Hepatitis C

Hepatitis C is an infection caused by the hepatitis C virus (HCV), which attacks liver cells and causes liver inflammation. The virus is mainly transmitted parenterally, especially through IV drug use or needlestick injuries in healthcare settings. Most patients are asymptomatic in the acute phase, but may develop fever, malaise, fatigue, or jaundice. Transition to chronic infections occurs in up to 85% of cases since asymptomatic patients are rarely diagnosed and treated. Chronic infection is associated with increased mortality due to cirrhosis and hepatocellular carcinoma. Suspicion of HCV infection due to exposure, clinical presentation, or elevated aminotransferase levels should be followed up with HCV antibody and HCV RNA testing to confirm the diagnosis. HCV infection is treated with a combination of two direct-acting antivirals (e.g., ledipasvir, sofosbuvir). More than 90% of patients are cured with adequate treatment.

• Acute hepatitis C: HCV infection that develops during the first 6 months following the exposure
• Chronic hepatitis C: HCV infection that persists beyond 6 months following the exposure ^[1]

• Prevalence: up to 2% of the US population has chronic HCV infection. ^[2]
• Incidence: 1 cases per 100,000 population, > 40,000 new infections per year in the US ^[3]
• Clinical progression: 75–85% of individuals with HCV infection go on to develop chronic disease ^[4]

Epidemiological data refers to the US, unless otherwise specified.

Pathogen

• Hepacivirus C (Hepatitis C virus): RNA virus of the Hepacivirus genus and Flaviviridae family
• The risk of chronic infection is multifactorial and depends on the host's ability to clear the pathogen through activation of multiple innate immunity pathways against the viral envelope. ^[5]
  • Flawed proofreading capability of RNA-dependent RNA polymerase (no 3'-5' exonuclease activity) introduces mutations into genes encoding viral glycoprotein envelope and enabling novel antigen production.
  • Rapid replication rate produces many antigenically unique viral envelopes.
  • Infection persists because the production rate of new mutant virions exceeds the production rate of host antibodies.
• There are six genotypes: In the US, the main ones are genotype 1 (65–80%) and genotype 2 (10–15%). ^[6]
• Reinfection with another HCV genotype is possible.

Transmission

• Parenteral
  • Needle sharing among IV drug users
  • Needlestick injury (e.g., health care workers) ^[7]
  • Blood transfusion ^[8]
  • Dialysis
• Organ transplantation
• Sexual: rare (in contrast to HBV and HIV)
• Perinatal (vertical)

High-risk groups for HCV infection

• IV drug users (especially long-time users) ^[9]
• Hepatitis B virus (HBV) or HIV-positive individuals
• Prison inmates
• Individuals born between 1945–1965 ^[10]
• Recipients of blood transfusions or organ transplants before 1992

Patients with a medical history indicating a high risk for HCV infection should be tested.

Incubation period

• 2 weeks to 6 months

Acute course

• Asymptomatic in 80% of cases
• Symptomatic (see “Acute viral hepatitis”)
  • Malaise, fever, myalgias, arthralgias
  • RUQ pain, tender hepatomegaly
  • Nausea, vomiting, diarrhea
  • Jaundice, possibly pruritus

Symptoms are nonspecific and may be similar to those of other acute viral infections.

Chronic course

• Seen especially in asymptomatic individuals (up to 85%), as the disease may go undiagnosed and treatment may be delayed or never initiated (carrier state). ^[1]
• Findings often mild, nonspecific (e.g., fatigue)
• Liver cirrhosis (up to 25% of cases) within 20 years of infection ^[11]
• Extrahepatic features (common)
  • Hematological
    • Mixed cryoglobulinemia
    • Lymphoma (especially B-cell non-Hodgkin lymphoma)
    • ITP
    • Autoimmune hemolytic anemia
    • Monoclonal gammopathies
  • Renal
    • Membranoproliferative glomerulonephritis (more common)
    • Membranous glomerulonephritis
  • Rheumatological
    • Polyarteritis nodosa
    • Sjogren syndrome
  • Dermatological
    • Porphyria cutanea tarda
    • Lichen planus
  • Endocrine
    • Diabetes mellitus
    • Autoimmune thyroiditis (may lead to hypothyroidism)
  • Vascular: leukocytoclastic vasculitis
  • Others: sialadenitis

• Detection of antibodies ^[11][12]
  1. EIA/ELISA: standard immunoassay tests for anti-HCV antibodies; (positive in cases of acute, chronic, and previous HCV infection)
  2. PCR for HCV RNA if antibodies are positive.
     • If positive PCR: active HCV infection (may be acute or chronic)
     • If negative PCR: no active infection, but prior infection
     • Determines HCV genotype and virus titer assists in treatment planning and monitoring
• Liver function tests
  • ↑ Transaminases with AST/ALT ratio
    • Ratio < 1: acute hepatitis
    • Ratio ≥ 1: chronic hepatitis
  • ↓ Total protein/albumin, coagulation (particularly ↑ prothrombin time), ↓ cholinesterase
  • Cholestasis parameters: ↑ γ-GT, ↑ alkaline phosphatase, ↑ bilirubin
• Inflammation markers: leukocytosis, ↑ ferritin ^[13]
• Liver biopsy indications (see “Pathology”)
  • If diagnosis is inconclusive
  • For evaluating fibrosis in patients with chronic hepatitis C
  • Evaluation of response to therapy
• Ultrasound: detection of cirrhosis and neoplasia, e.g., HCC
• Rule out coinfections: HIV, hepatitis A virus (HAV), hepatitis B virus (HBV) serology necessary

• Acute Phase ^[14]
  • Focal areas of macrovesicular steatosis
  • Bile duct injury
  • Sinusoidal inflammation of hepatic cells
  • Lobular involvement in the form of eosinophilic single-cell necrosis
• Chronic phase
  • Lymphoid follicles in portal triad
  • Necroinflammation of periportal liver cells
  • Variable degree of fibrosis
  • Severe hepatocyte injury

Without treatment, the disease will ultimately progress to liver fibrosis, cirrhosis, and hepatocellular carcinoma. See “Pathology of viral hepatitis.”

