HEPATITIS C

• ACRONYMS AND DEFINITIONS

• AASLD - American Association for the Study of Liver Diseases
• ACG - American College of Gastroenterology
• ALT - Alanine aminotransferase
• AST - Aspartate aminotransferase
• CDC - Centers for Disease Control and Prevention
• HCC - Hepatocellular carcinoma
• HCV - Hepatitis C virus
• IDSA - Infectious Diseases Society of America
• PegIFN - Pegylated interferon
• USPSTF - U.S. Preventive Services Task Force

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• OVERVIEW OF HEPATITIS

• Overview
• Viral hepatitis occurs when a virus infects the liver. A number of viruses including cytomegalovirus, Epstein-Barr virus, adenovirus, and others can infect the liver, but it is not a common site of infection for these viruses. Viruses that always infect the liver are designated by the letters A - G, and they cause the majority of viral hepatitis cases.

• Hepatitis A
• Overview
• Discovered in 1973
• Common virus - before widespread vaccination, up to 33% of US population would test positive for exposure
• Infection route
• Fecal-oral route (fecal-contaminated objects or food-sources reaching mouth)
• Incubation period for Hepatitis A is 15 - 50 days (average 30 days)
• Virus is excreted in the feces 1-2 weeks before symptoms and for 1 week afterwards
• Symptoms
• In many cases, will have mild or no symptoms
• May cause abrupt onset of diarrhea, nausea and vomiting, fever, and aching
• Jaundice, enlarged liver, and elevated liver enzymes may occur
• Symptoms usually resolve in 1-2 weeks, and liver enzymes typically return to normal by 3-6 months
• Treatment
• Supportive
• Long-term effects
• Rare
• Vaccine
• Yes [1,3]

• Hepatitis B
• See hepatitis B virus

• Hepatitis C
• Overview
• Formally referred to an "Non-A, Non-B virus"
• First cloned in 1989
• Common virus - worldwide infects about 180 million people
• Infection route
• Primary route of infection is blood-to-blood (needles, transfusions, etc.)
• Symptoms
• There are no symptoms in most cases
• Occasionally will have acute symptoms including jaundice, elevated liver enzymes, malaise, and nausea
• Treatment
• Very curable with modern therapy
• Long-term effects
• Cirrhosis and hepatocellular carcinoma
• Vaccine
• No [4]

• Hepatitis D
• Overview
• First described in 1977
• Hepatitis D is believed to infect 1% of the world's population. It is endemic in parts of Asia, Africa, Southern and Eastern Europe, the Middle East, and Brazil.
• Hepatitis D requires the presence of hepatitis B to replicate, so all patients with hepatitis D will also have hepatitis B
• Infection route
• The primary route of infection is blood-to-blood (needles, transfusions, etc.)
• IV drug abusers and men who have sex with men are at greater risk
• Symptoms / Diagnosis
• There are no symptoms in most cases
• Hepatitis D screening is performed with antibody testing (IgG), and a diagnosis is confirmed with hepatitis D RNA assays
• Treatment
• Pegylated interferon alpha for 12 months. Sustained response is low (25 - 30%), and relapse rates are high.
• Long-term effects
• Chronic hepatitis B/D infection progresses to cirrhosis in 70 - 80% of patients within 5 - 10 years. The risk of hepatocellular carcinoma is also increased compared to hepatitis B monoinfection.
• Vaccine
• Hepatitis B vaccination will help prevent [3,29]

• Hepatitis E
• Overview
• First identified in 1983
• More common in India and developing countries
• Infection route
• Fecal-oral route (fecal-contaminated objects or food-sources reaching mouth)
• Symptoms
• Brief period (1-2 weeks) of gastrointestinal symptoms including nausea, vomiting, abdominal pain, and jaundice
• May be asymptomatic in healthy patients
• In pregnant women, can cause severe infection including liver failure and death (10 - 25% of affected patients)
• Treatment
• Supportive in most
• Ribavirin and interferon may be used in immunosuppressed patients
• Long-term effects
• None in otherwise healthy patients
• May cause chronic infection with cirrhosis in immunosuppressed patients
• Vaccine
• None available
• Vaccines are being evaluated in trials [3,23]

