experiencing a single and small dose exposure, as occurs following a single stick from a needle contaminated with infected blood, or by mucosal exposure to infected blood (i.e., where there is no puncture of the skin),as occurs with sex or with childbirth. In more developed countries, like the U.S. and Western Europe, transmission appears to be primarily a result of illicit injection drug use; in less developed areas, such as Africa and Asia, the main mode of HCV transmission is by reuse of poorly disinfected needles and syringes in medical and dental care, and through blood transfusions from unscreened donors [3]. 

Initially in the U.S., the most common risk factors to contract hepatitis C infection were injection drug use and a history of exposure to blood or clotting factors (Figure below). The risk of getting HCV from a blood transfusion now is extremely low, about 1 chance in 2 million [4], as sensitive tests are used to look for HCV in donated blood. Consequently, in recent years, the most frequent risk factor reported in persons with acute HCV infection is injection drug use, seen in nearly 60% of persons under the age of 40 years, and 35% of those over the age of 40 years. In 20-35% of persons with recently contracted HCV, the source of the HCV infection cannot be identified, despite careful review [5]. Other risk factors for HCV infection include needlestick injury (related to providing medical or dental care), or any contact with an unsterilized needle or sharp instrument (e.g., tattoo, body piercing, blood brother rituals). Transmission of HCV from mother to infant can occur, as explained below.

Mother to Infant Transmission of Hepatitis C
The most common mode of transmission of HCV to children is during the delivery. Transmission from an HCV-infected mother to her infant occurs 5% of the time [6][7]. Mothers who also have human immunodeficiency virus (HIV) infection have a higher risk of HCV transmission. There are no therapies available to prevent or interrupt transmission between mother and infant. The risk of transmission does not differ in mothers who have a vaginal delivery versus Cesarean section. Breastfeeding is not associated with transmission of HCV. There are some studies suggesting that the risk of transmission may be increased by prolonged time with ruptured membranes (breaking of water), invasive fetal monitoring, and if blood loss during delivery is greater than ≥500 ml (2 cups), but additional studies are needed to confirm these findings. Thus, there may be benefit in minimizing invasive procedures and prolonged labor.

Sex and Hepatitis C
Hepatitis C virus can be transmitted by sexual contact, but much less efficiently than is seen in other sexually-transmitted viruses, including hepatitis B virus and HIV (the virus that causes AIDS). However, since sex is such a common behavior and the reservoir of HCV-infected individuals is sizable, sexual transmission of HCV likely contributes to the total burden of HCV infection in the U.S. In studies of persons who have acute hepatitis C infection (newly acquired), approximately 20% reported sexual contact with multiple sexual partners or sex with an HCV-infected person as their only risk factor for HCV acquisition (Figure above). The reporting of multiple sexual partners does not necessarily indicate that HCV was acquired by sexual contact but rather that individuals who engage in sex may expose themselves to acquiring HCV via other risky behaviors.

The risk of HCV transmission by sexual contact differs by the type of sexual relationship [8]. Persons in long-term monogamous partnerships are at lower risk of HCV acquisition (0 – 0.6% per year) than persons with multiple partners or those at risk for sexually transmitted diseases (0.4 to 1.8% per year). This difference in rate of HCV infection may reflect differences in sexual behaviors (frequency or type of sexual activities) or differences in rates of exposure to non-sexual sources of HCV between sex partners, such as injection drug use or shared razors and toothbrushes. HIV infection appears to increase the rate of acquiring HCV by sex.

WHO SHOULD REQUEST HEPATITIS C TESTING?
Since HCV infection is often silent, persons at risk for hepatitis C need to recognize that they are potentially at risk, and request testing to determine if they are infected. Even if the potential exposure to HCV occurred several decades ago and the individual is without any symptoms, infection may still be present. 

