Disease: Hepatitis C Infection
(HCV, Hep C)

    Hepatitis C infection (HCV, hep C) facts

    • Hepatitis C is one of several viruses that cause hepatitis (inflammation of the liver).
    • Up to 85% of individuals who are initially (acutely) infected with hep C will fail to eliminate the virus and will become chronically infected.
    • Hepatitis C is spread most commonly through inadvertent exposure to infected blood.
    • Intravenous drug abuse is the most common mode of transmission.
    • The risk of acquiring hepatitis C through sexual contact is low.
    • Generally, people with chronic infection with hepatitis C develop no symptoms until they have extensive scarring of the liver (cirrhosis). Some individuals, however, may have fatigue and other non-specific symptoms in the absence of cirrhosis. A minority of patients with hepatitis C have symptoms from organs outside of the liver.
    • In the U.S., infection with hepatitis C is the most common cause of chronic hepatitis and the most common reason for liver transplantation.
    • Hepatitis C is diagnosed by determining levels in the blood of antibodies to the virus and then confirming the infection with other tests for viral RNA. The amount of viral RNA in the blood (viral load) does not correlate with the severity of the disease but can be used to track the response to treatment.
    • A liver biopsy may be used to assess the amount of liver damage (liver cell injury and scarring), which can be important in planning treatment. Other tests that carry less risk than liver biopsy can be used to evaluate for scarring in some patients.
    • Considerable progress has been made in the treatment of hepatitis C. The rate of cure has increased (above 90%-95%) with the development of direct acting all-oral drug regimens.
    • Treatment results in reduced inflammation and scarring of the liver in most patients who are cured of hepatitis C and also occasionally (and to a much lesser extent) in those who relapse or are not cured.

    What is hepatitis C infection?

    Hepatitis C infection is an infection of the liver caused by the hepatitis C virus (HCV). It is difficult for the human immune system to eliminate hepatitis C from the body, and infection with hep C usually becomes chronic. Over decades, chronic infection with hepatitis C damages the liver and can cause liver failure. In the U.S., the number of new cases of hepatitis C infection has declined from a peak of 200,000 annually to about 17,000 in 2007. When the virus first enters the body, however, there usually are no symptoms, so these numbers are estimates. Up to 85% of newly-infected people fail to eliminate the virus and become chronically infected. In the U.S., more than three million people are chronically infected with hepatitis C. Infection is most commonly detected among people who are 40 to 60 years of age, reflecting the high rates of infection in the 1970s and 1980s. There are 8,000 to 10,000 deaths each year in the US related to hepatitis C infection. Hepatitis C infection is the leading cause of liver transplantation in the US and is a risk factor for liver cancer.

    What is the nature (biology) of the hepatitis C virus?

    'Hepatitis' means inflammation of the liver. Hepatitis C is one of several viruses that can cause hepatitis. It is unrelated to the other common hepatitis viruses (for example, hepatitis A or hepatitis B). Hepatitis C is a member of the Flaviviridae family of viruses. Other members of this family of viruses include those that cause yellow fever and dengue.

    Viruses belonging to this family all have ribonucleic acid (RNA) as their genetic material. All hepatitis C viruses are made up of an outer coat (envelope) and contain enzymes and proteins that allow the virus to reproduce within the cells of the body, in particular, the cells of the liver. Although this basic structure is common to all hepatitis C viruses, there are at least six distinctly different strains of the virus which have different genetic profiles (genotypes 1 to 6). In the U. S., genotype 1 is the most common form of hepatitis C. Even within a single genotype there may be some variations (genotype 1a and 1b, for example). Genotyping is important to guide treatment because some viral genotypes respond better to therapy than others. The genetic diversity of hepatitis C is one reason that it has been difficult to develop an effective vaccine since the vaccine must protect against all genotypes.

    How does liver damage occur in hepatitis C infection?

    The presence of hepatitis C in the liver triggers the human immune system, which leads to inflammation. Over time (usually decades), prolonged inflammation may cause scarring. Extensive scarring in the liver is called cirrhosis. When the liver becomes cirrhotic, it fails to perform its normal functions, (liver failure), and this leads to serious complications and even death. Cirrhotic livers also are more prone to become cancerous.

    What are the symptoms of hepatitis C infection?

    About 75% of people have no symptoms when they first acquire hepatitis C infection. The remaining 25% may complain of:

    • fatigue,
    • loss of appetite,
    • muscle aches, or
    • fever.

    Yellowing of the skin or eyes (jaundice) is rare at this early stage of infection.

    Over time, people with chronic infection may begin to experience the effects of the persistent inflammation of the liver caused by the immune reaction to the virus. Blood tests may show elevated levels of liver enzymes, a sign of liver damage, which is often the first suggestion that the infection may be present. Patients may become easily fatigued or complain of nonspecific symptoms.

    As cirrhosis develops, symptoms increase and may include:

    • weakness,
    • loss of appetite,
    • weight loss,
    • breast enlargement in men (gynecomastia),
    • a rash on the palms,
    • difficulty with the clotting of blood, and
    • spider-like blood vessels on the skin.

    In patients with advanced cirrhosis, the liver begins to fail. This is a life-threatening problem. Confusion and even coma (encephalopathy) may result from the inability of the liver to process certain toxic substances.

    Increased pressure in the blood vessels of the liver (portal hypertension) may cause fluid to build up in the abdominal cavity (ascites) and result in engorged veins in the swallowing tube (esophageal varices) that tear easily and can bleed suddenly and massively. Portal hypertension also can cause kidney failure or an enlarged spleen resulting in a decrease of red blood cells (anemia), or the development of low platelets (thrombocytopenia), which can promote bleeding.

    In advanced cirrhosis, liver failure causes decreased production of clotting factors. Patients with advanced cirrhosis often develop jaundice because the damaged liver is unable to eliminate a yellow compound, called bilirubin that is formed from the hemoglobin of old red blood cells.

    How is hepatitis C spread, and is it contagious?