• Hepatitis G
• Overview
• First identified in 1996
• Clinical importance of this virus is not well-defined
• Infection route
• Not completely defined
• Primary route of infection appears to be blood-to-blood (needles, transfusions, etc.)
• Symptoms
• Not well-defined
• Treatment
• None studied
• Long-term effects
• Not well-defined
• Vaccine
• No [5]

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• PREVALENCE OF HEPATITIS C

• Hepatitis C infects an estimated 180 million people worldwide
• In the United States, the estimated prevalence of hepatitis C among adults is 0.93%. About 52% of infected individuals live in 9 states: California, Texas, Florida, New York, Pennsylvania, Ohio, Michigan, Tennessee, and North Carolina. Hepatitis C is the leading cause of death from liver disease and the number one indication for liver transplantation. [6,27]

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• RISK FACTORS FOR HEPATITIS C

• IV drug abuse
• Number one risk factor in the U.S.
• Blood transfusion or organ transplant before 1992
• Blood and organs were not tested for hepatitis C before 1992
• Hemophiliacs who received clotting factors before 1987
• In 1987, processes to inactivate viruses were started
• Heterosexual intercourse
• The risk of transferring hepatitis C through heterosexual intercourse is low
• Studies of heterosexual couples who have been in long-term monogamous relationships where only one partner is infected have shown that the transfer rate is from 0 - 0.6% per year
• Current guidelines do not recommend that long-term monogamous couples (with one Hep C positive individual) use barrier protection to prevent hepatitis C transmission
• Individuals may choose to use barrier methods if they wish to lower the already negligible transmission rate [9]
• Perinatal (mother-to-child)
• Transmission rate for hepatitis C from mother-to-child during pregnancy range from 3 - 10%
• Maternal coinfection with HIV increases the transmission rate with some studies showing rates up to 25%
• Higher viral loads are associated with a greater risk of transmission
• There is no conclusive evidence that the mode of delivery ( C-section versus vaginal ) has an effect on transmission rates
• Longer rupture of membranes ( > 6 hours ) may increase the risk of transmission
• Breastfeeding (for up to one year) does not appear to increase the transmission rate [8,28]
• Tattoos and body piercings
• If performed under unsanitary conditions, tattoos and body piercings may transmit the virus
• Hemodialysis patients
• In the past, dialysis patients often received frequent blood transfusions which increased their risk for hepatitis C
• Patient-to-patient transfer of hepatitis C in dialysis units has occurred, but is rare today [10]

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• SCREENING FOR HEPATITIS C

• CDC recommendations
• Anyone who has ever injected illicit drugs
• Anyone born between 1945 - 1965 (baby boomers)
• Recipients of clotting factors before 1987 (typically hemophiliacs)
• Recipients of blood transfusions before 1992
• Recipients of organ transplants before 1992
• Chronic hemodialysis patients
• People with known exposure - ex. needlesticks in healthcare workers
• People with HIV infection
• Children born to hepatitis C positive mothers [14]


• USPSTF recommendations
• The USPSTF recommends screening all adults 18 - 79 years old for hepatitis C. Most adults only need to be screened once. Patients with ongoing risk factors should be screened periodically.