If you have any of these risk factors for hepatitis C, you should request testing from your doctor:                    

• Ever injected drugs, even once
• Received a blood transfusion prior to July 1992
• Received clotting factors made prior to 1987
• Received an organ transplant prior to July 1992
• Received an injection for medical purposes in setting where needles or syringes may have been reused
• Ever had hemodialysis for kidney failure
• Ever had a sexual partner with hepatitis (or who may have had hepatitis)
• Ever stuck by a needle after it was in another person
• Mother had HCV infection

ACUTE HCV INFECTION


WHAT IS THE USUAL COURSE OF ACUTE HEPATITIS C INFECTION?
The average incubation period for the infection is 7-8 weeks (time of exposure to the virus to first symptoms), but the course may range from 2 weeks to 6 months.  The usual time course for acute HCV infection is depicted in Figure below.  Following exposure, the levels of HCV rise quite rapidly and are detectable in the blood using tests for HCV RNA as early as 10 days after infection. HCV RNA tests detect hepatitis C virus genomes (genetic material) and therefore directly reflect the presence of virus. Hepatitis C antibody, abbreviated anti-HCV, is a protein produced by the immune system in response to the infection. Anti-HCV develops in over 80% of infected persons by 12 weeks after exposure.  In some cases, the development of anti-HCV can be delayed to 9 months, although this is rare. Anti-HCV, once produced, persists in the blood for the remainder of life, even if the virus is ultimately eliminated. Testing for the presence of anti-HCV in the blood is used to screen for the presence of acute and chronic hepatitis C infection. 

As shown in the figures above, there are two outcomes following infection with HCV.  Either the virus is eliminated by the immune system and the individual has no long-lasting effects of the viral infection, or the immune system is unsuccessful in clearing the virus and chronic infection develops. Unfortunately, the majority of persons infected with hepatitis C develop chronic infection. Only 15-40% of persons infected with HCV will clear the infection on their own. The factors associated with successful eradication of the virus following infection are only partially understood.  A healthy immune response is needed, so individuals who are older or who have other diseases that compromise their immune systems, have a higher likelihood of developing chronic infection, It also appears that persons with acute hepatitis, who have developed the more severe symptoms and become jaundiced (yellow-colored skin and eyes), are more likely to clear the virus than persons with milder symptoms.  Only those individuals who have chronic infection are at risk of developing permanent liver injury, including cirrhosis. For those persons who have acute hepatitis and clear the virus on their own, there are no residual effects. The liver will repair itself and return to the same state it was in prior to the infection.

Fulminant hepatitis (a severe form of acute HCV associated with liver failure) is exceedingly rare. This life-threatening manifestation of acute hepatitis C requires specialized care in a center that has expertise in treatment of liver failure and performing liver transplantation.

Symptoms in Patients with Acute Hepatitis C
The majority of persons infected with hepatitis C will be without any specific symptoms. If symptoms do develop, they typically appear about 7-8 weeks after exposure. The symptoms for acute hepatitis C are not unique but rather are the same symptoms seen in patients with acute hepatitis of any type. Typically the symptoms, if present, last a few weeks and then resolve.

Symptoms can be non-specific or “flu-like:”

• Fatigue
• Nausea, vomiting, loss of appetite
• Diarrhea, possibly weight loss
• Fever
• Discomfort in the right upper portion of the abdomen
• Dark urine
• Jaundice (yellowing of skin and eyes): seen in 20 to 30% of persons with acute HCV

The diagnosis of acute hepatitis C requires additional blood tests.  In persons with acute infection, the virus is detectable in the blood prior to and after the symptomatic phase of the infection.

Laboratory Test Abnormalities in Acute Hepatitis
The most important laboratory abnormalities in symptomatic patients are:

• Marked elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), usually 1000-2000 IU/L.  The ALT is usually higher than the AST. These tests reflect the severity of liver inflammation and injury.
• Elevated levels of bilirubin (causes yellowing of eyes and skin).
• There may also be changes in the tests that reflect liver function, including the prothrombin time (a measure of clotting capacity), and albumin (a measure of protein production and destruction).

HOW IS THE DIAGNOSIS OF ACUTE HEPATITIS C MADE?
Blood tests establish the diagnosis of acute hepatitis C. The tests used to make the diagnosis of acute HCV infection are shown in the Table below. The screening test for HCV is an antibody test. This test establishes whether a person has been exposed to the virus.  To distinguish acute HCV infection that has resolved from acute infection that has evolved to chronic infection requires additional testing. HCV RNA tests measure the amount of virus circulating in the blood and are used to determine if the infection is resolved or persistent (Table 1 below).