    • Hepatitis C is spread (transmitted) most efficiently through exposure to infected blood.
    • The most common route of transmission is needles shared among users of illicit drugs.
    • Accidental needle-sticks in healthcare workers also have transmitted the virus. The average risk of getting hepatitis C infection from a stick with a contaminated needle is 1.8% (range 0% to 10%)
    • Prior to 1992, some people acquired the hepatitis C infection from transfusions of blood or blood products. Since 1992, all blood products have been screened for hepatitis C, and cases of hepatitis C due to blood transfusion now are extremely rare.
    • Hepatitis C infection also can be passed from mother to unborn child. Approximately 4 of every 100 infants born to hepatitis C-infected mothers become infected with the virus.
    • A small number of cases are transmitted through sexual intercourse. The risk of transmission of hepatitis C from an infected individual to a non-infected spouse or sexual partner without the use of condoms over a lifetime has been estimated to be between 1% and 4%.
    • Poor infection control practices during tattooing and body piercing potentially can lead to spread of infection. (This has not been reported in licensed, commercial tattooing facilities where it has been studied.)
    • Finally, there have been some outbreaks of hepatitis C when instruments exposed to blood have been re-used without appropriate cleaning between patients.

    What conditions beyond the liver are associated with hepatitis C infection?

    Most of the signs and symptoms of hepatitis C infection relate to the liver. Less commonly, hepatitis C infection causes conditions beyond of the liver.

    • Hepatitis C infection can cause the body to produce unusual antibodies called 'cryoglobulins.' These cryoglobulins cause inflammation of the arteries (vasculitis) which may damage the skin, joints, and kidneys. Patients with cryoglobulinemia (cryoglobulins in the blood) may have:
      • joint pain,
      • arthritis,
      • a raised purple rash on the legs, and
      • generalized pain or swelling of their bodies.
    • In addition, these patients may develop Raynaud's phenomenon in which the fingers and toes turn color (white, then purple, then red) and become painful at cold temperatures.
    • Hepatitis C is known to be associated with two skin conditions, lichen planus and porphyria cutanea tarda.
    • For reasons that are unclear, diabetes is three times more common among patients with chronic hepatitis C infection than in the general population.
    • Low platelet counts may occur as a result of the destruction of platelets by antibodies.
    • Hepatitis C also is associated with B-cell lymphoma, a cancer of the lymph system.

    Who is at high risk and should be tested for hepatitis C infection?

    Currently, screening for hepatitis C is not recommended as part of a routine physical examination. Rather, testing should be done among:

    • Individuals at high risk for infection including current and past users of illicit injectable drugs, users of intranasal illicit drugs, and persons exposed to infected blood or organs from infected persons
    • Children born to chronically infected mothers
    • People who received blood, blood products, or transplanted organs prior to 1992 (before testing of blood for hepatitis C was begun)
    • Persons with abnormal levels of liver enzymes in the blood
    • Healthcare workers with work-related needle sticks or injuries
    • Persons with body tattoos from unregulated tattoo parlors
    • Persons who were ever incarcerated because of the high prevalence of hepatitis C in the prison population
    • Persons infected with hepatitis B or HIV virus since this suggests illicit drug use
    • Persons on long term hemodialysis which exposes them to hepatitis C infection

    These are not the only circumstances under which testing for hepatitis C infection may be done. In general, testing is recommended when exposure to the virus is suspected.

    What is the usual progression of chronic hepatitis C infection?

    Our understanding of the natural progression (history) of hepatitis C infection still is evolving.

    Of every 100 people infected with hepatitis C, it is estimated that:

    • 75 to 85 will become chronically infected,
    • 60 to 70 will develop liver disease,
    • 5 to 20 will develop cirrhosis, and
    • 1 to 5 will die from complications of liver disease such as cirrhosis or liver cancer.

    Scientists are learning more about what causes some people to have milder problems and others to have serious complications. Drinking alcohol and acquiring other hepatitis viruses are risk factors for severe disease. Thus, persons who have chronic hepatitis C infection should avoid drinking alcohol and should be vaccinated against the other hepatitis viruses (A and B).

    Live cancer (hepatocellular carcinoma) is associated with cirrhosis due to chronic hepatitis C infection. Some experts recommend screening patients with hepatitis C infection and cirrhosis for liver cancer every six months with abdominal ultrasound examinations and a blood test for alpha-fetoprotein (a marker for liver cancer). The effectiveness of this screening is unclear.

    How is hepatitis C diagnosed?

    There are several diagnostic tests currently are available for the diagnosis of hepatitis C infection. They can be categorized according to the way the tests are used.

    Screening tests are tests that are used to diagnose a condition or disease among individuals not known to have the disease. They are particularly useful for individuals who have risk factors for the condition or disease.

    The first step in screening for hepatitis C infection is to test blood for the antibody to hepatitis C using an enzyme mmuno-assays (EIAs). If the EIA test is negative (does not find the antibody), the patient is assumed to be free of hepatitis C. It takes several weeks (up to six months) for antibodies to develop after the initial infection with hepatitis C, so this screening test may miss a few newly-infected individuals. The EIA screening tests are very good (specific); if the test is positive the probability of having hepatitis C infection is greater than 99%.

    Recombinant immunoblot assay (RIBA) is used to confirm the positive results of EIAs since occasionally a positive EIA is a false positive, that is, the test is positive when Hepatitis C is not present. Although the direct detection of HCV RNA (HCV PCR) also is widely used to confirm the HCV infection, RIBA still is useful to differentiate false positive results in the few individuals whose immune systems have eliminated the virus but still have antibodies left over from the resolved infection.

    As previously described, HCV contains RNA. Several tests (assays) are available to measure the amount of HCV RNA in a person's blood. These tests are referred to as molecular tests because they examine the virus at the molecular level. A single negative test for RNA does not mean that there is no infection because the virus may appear in the blood intermittently or may exist in small amounts. Newer tests have helped by detecting smaller and smaller amounts of virus in the blood.

    Testing for RNA is useful in determining whether or not a patient has circulating virus in the blood (viremia). Hence, it can be used to confirm that a positive EIA/ELISA truly reflects active HCV infection.