• AASLD, IDSA, ACG
• In addition to the CDC recommendations above, the AASLD, IDSA, and ACG recommend testing the following people:
• Current sexual partners of hepatitis C infected individuals
• People with unexplained elevated liver enzymes
• Healthcare workers with a mucosal exposure to hepatitis C-positive blood [6]

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• DIAGNOSIS

• Exposure vs chronic infection
• When a person is exposed to hepatitis C, one of two things can happen:
• Scenario 1 - The immune system clears the infection and it is gone (about 15 - 45% of the time)
• Scenario 2 - The virus is able to infect the liver and a chronic infection is established (about 55 - 85% of the time) [6]


• Hepatitis C antibodies
• In both scenarios above, antibodies to hepatitis C will develop
• The test will turn positive 4 - 10 weeks after exposure in most patients
• The test will be positive in > 97% of patients 6 months after exposure [14]


• Hepatitis C viral load
• In Scenario 1, hepatitis C viral load will be detectable starting 2-3 weeks after exposure and remain detectable for 8 -16 weeks before becoming undetectable [6]
• In Scenario 2, hepatitis C viral load will remain detectable greater than 16 weeks after exposure [14]


• Exception
• There is one exception to the above rules if tests are done soon after exposure (between 2 - 10 weeks):
• Hepatitis C viral load may be positive and antibodies negative

• Testing exposed newborns
• Hepatitis C antibodies
• Mothers with hepatitis C infection will pass their antibodies on to their infants during pregnancy
• These antibodies will persist in the infant for up to 2 years in some cases
• In one study, maternal hepatitis C antibodies were present in uninfected infants at the following time points:
• Birth - 96.8%
• 6 months - 85%
• 9 months - 50%
• 12 months - 15.3%
• 18 months - 1.6%
• 24 months - 1.0% [8]
• Professional guidelines
• Current guidelines recommend antibody testing of infants born to HCV positive mothers at 18 months of age or later (not sooner) [14]


• Hepatitis C viral load (HCV RNA)
• Maternal HCV RNA may be present in a newborn at birth
• After birth, HCV RNA appears to quickly disappear in uninfected infants, but remains in infected infants [8]
• Professional guidelines
• Newborns may be tested for HCV RNA after 2 months of age
• The test should be repeated in 2 months regardless of the results [14]

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• NATURAL COURSE OF UNTREATED HCV

• Cirrhosis
• Over the course of 25 - 30 years of infection, approximately 5 - 25% of HCV-infected individuals will develop cirrhosis [6]
• Women and children have a lower risk of cirrhosis with rates of 1 - 3% over 20 - 30 years [6,7]
• Other factors that increase the risk of cirrhosis include:
• Advanced age
• Obesity
• Alcohol abuse
• Hepatitis B infection
• HIV infection
• Hemochromatosis (iron storage disease)

• Hepatocellular carcinoma (HCC)
• Patients who develop cirrhosis from HCV have an annual incidence of hepatocellular carcinoma of 1 - 4% [7]
• See post-treatment surveillance for recommendations on monitoring patients for HCC
• Successful treatment of hepatitis C appears to decrease the risk of HCC. The cohort study detailed below followed the incidence of HCC in a group of veterans who were treated for HCV.


• STUDY
  Risk of HCC after Successful Treatment of HCV, Hepatology (2016) [PubMed abstract]
• A retrospective cohort study published in Hepatology followed 33,005 veterans who received treatment for hepatitis C of whom 10,817 were treated successfully
• After 30,562 person-years of follow-up, the following was seen:
• Patients with successful treatment (annual incidence of HCC): 0.3%
• Patients with successful treatment and cirrhosis (annual incidence of HCC): 1.39%
• Patients treated unsuccessfully (annual incidence of HCC): 1.3%
• Cirrhosis, successful treatment after the age of 64, diabetes, and genotype 3 infection were all significant risk factors for HCC in multivariate adjusted models

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• LAB TESTS IN HEPATITIS C

• Hepatitis C antibody test
• The hepatitis C antibody test is the primary test used to screen for hepatitis C infection
• The test detects antibodies in the blood to hepatitis C virus
• The test has a very high sensitivity and specificity (> 95% in high-risk populations) [11]
• The test will turn positive 4 - 10 weeks after exposure in most infected patients
• The test will be positive in > 97% of infected patients at 6 months after exposure [14]
• If a person is exposed to hepatitis C, they will form hepatitis C antibodies even if the virus is cleared and no long-term infection occurs
• A positive antibody test does not mean a chronic infection is present
• A hepatitis C viral load is needed to confirm actual virus in the blood (chronic infection)