Acute and chronic hepatitis C cannot be distinguished from each other on the basis of blood tests alone. As shown above, anti-HCV is present and HCV RNA is detectable in both acute and chronic HCV.  Acute hepatitis differs from chronic hepatitis in that the ALT levels are generally higher (>500 IU/L), symptoms of a “flu-like” illness may be present, and the individual has a risk factor for recent exposure to HCV. Sometimes, however, acute hepatitis may have none of these distinguishing features. A liver biopsy may be considered as a final, definitive way to distinguish acute from chronic HCV, although this is infrequently done.  In the past, there was no major need to distinguish acute from chronic hepatitis as no specific treatment was given for acute hepatitis, however, that is not the case now. Given the importance of providing treatment to persons with acute hepatitis who are not clearing the infection on their own, if there is any doubt about whether the infection is acute or chronic, one should assume the infection is acute, and treat.

TREATMENT OF ACUTE HEPATITIS C

General Measures
The primary treatment of acute hepatitis C is support care. The focus is on alleviating symptoms. For most patients this includes:

• Bed rest
• Insuring adequate fluid intake (especially if vomiting and diarrhea present)
• Use of acetaminophen in limited amounts (no more than 2000 mg every 24 hours) for fever and joint pains

Close follow-up with a physician is essential and all medications taken, even over-the-counter products, should be taken only with physician approval, to minimize any risk of additional harm to the liver.

Prophylactic Therapy After Exposure to Hepatitis C
There is no effective therapy to prevent infection after exposure. There is no vaccine available and immune globulin (antibody) therapy is ineffective. In this regard, hepatitis C is very different from hepatitis B and hepatitis A.  However, if exposed to HCV, it is important to be tested at specific intervals after the exposure to see whether acute infection develops. If infection occurs, early treatment needs to be considered.

Treatment of Acute Infection
For persons with acute HCV infection, treatment with peginterferon, with or without ribavirin, results in eradication of the virus and resolution of infection in at least 80% of patients. Thus, providing antiviral therapy to persons with acute HCV infection can substantially reduce the likelihood of the acute infection progressing to chronic, persistent infection. Once the diagnosis of acute hepatitis is made, it is common to follow the liver tests and HCV viral levels over a period of 8-12 weeks to see whether the person successfully clears the virus on their own (without the need for antiviral therapy). If the HCV viral level in the blood shows a progressive decline, continued waiting to see if virus is eradicated may be considered. If, however, the HCV viral level is not declining progressively, treatment should be initiated.

There is no consensus as to whether to treat with peginterferon plus ribavirin or peginterferon alone; in clinical practice most physicians use combination therapy. The duration of treatment is at least 24 weeks. A longer period of treatment can be considered if there is a slow response (Figure below).

PREVENTING TRANSMISSION OF HCV INFECTION TO OTHERS
As discussed, HCV is transmitted to others by blood or blood-contaminated items [9]. The virus can survive in blood-stained surfaces for at least 16 hours [10].

If you are infected:

• Never share personal care items that might have blood on them such as toothbrushes, nail clippers, or razors
• Never inject drugs or if you can't stop injecting drugs, never share needles, syringes, or "works” with others
• If you are a health care or public safety worker, always follow routine barrier precautions
• Cover open cuts, abrasions, or sores 
• Do not donate blood, organs, or tissue
• Test all children born to mothers who are HCV positive
• HCV can be spread by sex, but this is rare. If you are having sex with more than one sex partner, use latex condoms every time to prevent the spread of HCV. The risk of transmission of HCV among persons in monogamous relationships is low, and for this reason it is not recommended that couples specifically change their sexual practices to include use of barrier methods. However, this decision will vary with each couple’s comfort level with the predicted risk of transmitting HCV.  Additional “common sense” recommendations (since HCV is transmitted in blood) are:

o If sexual activities cause trauma to the mucosa or skin (resulting in blood exposure), use barrier protection or abstain from sex
o If having sex during menses, use barrier protection or abstain from sex
o If one or more of the partners has herpes or other open or ulcerating lesions, use barrier protection or abstain from sex