    RNA testing also should be done in individuals who may have been recently exposed to hepatitis C. HCV RNA testing is more sensitive (that is, will detect more cases) than the conventional EIA testing in this setting. The reason for this greater sensitivity is that it may take a person several weeks after exposure to hep C to develop the antibodies that give rise to a positive EIA, whereas HCV RNA becomes detectable one to three weeks after exposure. Finally, HCV RNA testing may be helpful to assess a patient's response to treatment at certain time points during antiviral therapy (see treatment of hepatitis C below).

    Currently, an anti-hepatitis C test is recommended as a hepatitis C screening test, and if the result is positive, current infection should be confirmed by a sensitive HCV RNA test. HCV RNA testing also should be done before starting any therapy. If a person is negative on screening test, no further testing is required, but if exposure to hepatitis C persists (for example, drug users) the test should be repeat at regular interval (i.e., annually). Patients whose immune systems are suppressed, including patients with HIV infection, should have HCV RNA testing to exclude hepatitis C infection. Blood tests also have been developed to identify subtypes of HCV, referred to as genotypes. This information is used to help guide treatment since genotypes respond differently to treatment. Genotype identification is recommended prior to initiation of treatment to guide selection of the most appropriate antiviral regimen.

    The table below provides guidelines for interpreting the results of testing for HCV antibodies by EIA and RIBA and for hepatitis C virus RNA. These are standard interpretations, but it is important to remember that the diagnosis of hepatitis C infection should be made by an experienced clinician who is familiar with the patient's medical history.

    Anti-HCV (ELISA/EIA) Anti-HCV (RIBA) HCV RNA Interpretation Negative Negative Negative No infection Positive Positive Positive Ongoing infection Positive Positive Negative Past or current infection. Additional or repeat testing should be done to exclude fluctuating or low levels of virus. Positive Negative Negative False positive ELISA; no infection Positive Indeterminate Negative Situation unclear, consider additional testing Negative Negative Positive New (acute) hepatitis C infection or chronic hepatitis C infection in an immunocompromised person unable to make adequate antibodies.

    What about liver biopsy in the diagnosis of chronic hepatitis C?

    Blood tests can tell the clinician whether hepatitis C is present but cannot tell the level of liver damage that has occurred. Liver biopsy allows the clinician to determine how much inflammation and scarring is present by examining a small sample of liver tissue. Liver biopsy gives information useful in the decision to initiate therapy. Significant liver damage is a risk factor for other conditions such as hepatocellular carcinoma and esophageal varices. Liver biopsy may be recommended when the clinician is uncertain about whether to begin treatment or wishes to monitor the response within the liver to therapy.

    It is possible to measure liver stiffness with transient elastography, a safe non-invasive test. Stiffer livers mean that advanced liver fibrosis or cirrhosis may be present; however such tests do not completely replace the need for liver biopsy in routine clinical practice.

    Several batteries of blood tests also have been found to be useful in diagnosing cirrhosis; however, like transient elastography, these tests have not completely replaced the need for liver biopsy.

    What is the treatment for hepatitis C infection?

    There are six genotypes of hepatitis C, and they may respond differently to treatment. Careful screening is necessary before starting treatment to determine the best treatment for the patient.

    Combination antiviral therapy with interferon injection and oral ribavirin (Rebetol, Copegus, Ribasphere, RibaPak, Moderiba) has been the mainstay of hepatitis C treatment in the past. Unfortunately, interferon is not widely available globally, it is not always well tolerated, some virus genotypes respond better to interferon than others, many people who take interferon do not finish their treatment, and only 60% of patients respond to the treatment. This means that while hepatitis C is generally considered to be a curable disease, for many people this was not a reality.

    Learn more about: Rebetol | Copegus

    Pegylated interferon: Interferons are a family of naturally occurring proteins that are produced by the body to fight viral infections. To produce pegylated interferon, the interferon is processed by attaching ethylene glycol to it. This process is called pegylation and it slows the elimination of interferon from the body so that its effects are more prolonged. There are currently two types of pegylated interferons.

    • pegylated interferon alpha 2b (Peg-Intron A), and
    • pegylated interferon alpha 2a (Pegasys).

    Learn more about: Peg-Intron | Pegasys

    Both pegylated interferon alpha 2b and 2a; are given as a subcutaneous injection once a week.

    Optimally, pegylated interferon therapy should be combined with oral ribavirin. In persons who cannot take ribavirin, monotherapy with pegylated interferon may be used; however, monotherapy has been shown to achieve sustained virologic response rates of only25%. Older preparations (nonpegylated forms) of interferon are even less effective than pegylated interferon.

    Ribavirin: The antiviral agent, ribavirin (Rebetol, Copegus), is a nucleoside analogue that is taken by mouth. Nucleoside analogues are man-made molecules that closely resemble the biochemical units that make up genetic material (RNA and DNA). Ribavirin works by fooling the virus into using it instead of the normal building blocks of RNA, thereby slowing viral reproduction. Ribavirin has not worked well when used alone for hepatitis C.

    Combined pegylated interferon and ribavirin: Combined therapy with both pegylated interferon and ribavirin produces a sustained virologic response or cure in 28% to 50% of patients with genotype 1. (Genotype 1 is the most common genotype in the U.S., but also the most resistant to treatment.) For unknown reasons, response rates are lower in African American persons and higher in Caucasians. In patients with genotype 2, sustained response rates are higher (76% to 82%). Duration of therapy depends on the genotype. Recommended duration of treatment for Genotype 1 is 48 weeks and for genotype 2 and 3 is 24 weeks.

    Combination therapy is associated with more side effects than therapy with pegylated interferon alone. (See below.) In research studies, up to 20% of patients receiving combination therapy required a reduction in the doses or discontinuation of therapy because of the side effects. Nevertheless, combination therapy represented significant progress in the treatment of chronic hepatitis C.

    Some patients treated successfully with combination therapy still have detectable virus after 24 weeks of treatment. Few of these patients go on to have a sustained response. Therefore, patients on combination therapy should have hepatitis C virus RNA measured at 24 weeks of therapy. In those who are still positive for the virus at that time, consideration is given to stopping treatment, since the chance of a sustained response with further treatment is small.