• Hepatitis C viral load
• Also referred to as "HCV RNA PCR," "Viral Quant," "HCV RNA"
• Hepatitis C is an RNA virus meaning it has ribonucleic acid in its nucleus
• The hepatitis C viral load test measures the amount of hepatitis C RNA present in the blood
• The test has a very high specificity (98-99%) and can measure virus levels down to 12 IU/ml in some assays
• A positive viral load means that hepatitis C virus infection is present [6]
• The test will turn positive 2 - 3 weeks after exposure [14]
• Some people may clear the infection and develop undetectable viral loads. See exposure vs chronic infection above

• Hepatitis C genotype
• A genotype is a particular group of genes that make up an organism
• The hepatitis C virus has six different genotypes and genotype 1 has two subtypes, a and b
• Hepatitis C genotypes are important because they predict how the virus will respond to therapy
• Genotype 1 (subtypes 1a and 1b)
• Most common genotype worldwide and most common in U.S. (70 - 80% of cases)
• Subtype 1a is more common in the U.S., and subtype 1b is more common in Europe
• Genotypes 2 and 3
• Genotypes 2 and 3 are the second most common in the U.S. (20 - 30% of cases)
• Genotype 4
• Common in the Middle East and Africa (uncommon in North America)
• Genotypes 5 and 6
• Not commonly seen

• Liver enzyme test (ALT, AST)
• Liver enzyme tests are used to detect inflammation in the liver (see AST and ALT for more)
• Patients with hepatitis C and normal liver enzymes are less likely to develop liver fibrosis, but fibrosis still occurs in 5 - 30% of these patients
• In the past, liver enzyme levels were used to help select patients for treatment. With newer, less toxic and more effective therapies, liver enzyme values are no longer a part of treatment recommendations

• Liver biopsy
• Liver biopsy with histology is the "gold standard" for measuring the severity of liver damage caused by hepatitis C
• In the past, liver biopsy was sometimes recommended when deciding which patients to treat. With newer, less toxic and more effective therapies, liver biopsy is no longer a part of treatment recommendations

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• WHOM TO TREAT

• The AASLD/IDSA guidelines currently recommend that all patients with HCV infection be treated as long as they do not have a short life expectancy that cannot be increased with HCV therapy, liver transplantation, or another directed therapy
• See AASLD recommendations for more

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• CURRENT TREATMENT RECOMMENDATIONS

• Hepatitis C treatment recommendations

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• EXTRAHEPATIC (NONLIVER) EFFECTS OF HEPATITIS C

• Mixed cryoglobulinemia vasculitis (MCV)
• Physiology
• HCV is associated with a syndrome called mixed cryoglobulinemia vasculitis (MCV)
• Cryoglobulinemia refers to a syndrome where antibodies produced in response to HCV form complexes with the virus or parts of the virus
• The antibody-HCV complexes then deposit themselves in the walls of blood vessels
• These deposits may lead to inflammation of the blood vessel (vasculitis)
• Occurs in 19 - 50% of patients with HCV
• Symptoms
• MCV typically has no symptoms (> 85% of patients)
• When symptoms do occur, one of the following is typically seen:
• Vasculitis (palpable purpura)
• presents as red or purple bumps on the skin that do not blanch when pressed (18 - 33% of patients)
• Fatigue (35-54%)
• Muscle and joint aches (35-54%)
• Dry eyes and mouth (10 - 25%)
• Neuropathy (11-30%)
• Treatment
• Successful treatment of HCV typically makes the condition resolve
• For severe disease, plasmapheresis or immunological agents like rituximab (Rituxan®) may be used [19]

• Immune thrombocytopenia (ITP)
• Immune thrombocytopenia is a condition where autoimmune antibodies form against platelets. Platelet-antibody complexes are then removed by the spleen leading to a decrease in platelets.
• Hepatitis C infection is a major risk factor for ITP and is thought to account for up to 20% of ITP cases
• HCV antibodies that cross-react with platelet GPIIIa antigens and B-cell activation are possible mechanisms [26]