CHRONIC HCV INFECTION

WHAT ARE THE SYMPTOMS AND SIGNS OF CHRONIC HEPATITIS C?
Most persons with chronic hepatitis C infection are without any symptoms, and consequently many persons with HCV do not know they have it.  When symptoms are present, they are not very specific for liver disease and may be overlooked.  The most common symptom reported is fatigue. If suspected, the infection can be easily diagnosed with blood tests.

Once cirrhosis develops, symptoms may become more obvious. These symptoms include decreased mental alertness, swelling of legs and abdomen, bleeding complications, and infections. Individuals with cirrhosis require regular blood tests and physician visits to monitor for changes. 

Physical findings are typically absent.  Liver enlargement or tenderness may be seen. Patients with cirrhosis may have skin changes indicative of cirrhosis, an enlarged spleen, swelling of lower legs or abdomen, or jaundice.

WHAT IS THE RISK OF CIRRHOSIS AND LIVER CANCER IN PATIENTS WITH CHRONIC HEPATITIS C?
For individuals with chronic HCV infection, the complications of greatest concerns are cirrhosis and liver cancer, as these are potentially life threatening. These complications do not develop in all persons with chronic infection. It is estimated that 5-20% of persons with chronic HCV infection will develop cirrhosis after 20 years of chronic infection. This percent increases with longer duration of chronic infection but, in general, the development of cirrhosis takes several decades.  Liver cancer only develops in those with cirrhosis. The risk of liver cancer in persons with chronic HCV infection and cirrhosis is approximately 2-3% per year (Figure below). Liver cancer is more common in men.

There are several factors that have been associated with a higher risk of developing cirrhosis (table below). The only factors that can be modified are alcohol use, marijuana use, and weight.

Alcohol Use
Alcohol negatively affects the liver.  Alcohol is processed by the liver and broken down into byproducts.  These byproducts are toxic to the liver and accelerate liver damage. Regular alcohol usage can cause continuous damage to the liver, resulting in the development of progressive fibrosis and eventually cirrhosis [11]. Data shows that inflammation and fibrosis is increased in HCV-infected persons who consume more than 2 drinks per day, as compared with HCV-infected persons who drink less. For women, drinking only 1 alcoholic beverage a day is associated with an increased rate of liver injury [12].  It is not known whether drinking lesser amounts or less frequently (e.g., 1-2 drinks on a weekend), has a negative effect on HCV. However, the safest approach is limit alcohol use to less than one drink per day or to not drink at all.  What constitutes “1 drink” is shown in the Figure below.

Alcohol use also increases the risk of liver cancer, with heavy drinkers (more than 4-6 drinks per day) having a 2-4 times higher rate of liver cancers than non-drinkers with HCV and cirrhosis [13][14]. Women have a higher risk of developing alcohol-related liver damage and cirrhosis than men drinking equivalent amounts of alcohol.

In addition to the effects of alcohol on risk of cirrhosis and liver cancer, studies show that use of alcohol during HCV treatment may reduce its effectiveness [15][16]. Persons who continue to use alcohol are less likely to complete the treatment course, and if treatment is stopped prematurely, it reduces the likelihood of success.

Marijuana Use
Marijuana or Cannabis sativa is used for both medicinal and recreational purposes. Recent studies in persons with chronic HCV infection have found that daily cannabis use is associated with a much higher risk of fibrosis (scarring) and cirrhosis than in those who use marijuana less often or do not use it [17][18]. Furthermore, daily cannabis use and moderate to heavy alcohol use appeared to have at least multiplicative effects on the chances of having severe fibrosis [17].  While the exact mechanism of how cannabis causes more fibrosis is still being investigated, there are studies showing that receptors that bind the cannabis compounds exist within the liver. Based on studies to date, it is advised that individuals with chronic HCV infection reduce or abstain from cannabis use.