    Newer drugs and therapeutic medications for hepatitis C

    Scientific advances have led to the development of new drugs for hepatitis C, which may be more effective and better tolerated than existing therapies. There are few newer therapeutic medications in the market, which are approved by FDA, and many others are in process of development.

    Telaprevir (Incivek) and boceprevir (Victrelis) are therapeutic drugs used in addition to interferon and ribavirin. These combinations are commonly known as triple therapy (comprising of three medications- interferon, ribavirin and a new agent). The response to triple therapy was better than with pegylated interferon and ribavirin, reaching approximately 80%. Telaprevir (Incivek) was withdrawn from the market in 2014 by the manufacturer due to the availability of better drugs.

    Learn more about: Incivek | Victrelis

    Sofosbuvir (Sovaldi) and simeprevir (Olysio) are oral therapeutic drugs, which were approved by the FDA in 2013. These drugs can be used in combination with ribavirin and interferon, but with simeprevir it is possible to eliminate the interferon. The effectiveness of treatment with these combinations of medications is extremely high (greater than 90%), and it now provides an all oral treatment.

    Learn more about: Sovaldi | Olysio

    Some of these new medications are also are known as direct acting antivirals (DAA) because they:

    • Directly attack and help kill the hepatitis C virus in the body
    • Are highly effective with a rate of sustained responses of >90%.
    • Are taken as all oral regimens i.e. pill only form

    Ledipasvir and sofosbuvir (Harvoni) is a combination that is taken as one pill once a day is the latest addition to the list of direct acting antivirals approved in 2014. With this therapy, the effectiveness is even greater with a rate of sustained responses of 94%-99% with fewer side effects. Duration of therapy also is reduced to 12 weeks (instead of the traditional 48 weeks with interferon and ribavirin).

    Learn more about: Harvoni

    Ombitasvir, paritaprevir and ritonavir co-packaged with dasabuvir tablets (Viekira Pak), another combination of oral direct acting antivirals was approved by the FDA in December 2014. The sustained response rate of this combination was 91%-100%. As these medications are very new, data is still limited, and more data is expected to be available in the near future.

    Many other medications are under investigation but are not approved yet. The latest treatment guidelines by American Association for the Study of Liver Disease (AASLD) and Infectious Disease Society of America (IDSA) recommends use of these newer medications (direct acting antivirals) as the primary treatment for hepatitis C infection and no longer recommend treatment with pegylated interferon and ribavirin. The choice of direct acting antiviral varies by specific virus genotype and the presence or absence of cirrhosis. In the U.S., specific insurance providers also might influence the choice due to the high cost of direct acting antivirals. Patients are encouraged to discuss these options with their physician on an individual basis.

    Who should receive antiviral therapy for hepatitis C virus infection?

    Patients with hepatitis C infection should discuss treatment options with a physician who is experienced in treating the disease.

    In the past, frequent side effects and ineffectiveness of treatment made decisions to treat or not to treat more difficult. Decisions to treat or not to treat focused on identifying patients who would be most likely to respond to therapy, and who were most likely to suffer liver-related damage without successful treatment. With the newer treatments that are safer and more effective, the decision making has become less complicated. Treatment is recommended in patients at increased risk for cirrhosis unless there are reasons that would make treatment unsafe. According to the American Association for the Study of Liver Disease (AASLD) and Infectious Disease Society of America (IDSA) these include patients with:

    • Persistent elevation of ALT (alanine aminotransferase, a liver enzyme in the blood)
    • High levels of HCV RNA in the blood
    • Evidence of early fibrosis (scarring) on imaging or moderate inflammation and injury of liver cells on liver biopsy
    • Liver transplant recipients
    • Coexisting liver disease or advanced kidney disease
    • Coexisting HIV and/or diabetes
    • Symptomatic hepatitis C infection (for example, with debilitating fatigue or other less severe extra hepatic manifestations)

    Potential for transmission of hepatitis C is an additional consideration that might prioritize treatment for a given patient, including:

    • Men who have sex with men (MSM) with high-risk sexual practices
    • Active injection drug users
    • Incarcerated persons
    • Persons on long-term hemodialysis
    • Hepatitis C-infected women of child-bearing potential wishing to get pregnant

    These are general guidelines. Patients and health-care professionals may decide that treatment is needed for other reasons. For example, hepatitis C infection may cause ryoglobulinemia. (See above.) Persistent cryoglobulinemia may be a reason for treating hepatitis C. Availability of newer therapies with direct acting antivirals; highly effective, all-oral regimens have allowed more and more patients to be able to receive treatments.

    Who should not receive treatment with antiviral therapy?

    Individuals who should not be treated with antiviral therapy include those who:

    • Are unable to comply with the treatment schedule
    • Have reasons that may make treatment unsafe (for example, allergy to the medications)
    • Have received a solid organ transplant
    • Are pregnant or unwilling to practice adequate birth control (contraception) during treatment
    • Have reversible serious untreated conditions such as unstable heart disease, uncontrolled high blood pressure, or untreated major depression.

    Patients with unstable (decompensated) cirrhosis are at higher risk for complications with treatment and in the past usually have not received treatment except in research settings. This is changing, however, since studies are beginning to show that even these patients can be treated safely and successfully. Fundamentally, the decision regarding antiviral therapy in chronic hepatitis C infection should be tailored to the individual patient with careful consideration of the risks and benefits.

    All patients with hepatitis C should be:

    • Vaccinated against hepatitis B and hepatitis A
    • Counseled regarding abstinence from alcohol use.
    • Counseled on measures to prevent the spread of hepatitis C
    • Tested for HIV (The behaviors for people with hepatitis C overlap with those of people with HIV, and all patients with hepatitis C should be tested for HIV.)

    Ongoing and continuing evaluation for advanced fibrosis using liver biopsy, imaging, or noninvasive blood tests and liver stiffness is also very important for all persons with hepatitis C infection to help make appropriate decisions regarding treatment. Development of new complications might change the course of disease; the need for more frequent monitoring or the decision to treat or not treat.

    What is hepatitis C infection?