• Kidney disease
• Physiology
• HCV is associated with kidney disease
• If vasculitis from mixed cryoglobulinemia develops, it may affect the kidneys and lead to glomerulonephritis (inflammation and damage of the glomerulus)
• Glomerulonephritis can also occur when mixed cryoglobulinemia is not present
• All patients with chronic kidney disease should be screened for HCV
• Symptoms
• Decreased kidney function
• Protein in the urine
• Blood in the urine
• Treatment
• If glomerulonephritis is from mixed cryoglobulinemia, then treatment of HCV is recommended [19]

• Lymphoma
• Patients with HCV infection have a higher risk of developing lymphoma, particularly B-cell non-Hodgkin lymphoma [19]

• Diabetes and insulin resistance
• Patients with HCV may be at an increased risk for developing diabetes or insulin resistance [19]

• Sicca syndrome
• Sicca syndrome is an autoimmune syndrome that affects the lacrimal and salivary glands. Glandular autoantibodies cause inflammation and a loss of secretions which leads to dry mouth and dry eyes.
• Sicca syndrome has been reported in 9 - 67% of patients with HCV depending on the study
• Treatment of HCV does not appear to improve sicca syndrome [19]

• Joint pain
• Joint pain is common in HCV (up to 23% of patients). The pathology behind HCV-induced joint pain has not been determined but may be related to mixed cryoglobulinemia.
• Patients with HCV-induced joint pain often have a positive rheumatoid factor (50 - 80% of cases), but HCV infection alone is associated with a positive rheumatoid factor, so the significance of this is unclear [19,20]

• Autoimmune antibodies
• HCV infection often leads to the production of autoimmune antibodies that are seen in other diseases

• Reference [19,20]

Autoimmune antibodies in hepatitis C
Antibody	Presence in HCV-infected people
Antinuclear antibodies (ANA)	17 - 41%
Anti-smooth muscle cell	9 - 40%
Antithyroglobulin	8 - 13%
Anticardiolipin antibodies	20 - 27%
Rheumatoid factor	up to 71%

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• POST-EXPOSURE PROPHYLAXIS

• Overview
• The risk of HCV transmission from percutaneous and mucocutaneous exposure is 0.2% and 0%, respectively. Given the low transmission rate, the CDC does not recommend post-exposure prophylaxis with medications.


• Testing (CDC recommendations)
• All initial testing should be done as soon as possible, preferably within 48 hours
• Source patient
• Nucleic acid testing (viral load) is preferred. If nucleic acid testing is not available, HCV antibody test should be performed.
• If the nucleic acid test or the antibody test is negative, no further testing is necessary
• Detectable nucleic acid levels usually occur within 1 - 2 weeks after exposure. Positive antibody tests occur 4 - 10 weeks after exposure.
• Healthcare professional (if source patient is positive)
• Baseline test: Perform baseline HCV antibody test with reflex to nucleic acid test (viral load) if positive
• 3 - 6 weeks post-exposure: Perform nucleic acid test 3 - 6 weeks after exposure
• 4 - 6 months post-exposure: Perform HCV antibody test with reflex to nucleic acid test (viral load) if positive [3]


• Testing (UCSF)
• The University of California at San Francisco (UCSF) provides recommendations on lab testing after occupational HCV exposure at the link below
• Recommendations for Occupational Exposures to HIV, Hep B, and Hep C
• They also offer free, rapid expert consultation by phone - UCSF consultation

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• BIBLIOGRAPHY

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• 28 - PMID 23437438 - Reducing Risk for Mother-To-Infant Transmission of Hepatitis C Virus: A Systematic Review for the U.S. Preventive Services Task Force, Annals of Internal Medicine (2013)
• 29 - PMID 35696255 - A Patient With Jaundice and Malaise, JAMA (2022)