Overweight and Obesity
Being overweight or obese is associated with many health risks and diseases, including liver disease.  Excess weight can result in deposition of fat in the liver cells, called steatosis. Other conditions associated with the steatosis (fat in the liver) are diabetes, elevated levels of triglycerides, and certain medications. Steatosis can cause damage to the liver, just as with alcohol. 

In persons with chronic HCV infection, steatosis  is associated with these important consequences [19]:

o A higher degree of liver inflammation and fibrosis
o A reduced likelihood of responding to hepatitis C treatment
o An increased risk of liver cancer

To prevent these unfavorable effects on hepatitis C, optimization of weight is an important goal in persons infected with HCV. Body mass index (BMI) is used to define healthy weight versus overweight and obese. BMI takes into account height as well as weight.

The National Institute of Health provides an online BMI calculator: http://www.nhlbisupport.com/bmi/

Under Weight          Healthy Weight               Overweight                   Obese       
BMI < 18.5            BMI is 18.6 – 24.9         BMI is 25 – 29.9                 BMI > 30.0

A combination of dietary changes and increased exercise are recommended to achieve a healthy weight. Even modest weight loss, ~10% of body weight, can result in improvements in the liver [20]. For individuals with a BMI >30 (obese), participation in weight loss programs is recommended.

TESTS USED TO EVALUATE PERSONS WITH CHRONIC HCV INFECTION
There are 3 kinds of tests used to assess persons with chronic HCV infection:

o Antibody tests (anti-HCV)
o HCV RNA tests (also called HCV viral load)
o HCV genotype

Tests to Distinguish Resolved from Chronic HCV Infection
All persons who have been exposed to hepatitis C virus will have antibody present in the blood. To distinguish persons who have chronic infection (virus still present) from those who have resolved infection (cleared virus), additional testing is needed. Only those with chronic infection are at risk for liver damage and the development of cirrhosis.

The test used to identify those with chronic HCV infection is a blood test called HCV RNA (Table 1 above). If the HCV RNA test result is negative, this means the virus has been cleared and the person does not have chronic infection. If the test is positive, chronic infection is present.  However, there are few important aspects of interpreting this test:

• The HCV RNA test must have a detection limit that is very low to be accurate. The FDA has required that such tests be able to detect to a limit of 50 IU/ml or less to be used for this purpose. If the test is not sensitive enough, the result can be misleading.
• If the test were negative, indicating no infection, a repeat, confirmatory test would be recommended since the implications are so important.  It would be expected that a person with a negative HCV RNA test result would also have normal liver tests (ALT and AST).
• If the test is positive, indicating chronic infection, additional tests are needed (see below)

Initial Evaluation of Patient with Chronic HCV Infection
The initial evaluation of a patient diagnosed with hepatitis C infection includes the following:

1. Review of History

• Determination of how infection was likely acquired (to estimate duration of infection)
• Alcohol and marijuana use (as these factors affects HCV disease severity)

2. Diagnostic tests in Persons with Chronic HCV Infection (Table below)

• Alanine aminotransferase (ALT or SGPT) and aspartate aminotransferase (AST or SGOT) = indication of liver inflammation
• Total bilirubin, albumin, prothrombin time are tests of liver function; these are abnormal if cirrhosis is present
• Blood test for HCV RNA (measures amount of virus in the blood)
• Blood test for HCV genotype (defines the type of virus) There are 6 different genotypes of HCV. In the U.S., the most common HCV genotype among those with chronic HCV infection is genotype 1 (1a or 1b). This is present in ~70% of persons. Genotypes 2 and 3 are next most common and genotypes 4-6 are rare, unless the HCV was acquired outside the U.S. Genotype is a very important predictor of how successful treatment will be, if undertaken, and therefore is always measured if treatment is being considered. 

3. Liver biopsy
A liver biopsy is the usual method used to assess the severity of liver disease. In chronic hepatitis C, the severity of infection is measured by the degree of necroinflammatory activity (grade) and amount of fibrosis or scarring (stage). The grade and stage of disease is often used to determine whether treatment is needed. The presence of normal liver tests does not exclude liver disease. For this reason, it has been recommended that a liver biopsy be considered in patients with chronic HCV infection, regardless of the ALT levels.