    Hepatitis C infection is an infection of the liver caused by the hepatitis C virus (HCV). It is difficult for the human immune system to eliminate hepatitis C from the body, and infection with hep C usually becomes chronic. Over decades, chronic infection with hepatitis C damages the liver and can cause liver failure. In the U.S., the number of new cases of hepatitis C infection has declined from a peak of 200,000 annually to about 17,000 in 2007. When the virus first enters the body, however, there usually are no symptoms, so these numbers are estimates. Up to 85% of newly-infected people fail to eliminate the virus and become chronically infected. In the U.S., more than three million people are chronically infected with hepatitis C. Infection is most commonly detected among people who are 40 to 60 years of age, reflecting the high rates of infection in the 1970s and 1980s. There are 8,000 to 10,000 deaths each year in the US related to hepatitis C infection. Hepatitis C infection is the leading cause of liver transplantation in the US and is a risk factor for liver cancer.

    What is the nature (biology) of the hepatitis C virus?

    'Hepatitis' means inflammation of the liver. Hepatitis C is one of several viruses that can cause hepatitis. It is unrelated to the other common hepatitis viruses (for example, hepatitis A or hepatitis B). Hepatitis C is a member of the Flaviviridae family of viruses. Other members of this family of viruses include those that cause yellow fever and dengue.

    Viruses belonging to this family all have ribonucleic acid (RNA) as their genetic material. All hepatitis C viruses are made up of an outer coat (envelope) and contain enzymes and proteins that allow the virus to reproduce within the cells of the body, in particular, the cells of the liver. Although this basic structure is common to all hepatitis C viruses, there are at least six distinctly different strains of the virus which have different genetic profiles (genotypes 1 to 6). In the U. S., genotype 1 is the most common form of hepatitis C. Even within a single genotype there may be some variations (genotype 1a and 1b, for example). Genotyping is important to guide treatment because some viral genotypes respond better to therapy than others. The genetic diversity of hepatitis C is one reason that it has been difficult to develop an effective vaccine since the vaccine must protect against all genotypes.

    How does liver damage occur in hepatitis C infection?

    The presence of hepatitis C in the liver triggers the human immune system, which leads to inflammation. Over time (usually decades), prolonged inflammation may cause scarring. Extensive scarring in the liver is called cirrhosis. When the liver becomes cirrhotic, it fails to perform its normal functions, (liver failure), and this leads to serious complications and even death. Cirrhotic livers also are more prone to become cancerous.

    What are the symptoms of hepatitis C infection?

    About 75% of people have no symptoms when they first acquire hepatitis C infection. The remaining 25% may complain of:

    • fatigue,
    • loss of appetite,
    • muscle aches, or
    • fever.

    Yellowing of the skin or eyes (jaundice) is rare at this early stage of infection.

    Over time, people with chronic infection may begin to experience the effects of the persistent inflammation of the liver caused by the immune reaction to the virus. Blood tests may show elevated levels of liver enzymes, a sign of liver damage, which is often the first suggestion that the infection may be present. Patients may become easily fatigued or complain of nonspecific symptoms.

    As cirrhosis develops, symptoms increase and may include:

    • weakness,
    • loss of appetite,
    • weight loss,
    • breast enlargement in men (gynecomastia),
    • a rash on the palms,
    • difficulty with the clotting of blood, and
    • spider-like blood vessels on the skin.

    In patients with advanced cirrhosis, the liver begins to fail. This is a life-threatening problem. Confusion and even coma (encephalopathy) may result from the inability of the liver to process certain toxic substances.

    Increased pressure in the blood vessels of the liver (portal hypertension) may cause fluid to build up in the abdominal cavity (ascites) and result in engorged veins in the swallowing tube (esophageal varices) that tear easily and can bleed suddenly and massively. Portal hypertension also can cause kidney failure or an enlarged spleen resulting in a decrease of red blood cells (anemia), or the development of low platelets (thrombocytopenia), which can promote bleeding.

    In advanced cirrhosis, liver failure causes decreased production of clotting factors. Patients with advanced cirrhosis often develop jaundice because the damaged liver is unable to eliminate a yellow compound, called bilirubin that is formed from the hemoglobin of old red blood cells.

    How is hepatitis C spread, and is it contagious?

    • Hepatitis C is spread (transmitted) most efficiently through exposure to infected blood.
    • The most common route of transmission is needles shared among users of illicit drugs.
    • Accidental needle-sticks in healthcare workers also have transmitted the virus. The average risk of getting hepatitis C infection from a stick with a contaminated needle is 1.8% (range 0% to 10%)
    • Prior to 1992, some people acquired the hepatitis C infection from transfusions of blood or blood products. Since 1992, all blood products have been screened for hepatitis C, and cases of hepatitis C due to blood transfusion now are extremely rare.
    • Hepatitis C infection also can be passed from mother to unborn child. Approximately 4 of every 100 infants born to hepatitis C-infected mothers become infected with the virus.
    • A small number of cases are transmitted through sexual intercourse. The risk of transmission of hepatitis C from an infected individual to a non-infected spouse or sexual partner without the use of condoms over a lifetime has been estimated to be between 1% and 4%.
    • Poor infection control practices during tattooing and body piercing potentially can lead to spread of infection. (This has not been reported in licensed, commercial tattooing facilities where it has been studied.)
    • Finally, there have been some outbreaks of hepatitis C when instruments exposed to blood have been re-used without appropriate cleaning between patients.

    What conditions beyond the liver are associated with hepatitis C infection?

    Most of the signs and symptoms of hepatitis C infection relate to the liver. Less commonly, hepatitis C infection causes conditions beyond of the liver.