4. Other tests to assess liver fibrosis (scarring)
There are several unapproved blood tests that may be used to estimate the amount of fibrosis in the liver.  These tests may replace the need for liver biopsy in some patients, although liver biopsy is still the “gold standard” for measuring the amount of liver damage. Examples of such tests are:

o HCV Fibrosure™
o Fibrotest™
o ELF™

5. Surveillance tests for liver cancer in those with cirrhosis (see Surveillance for Hepatocellular Carcinoma section below)

• Ultrasound or CT scan of the liver
• Alpha-fetoprotein

6. Other tests
Since persons with chronic HCV infection are at higher risk of complications if they become infected with another hepatitis virus, it is recommended that testing be performed to determine if there is a need for vaccination against hepatitis A virus and/or hepatitis B virus. The specific tests are:

o Antibody to hepatitis A virus (anti-HAV).  If negative, vaccination is recommended to prevent infection with this virus.
o Hepatitis B virus (HBsAg, antibody to HBc).  If negative, vaccination is recommended to prevent infection with this virus in those at risk.

MANAGEMENT OF CHRONIC HCV INFECTION

1. General Measures

2. Antiviral Treatment
Hepatitis C can be eradicated. Persons who clear the virus with treatment have a reduced rate of liver complications, improved quality of life, and longer survival than those who remain chronically infected. However, not every person with chronic HCV infection NEEDS to be treated and not every person CAN be treated with currently available drugs. The final decision as to whether to proceed with treatment or not usually requires a weighing of risks and benefits for each individual person. 

The current standard treatment for chronic hepatitis C infection is a combination of two medications, peginterferon and ribavirin.
 

• Peginterferon is a medication taken once a week by injection. The injection is given subcutaneously (under the skin).  There are two different types of peginterferon that are approved by the FDA for treatment of chronic HCV.

o Peginterferon alfa-2a, called Pegasys®
o Peginterferon alfa-2b, called Peg-Intron®

• Ribavirin is a medication taken by mouth twice a day. The dose of ribavirin depends on weight and kidney function.  

These drugs have a number of different side effects. Patients on treatment require close follow-up with their physicians during treatment to manage the side effects.

The length of treatment depends on which HCV genotype is present. The usual lengths of treatment are:

o 24 weeks for HCV genotype 2 or 3
o 48 weeks for HCV genotype 1, 4, 5, or 6

The response to treatment is determined by measuring the levels of HCV RNA in the blood (Table below).  If a patient is  responding to the treatment, the HCV RNA level will decline and become undetectable. The duration of treatment may be lengthened if treatment response is slow.

WHO SHOULD BE TREATED?
All persons with chronic HCV infection should be considered for treatment. The minimum requirements for a person to be considered a candidate for treatment are:

• HCV RNA positive (virus detectable in blood)
• Absence of signs of liver failure
• Absence of other medical conditions that would make the treatment too risky
• ALT level can be normal or elevated

The decision to undertake treatment is not an easy one for most persons with chronic HCV infection. Since treatment is not successful in all persons treated, and there are side effects associated with treatment, there is a need to carefully weigh the pros and cons of proceeding with immediate treatment versus deferring treatment to a later time.  Some patients choose to wait, hoping for the development of more effective and “easier-to-take” therapies.

The key factors to consider when deciding whether to proceed with treatment or not are:

1. The risk of liver complications if treatment is NOT undertaken
This determination requires information about severity of liver disease (from liver biopsy or other tests). If the amount of fibrosis (scarring) is moderate to severe, treatment is recommended because such individuals are at risk for progression of the HCV disease and liver complications in the short-term (5-10 year period). For persons with mild fibrosis, treatment can generally be deferred, if desired.

2. The rate of treatment success with currently available drugs
The most important factor determining the likelihood of achieving eradication of the virus is HCV genotype.  The rate of viral clearance with treatment is approximately:
o 40-45% for HCV genotype 1
o 90% for HCV genotype 2
o 60-70% for HCV genotype 3
o 50-70% for HCV genotype 4
o Insufficient data for genotypes 5 and 6 to estimate response rates

Other factors that influence response include HCV viral load, weight, race, and sex (Table below), so the percentages listed above for HCV genotype represent only approximations, and may be higher or lower depending upon the presence of other factors.

3. The possible risks associated with treatment
Most patients experience some side effects during treatment. The common symptoms that occur are listed in the Table above.  Most symptoms are mild to moderate in severity and can be easily managed. During treatment, patients need to be followed closely to monitor for side effects and to make adjustments. With a good medical support team in place, more than 90% of persons starting treatment will complete the planned treatment course.

Additional medications may be needed to treat the side effects of the treatment, such as anti-depressants or topical creams for rashes. The symptoms are dependent on the drug doses, so sometimes the doses are reduced, to help decrease the side effects. The side effects will go away after the treatment is stopped, though it can takes several months to recover. Almost all of the side effects are reversible.

The rare but serious side effects that are not reversible include:
o Damage to the retina (part of the vision can be lost)
o Thyroid disease that requires medication to control
o Ribavirin can cause severe birth defects. It is important for women AND men to use birth control during treatment, and for 6 months after treatment is completed, to prevent pregnancy.

4. Is it a good time in my life to undergo treatment?
Treatment should be timed to occur when an individual has the ability to focus on treatment and management of side effects. The treatment course typically is 6-12 months in duration, and can be longer.  Treatment during a potentially busy or stressful time in your life is not ideal, e.g., starting a new job, getting married, starting college.  To help deal with the side effects related to treatment, it is important get enough sleep nightly, engage in regular light exercise, and eat regular, healthy meals. Most individuals are able to continue working during treatment, but modification of work duties may be needed for some jobs.

Special Considerations Related to Pregnancy and Treatment
HCV-infected women of child-bearing age often seek guidance on the timing of antiviral therapy in the context of future pregnancy. The main reason for a woman to consider antiviral therapy prior to pregnancy is to eliminate the 5% risk of HCV transmission to the infant.  However, antiviral therapy prior to pregnancy results in delays to the time to conception and treatment will be successful in eliminating HCV in only a proportion of those treated. Most importantly, treatment cannot be taken on during pregnancy or when breast-feeding. Ribavirin is teratogenic (causes birth defects in the fetus) and its use in women AND in their partners trying to conceive and in those pregnant is absolutely contraindicated. The effects of ribavirin are prolonged and it is necessary to wait 6 months after the last dose of ribavirin before trying to conceive. 

MONITORING PATIENTS WHO ARE NOT ON TREATMENT
All patients require periodic monitoring of their liver disease. Periodic visits even with those patients not undergoing treatment allow for discussion of new information on lifestyle factors that affect liver health and to review new developments in HCV treatment.

For patients with advanced fibrosis (bridging fibrosis or cirrhosis), laboratory monitoring every 6 months is recommended.  Additionally, these individuals require monitoring for the development of liver cancer.

MONITORING FOR HEPATOCELLULAR CANCER (LIVER CANCER)
Individuals with chronic HCV infection and cirrhosis are at risk for hepatocellular carcinoma. The risk if estimated to be 3-5% per year. Performing surveillance tests to look for cancer is important in detecting the cancers at an early stage, when curative therapy can be obtained. It is recommended that all persons with chronic hepatitis C and cirrhosis have scheduled screening tests every 6 to 12 months [21]. The screening tests include:

o Abdominal ultrasound
o Helical computed tomography (CT) scan of the abdomen
o Magnetic Resonance Imaging (MRI) of the abdomen

Additionally, some physicians also use a blood test called alpha-fetoprotein as an additional screening test. This test is less definitive for liver cancer and is frequently elevated in patents with chronic HCV infection who do not have liver cancer. However, very high levels of alpha-fetoprotein (e.g., >300 ng/ml) or an alpha-fetoprotein level that is increasingly progressively are more concerning for liver cancer and warrant additional testing.

Individuals who had chronic HCV infection but who have been successfully treated to eradicate the hepatitis C are still at risk for liver cancer if cirrhosis was already present at the time they were treated.  However, the risk of liver cancer in those who have been successfully treated is substantially less than those with cirrhosis who remain chronically infected.