    • Hepatitis C infection can cause the body to produce unusual antibodies called 'cryoglobulins.' These cryoglobulins cause inflammation of the arteries (vasculitis) which may damage the skin, joints, and kidneys. Patients with cryoglobulinemia (cryoglobulins in the blood) may have:
      • joint pain,
      • arthritis,
      • a raised purple rash on the legs, and
      • generalized pain or swelling of their bodies.
    • In addition, these patients may develop Raynaud's phenomenon in which the fingers and toes turn color (white, then purple, then red) and become painful at cold temperatures.
    • Hepatitis C is known to be associated with two skin conditions, lichen planus and porphyria cutanea tarda.
    • For reasons that are unclear, diabetes is three times more common among patients with chronic hepatitis C infection than in the general population.
    • Low platelet counts may occur as a result of the destruction of platelets by antibodies.
    • Hepatitis C also is associated with B-cell lymphoma, a cancer of the lymph system.

    Who is at high risk and should be tested for hepatitis C infection?

    Currently, screening for hepatitis C is not recommended as part of a routine physical examination. Rather, testing should be done among:

    • Individuals at high risk for infection including current and past users of illicit injectable drugs, users of intranasal illicit drugs, and persons exposed to infected blood or organs from infected persons
    • Children born to chronically infected mothers
    • People who received blood, blood products, or transplanted organs prior to 1992 (before testing of blood for hepatitis C was begun)
    • Persons with abnormal levels of liver enzymes in the blood
    • Healthcare workers with work-related needle sticks or injuries
    • Persons with body tattoos from unregulated tattoo parlors
    • Persons who were ever incarcerated because of the high prevalence of hepatitis C in the prison population
    • Persons infected with hepatitis B or HIV virus since this suggests illicit drug use
    • Persons on long term hemodialysis which exposes them to hepatitis C infection

    These are not the only circumstances under which testing for hepatitis C infection may be done. In general, testing is recommended when exposure to the virus is suspected.

    What is the usual progression of chronic hepatitis C infection?

    Our understanding of the natural progression (history) of hepatitis C infection still is evolving.

    Of every 100 people infected with hepatitis C, it is estimated that:

    • 75 to 85 will become chronically infected,
    • 60 to 70 will develop liver disease,
    • 5 to 20 will develop cirrhosis, and
    • 1 to 5 will die from complications of liver disease such as cirrhosis or liver cancer.

    Scientists are learning more about what causes some people to have milder problems and others to have serious complications. Drinking alcohol and acquiring other hepatitis viruses are risk factors for severe disease. Thus, persons who have chronic hepatitis C infection should avoid drinking alcohol and should be vaccinated against the other hepatitis viruses (A and B).

    Live cancer (hepatocellular carcinoma) is associated with cirrhosis due to chronic hepatitis C infection. Some experts recommend screening patients with hepatitis C infection and cirrhosis for liver cancer every six months with abdominal ultrasound examinations and a blood test for alpha-fetoprotein (a marker for liver cancer). The effectiveness of this screening is unclear.

    How is hepatitis C diagnosed?

    There are several diagnostic tests currently are available for the diagnosis of hepatitis C infection. They can be categorized according to the way the tests are used.

    Screening tests are tests that are used to diagnose a condition or disease among individuals not known to have the disease. They are particularly useful for individuals who have risk factors for the condition or disease.

    The first step in screening for hepatitis C infection is to test blood for the antibody to hepatitis C using an enzyme mmuno-assays (EIAs). If the EIA test is negative (does not find the antibody), the patient is assumed to be free of hepatitis C. It takes several weeks (up to six months) for antibodies to develop after the initial infection with hepatitis C, so this screening test may miss a few newly-infected individuals. The EIA screening tests are very good (specific); if the test is positive the probability of having hepatitis C infection is greater than 99%.

    Recombinant immunoblot assay (RIBA) is used to confirm the positive results of EIAs since occasionally a positive EIA is a false positive, that is, the test is positive when Hepatitis C is not present. Although the direct detection of HCV RNA (HCV PCR) also is widely used to confirm the HCV infection, RIBA still is useful to differentiate false positive results in the few individuals whose immune systems have eliminated the virus but still have antibodies left over from the resolved infection.

    As previously described, HCV contains RNA. Several tests (assays) are available to measure the amount of HCV RNA in a person's blood. These tests are referred to as molecular tests because they examine the virus at the molecular level. A single negative test for RNA does not mean that there is no infection because the virus may appear in the blood intermittently or may exist in small amounts. Newer tests have helped by detecting smaller and smaller amounts of virus in the blood.

    Testing for RNA is useful in determining whether or not a patient has circulating virus in the blood (viremia). Hence, it can be used to confirm that a positive EIA/ELISA truly reflects active HCV infection.

    RNA testing also should be done in individuals who may have been recently exposed to hepatitis C. HCV RNA testing is more sensitive (that is, will detect more cases) than the conventional EIA testing in this setting. The reason for this greater sensitivity is that it may take a person several weeks after exposure to hep C to develop the antibodies that give rise to a positive EIA, whereas HCV RNA becomes detectable one to three weeks after exposure. Finally, HCV RNA testing may be helpful to assess a patient's response to treatment at certain time points during antiviral therapy (see treatment of hepatitis C below).

    Currently, an anti-hepatitis C test is recommended as a hepatitis C screening test, and if the result is positive, current infection should be confirmed by a sensitive HCV RNA test. HCV RNA testing also should be done before starting any therapy. If a person is negative on screening test, no further testing is required, but if exposure to hepatitis C persists (for example, drug users) the test should be repeat at regular interval (i.e., annually). Patients whose immune systems are suppressed, including patients with HIV infection, should have HCV RNA testing to exclude hepatitis C infection. Blood tests also have been developed to identify subtypes of HCV, referred to as genotypes. This information is used to help guide treatment since genotypes respond differently to treatment. Genotype identification is recommended prior to initiation of treatment to guide selection of the most appropriate antiviral regimen.

    The table below provides guidelines for interpreting the results of testing for HCV antibodies by EIA and RIBA and for hepatitis C virus RNA. These are standard interpretations, but it is important to remember that the diagnosis of hepatitis C infection should be made by an experienced clinician who is familiar with the patient's medical history.

    Anti-HCV (ELISA/EIA) Anti-HCV (RIBA) HCV RNA Interpretation Negative Negative Negative No infection Positive Positive Positive Ongoing infection Positive Positive Negative Past or current infection. Additional or repeat testing should be done to exclude fluctuating or low levels of virus. Positive Negative Negative False positive ELISA; no infection Positive Indeterminate Negative Situation unclear, consider additional testing Negative Negative Positive New (acute) hepatitis C infection or chronic hepatitis C infection in an immunocompromised person unable to make adequate antibodies.