References

1. Alter MJ. Epidemiology of hepatitis C virus infection. World J Gastroenterol 2007;13(17):2436-41.
2. Armstrong G, Wasley A, Simard E, McQuillan G, Kuhnert W, Alter M. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med 2006;144(10):705-14.
3. Bialek SR, Terrault NA. The changing epidemiology and natural history of hepatitis C virus infection. Clin Liver Dis 2006;10(4):697-715.
4. Stramer SL, Glynn SA, Kleinman SH, Strong DM, Caglioti S, Wright DJ, et al. Detection of HIV-1 and HCV infections among antibody-negative blood donors by nucleic acid-amplification testing. N Engl J Med 2004;351(8):760-8.
5. MMWR. Morbidity and mortality report: Surveillance Summaries. 2007;56:No. SS-3.
6. Mast EE, Hwang LY, Seto DS, Nolte FS, Nainan OV, Wurtzel H, et al. Risk factors for perinatal transmission of hepatitis C virus (HCV) and the natural history of HCV infection acquired in infancy. J Infect Dis 2005;192(11):1880-9.
7. European Pediatric Hepatitis C Network. A significant sex--but not elective cesarean section--effect on mother-to-child transmission of hepatitis C virus infection. J Infect Dis 2005;192(11):1872-9.
8. Terrault N. Sexual activity as a risk factor for hepatitis C. Hepatology. 2002;36(5 Suppl 1):S99-105.
9. CDC. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR 1998;47(RR-19):1-38.
10. Kamili S, Krawczynski K, McCaustland K, Li X, Alter MJ. Infectivity of hepatitis C virus in plasma after drying and storing at room temperature. Infect Control Hosp Epidemiol 2007;28(5):519-24.
11. Peters MG, Terrault NA. Alcohol use and hepatitis C. Hepatology 2002;36(5 Suppl 1):S220-5.
12. Hezode C, Lonjon I, Roudot-Thoraval F, Pawlotsky JM, Zafrani ES, Dhumeaux D. Impact of moderate alcohol consumption on histological activity and fibrosis in patients with chronic hepatitis C, and specific influence of steatosis: a prospective study. Aliment Pharmacol Ther 2003;17(8):1031-7.
13. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004;127(5 Suppl 1):S35-50.
14. Donato F, Gelatti U, Limina RM, Fattovich G. Southern Europe as an example of interaction between various environmental factors: a systematic review of the epidemiologic evidence. Oncogene 2006;25(27):3756-70.
15. Ohnishi K, Matsuo S, Matsutani K, Itahashi M, Kakihara K, Suzuki K, et al. Interferon therapy for chronic hepatitis C in habitual drinkers: comparison with chronic hepatitis C in infrequent drinkers. Am J Gastroenterol 1996;91(7):1374-9.
16. Tabone M, Sidoli L, Laudi C, Pellegrino S, Rocca G, Della Monica P, et al. Alcohol abstinence does not offset the strong negative effect of lifetime alcohol consumption on the outcome of interferon therapy. J Viral Hepat 2002;9(4):288-94.
17. Ishida JH, Peters MG, Jin C, Louie K, Tan V, Bacchetti P, et al. Influence of cannabis use on severity of hepatitis C disease. Clin Gastroenterol Hepatol 2008;6(1):69-75.
18. Hezode C, Roudot-Thoraval F, Nguyen S, Grenard P, Julien B, Zafrani ES, et al. Daily cannabis smoking as a risk factor for progression of fibrosis in chronic hepatitis C. Hepatology 2005;42(1):63-71.
19. Asselah T, Rubbia-Brandt L, Marcellin P, Negro F. Steatosis in chronic hepatitis C: why does it really matter? Gut 2006;55(1):123-30.
20. Hickman IJ, Clouston AD, Macdonald GA, Purdie DM, Prins JB, Ash S, et al. Effect of weight reduction on liver histology and biochemistry in patients with chronic hepatitis C. Gut 2002;51(1):89-94.
21. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42(5):1208-36.