    What about liver biopsy in the diagnosis of chronic hepatitis C?

    Blood tests can tell the clinician whether hepatitis C is present but cannot tell the level of liver damage that has occurred. Liver biopsy allows the clinician to determine how much inflammation and scarring is present by examining a small sample of liver tissue. Liver biopsy gives information useful in the decision to initiate therapy. Significant liver damage is a risk factor for other conditions such as hepatocellular carcinoma and esophageal varices. Liver biopsy may be recommended when the clinician is uncertain about whether to begin treatment or wishes to monitor the response within the liver to therapy.

    It is possible to measure liver stiffness with transient elastography, a safe non-invasive test. Stiffer livers mean that advanced liver fibrosis or cirrhosis may be present; however such tests do not completely replace the need for liver biopsy in routine clinical practice.

    Several batteries of blood tests also have been found to be useful in diagnosing cirrhosis; however, like transient elastography, these tests have not completely replaced the need for liver biopsy.

    What is the treatment for hepatitis C infection?

    There are six genotypes of hepatitis C, and they may respond differently to treatment. Careful screening is necessary before starting treatment to determine the best treatment for the patient.

    Combination antiviral therapy with interferon injection and oral ribavirin (Rebetol, Copegus, Ribasphere, RibaPak, Moderiba) has been the mainstay of hepatitis C treatment in the past. Unfortunately, interferon is not widely available globally, it is not always well tolerated, some virus genotypes respond better to interferon than others, many people who take interferon do not finish their treatment, and only 60% of patients respond to the treatment. This means that while hepatitis C is generally considered to be a curable disease, for many people this was not a reality.

    Learn more about: Rebetol | Copegus

    Pegylated interferon: Interferons are a family of naturally occurring proteins that are produced by the body to fight viral infections. To produce pegylated interferon, the interferon is processed by attaching ethylene glycol to it. This process is called pegylation and it slows the elimination of interferon from the body so that its effects are more prolonged. There are currently two types of pegylated interferons.

    • pegylated interferon alpha 2b (Peg-Intron A), and
    • pegylated interferon alpha 2a (Pegasys).

    Learn more about: Peg-Intron | Pegasys

    Both pegylated interferon alpha 2b and 2a; are given as a subcutaneous injection once a week.

    Optimally, pegylated interferon therapy should be combined with oral ribavirin. In persons who cannot take ribavirin, monotherapy with pegylated interferon may be used; however, monotherapy has been shown to achieve sustained virologic response rates of only25%. Older preparations (nonpegylated forms) of interferon are even less effective than pegylated interferon.

    Ribavirin: The antiviral agent, ribavirin (Rebetol, Copegus), is a nucleoside analogue that is taken by mouth. Nucleoside analogues are man-made molecules that closely resemble the biochemical units that make up genetic material (RNA and DNA). Ribavirin works by fooling the virus into using it instead of the normal building blocks of RNA, thereby slowing viral reproduction. Ribavirin has not worked well when used alone for hepatitis C.

    Combined pegylated interferon and ribavirin: Combined therapy with both pegylated interferon and ribavirin produces a sustained virologic response or cure in 28% to 50% of patients with genotype 1. (Genotype 1 is the most common genotype in the U.S., but also the most resistant to treatment.) For unknown reasons, response rates are lower in African American persons and higher in Caucasians. In patients with genotype 2, sustained response rates are higher (76% to 82%). Duration of therapy depends on the genotype. Recommended duration of treatment for Genotype 1 is 48 weeks and for genotype 2 and 3 is 24 weeks.

    Combination therapy is associated with more side effects than therapy with pegylated interferon alone. (See below.) In research studies, up to 20% of patients receiving combination therapy required a reduction in the doses or discontinuation of therapy because of the side effects. Nevertheless, combination therapy represented significant progress in the treatment of chronic hepatitis C.

    Some patients treated successfully with combination therapy still have detectable virus after 24 weeks of treatment. Few of these patients go on to have a sustained response. Therefore, patients on combination therapy should have hepatitis C virus RNA measured at 24 weeks of therapy. In those who are still positive for the virus at that time, consideration is given to stopping treatment, since the chance of a sustained response with further treatment is small.

    Newer drugs and therapeutic medications for hepatitis C

    Scientific advances have led to the development of new drugs for hepatitis C, which may be more effective and better tolerated than existing therapies. There are few newer therapeutic medications in the market, which are approved by FDA, and many others are in process of development.

    Telaprevir (Incivek) and boceprevir (Victrelis) are therapeutic drugs used in addition to interferon and ribavirin. These combinations are commonly known as triple therapy (comprising of three medications- interferon, ribavirin and a new agent). The response to triple therapy was better than with pegylated interferon and ribavirin, reaching approximately 80%. Telaprevir (Incivek) was withdrawn from the market in 2014 by the manufacturer due to the availability of better drugs.

    Learn more about: Incivek | Victrelis

    Sofosbuvir (Sovaldi) and simeprevir (Olysio) are oral therapeutic drugs, which were approved by the FDA in 2013. These drugs can be used in combination with ribavirin and interferon, but with simeprevir it is possible to eliminate the interferon. The effectiveness of treatment with these combinations of medications is extremely high (greater than 90%), and it now provides an all oral treatment.

    Learn more about: Sovaldi | Olysio

    Some of these new medications are also are known as direct acting antivirals (DAA) because they:

    • Directly attack and help kill the hepatitis C virus in the body
    • Are highly effective with a rate of sustained responses of >90%.
    • Are taken as all oral regimens i.e. pill only form

    Ledipasvir and sofosbuvir (Harvoni) is a combination that is taken as one pill once a day is the latest addition to the list of direct acting antivirals approved in 2014. With this therapy, the effectiveness is even greater with a rate of sustained responses of 94%-99% with fewer side effects. Duration of therapy also is reduced to 12 weeks (instead of the traditional 48 weeks with interferon and ribavirin).

    Learn more about: Harvoni

    Ombitasvir, paritaprevir and ritonavir co-packaged with dasabuvir tablets (Viekira Pak), another combination of oral direct acting antivirals was approved by the FDA in December 2014. The sustained response rate of this combination was 91%-100%. As these medications are very new, data is still limited, and more data is expected to be available in the near future.

    Many other medications are under investigation but are not approved yet. The latest treatment guidelines by American Association for the Study of Liver Disease (AASLD) and Infectious Disease Society of America (IDSA) recommends use of these newer medications (direct acting antivirals) as the primary treatment for hepatitis C infection and no longer recommend treatment with pegylated interferon and ribavirin. The choice of direct acting antiviral varies by specific virus genotype and the presence or absence of cirrhosis. In the U.S., specific insurance providers also might influence the choice due to the high cost of direct acting antivirals. Patients are encouraged to discuss these options with their physician on an individual basis.

    Who should receive antiviral therapy for hepatitis C virus infection?

    Patients with hepatitis C infection should discuss treatment options with a physician who is experienced in treating the disease.

    In the past, frequent side effects and ineffectiveness of treatment made decisions to treat or not to treat more difficult. Decisions to treat or not to treat focused on identifying patients who would be most likely to respond to therapy, and who were most likely to suffer liver-related damage without successful treatment. With the newer treatments that are safer and more effective, the decision making has become less complicated. Treatment is recommended in patients at increased risk for cirrhosis unless there are reasons that would make treatment unsafe. According to the American Association for the Study of Liver Disease (AASLD) and Infectious Disease Society of America (IDSA) these include patients with:

    • Persistent elevation of ALT (alanine aminotransferase, a liver enzyme in the blood)
    • High levels of HCV RNA in the blood
    • Evidence of early fibrosis (scarring) on imaging or moderate inflammation and injury of liver cells on liver biopsy
    • Liver transplant recipients
    • Coexisting liver disease or advanced kidney disease
    • Coexisting HIV and/or diabetes
    • Symptomatic hepatitis C infection (for example, with debilitating fatigue or other less severe extra hepatic manifestations)

    Potential for transmission of hepatitis C is an additional consideration that might prioritize treatment for a given patient, including:

    • Men who have sex with men (MSM) with high-risk sexual practices
    • Active injection drug users
    • Incarcerated persons
    • Persons on long-term hemodialysis
    • Hepatitis C-infected women of child-bearing potential wishing to get pregnant

    These are general guidelines. Patients and health-care professionals may decide that treatment is needed for other reasons. For example, hepatitis C infection may cause ryoglobulinemia. (See above.) Persistent cryoglobulinemia may be a reason for treating hepatitis C. Availability of newer therapies with direct acting antivirals; highly effective, all-oral regimens have allowed more and more patients to be able to receive treatments.

    Who should not receive treatment with antiviral therapy?

    Individuals who should not be treated with antiviral therapy include those who:

    • Are unable to comply with the treatment schedule
    • Have reasons that may make treatment unsafe (for example, allergy to the medications)
    • Have received a solid organ transplant
    • Are pregnant or unwilling to practice adequate birth control (contraception) during treatment
    • Have reversible serious untreated conditions such as unstable heart disease, uncontrolled high blood pressure, or untreated major depression.

    Patients with unstable (decompensated) cirrhosis are at higher risk for complications with treatment and in the past usually have not received treatment except in research settings. This is changing, however, since studies are beginning to show that even these patients can be treated safely and successfully. Fundamentally, the decision regarding antiviral therapy in chronic hepatitis C infection should be tailored to the individual patient with careful consideration of the risks and benefits.

    All patients with hepatitis C should be:

    • Vaccinated against hepatitis B and hepatitis A
    • Counseled regarding abstinence from alcohol use.
    • Counseled on measures to prevent the spread of hepatitis C
    • Tested for HIV (The behaviors for people with hepatitis C overlap with those of people with HIV, and all patients with hepatitis C should be tested for HIV.)

    Ongoing and continuing evaluation for advanced fibrosis using liver biopsy, imaging, or noninvasive blood tests and liver stiffness is also very important for all persons with hepatitis C infection to help make appropriate decisions regarding treatment. Development of new complications might change the course of disease; the need for more frequent monitoring or the decision to treat or not treat.

    Source: http://www.rxlist.com

    About 75% of people have no symptoms when they first acquire hepatitis C infection. The remaining 25% may complain of:

    • fatigue,
    • loss of appetite,
    • muscle aches, or
    • fever.

    Yellowing of the skin or eyes (jaundice) is rare at this early stage of infection.

    Over time, people with chronic infection may begin to experience the effects of the persistent inflammation of the liver caused by the immune reaction to the virus. Blood tests may show elevated levels of liver enzymes, a sign of liver damage, which is often the first suggestion that the infection may be present. Patients may become easily fatigued or complain of nonspecific symptoms.

    As cirrhosis develops, symptoms increase and may include:

    • weakness,
    • loss of appetite,
    • weight loss,
    • breast enlargement in men (gynecomastia),
    • a rash on the palms,
    • difficulty with the clotting of blood, and
    • spider-like blood vessels on the skin.

    In patients with advanced cirrhosis, the liver begins to fail. This is a life-threatening problem. Confusion and even coma (encephalopathy) may result from the inability of the liver to process certain toxic substances.

    Increased pressure in the blood vessels of the liver (portal hypertension) may cause fluid to build up in the abdominal cavity (ascites) and result in engorged veins in the swallowing tube (esophageal varices) that tear easily and can bleed suddenly and massively. Portal hypertension also can cause kidney failure or an enlarged spleen resulting in a decrease of red blood cells (anemia), or the development of low platelets (thrombocytopenia), which can promote bleeding.

    In advanced cirrhosis, liver failure causes decreased production of clotting factors. Patients with advanced cirrhosis often develop jaundice because the damaged liver is unable to eliminate a yellow compound, called bilirubin that is formed from the hemoglobin of old red blood cells.

    Source: http://www.rxlist.com

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