• Autoimmune hepatitis
• Cholangitis
• See “Differential diagnosis of viral hepatitis.”

The differential diagnoses listed here are not exhaustive.

General recommendations

• Avoid hepatotoxic drugs (e.g., acetaminophen) and alcohol use.
• Refer to an addiction specialist to treat substance use.

Acute hepatitis C ^[15][16]

• Treatment goal: prevent transition to chronic infection
• Antiviral therapy: the same regimens as for chronic HCV infection (see “Chronic hepatitis C” below)
• Monitoring: regular monitoring of HCV RNA every 4–8 weeks for 6–12 months

There is neither a pre-exposure or postexposure prophylaxis nor a vaccine for HCV.

Chronic hepatitis C ^[15][16]

• Treatment goals
  • Complete cure ^[17]
  • Eradication of HCV RNA in serum as defined by sustained virologic response (SVR)
• Treatment regimens
  • Chronic HCV infection is always treated with a multidrug approach (no antivirals are approved as monotherapy).
  • Chosen based on the history of antiviral treatment, degree of liver fibrosis, viral genotype, and viral load
  • Combination of two direct-acting antivirals (DAAs): Antivirals target and inhibit HCV-encoded proteins that are essential for the HCV replication cycle.
    • Ledipasvir PLUS sofosbuvir (genotypes 1, 4, 5, and 6) ^[18]
    • Sofosbuvir PLUS velpatasvir (all 6 genotypes)
    • Elbasvir PLUS grazoprevir
    • Glecaprevir PLUS pibrentasvir (all genotypes)
    • Sofosbuvir PLUS daclatasvir
    • Sofosbuvir PLUS simeprevir
    • Ombitasvir/paritaprevir/ritonavir PLUS dasabuvir
  • Interferon PLUS ribavirin ^[19]
    • Interferon-based treatment is still used as a last resort in cases of treatment failure.
    • Can be used in the treatment of all genotypes
    • Ribavirin on its own may be combined with DAAs to increase antiviral activity.
  • Vaccinations for hepatitis A and B should be given in addition to any treatment regimen.
  • See “Antivirals against hepatitis B and C.”

Interferon and ribavirin are associated with severe adverse effects (e.g., arthralgias, thrombocytopenia, leukopenia, depression, and anemia) and teratogenicity.

Treatment algorithm for all genotypes in treatment-naive patients

Treatment algorithm for patients with decompensated cirrhosis (Child-Pugh class B or C)

• Refer to a medical professional with expertise and/or liver transplant center
• Regimens
  • Ledipasvir PLUS sofosbuvir PLUS ribavirin for 12 weeks (genotype 1, 4, 5, or 6)
  • Sofosbuvir PLUS velpatasvir PLUS ribavirin for 12 weeks (all genotypes)
  • If ribavirin is contraindicated: administer the DAAs for 24 weeks
• Interferon is contraindicated (high risk of worsening cirrhosis decompensation)
• Endstage liver failure: liver transplantation

Retreatment algorithm for treatment-experienced patients

• Failed glecaprevir PLUS pibrentasvir treatment (all genotypes)
  • Glecaprevir PLUS pibrentasvir PLUS sofosbuvir PLUS ribavirin for 16 weeks
  • Sofosbuvir PLUS velpatasvir PLUS voxilaprevir for 12 weeks
    • PLUS ribavirin for patients with compensated cirrhosis
• Failed sofosbuvir PLUS velpatasvir PLUS voxilapravir (all genotypes) with or without compensated cirrhosis
  • Glecaprevir PLUS pirentasvir PLUS sofosbuvir PLUS ribavirin for 16 weeks
  • Sofosbuvir PLUS velpatasvir PLUS voxilaprevir PLUS ribavirin for 24 weeks

• Rarely fulminant hepatitis (liver failure) ^[20][21]
• Liver cirrhosis
• Hepatocellular carcinoma
• Secondary hemochromatosis

We list the most important complications. The selection is not exhaustive.

• Screening recommendations ^[22]
  • Universal hepatitis C screening
    • All individuals aged 18–79 years should be screened at least once in their lifetimes.
    • All women should be screened at each pregnancy.
  • Periodic testing is indicated in individuals with ongoing high-risk of exposure
    • IV drug users
    • Long-term hemodialysis patients
  • One-time testing is indicated in individuals exposed to (potentially) HCV-positive blood, especially: ^[23]
    • Infants born to HCV-positive mothers
    • Healthcare personnel with percutaneous or parenteral exposure to blood with known HCV-positive or unknown HCV status
• Screening protocol
  • Anti-HCV antibody test
  • Confirmatory PCR for HCV RNA

Considerations in pregnancy ^[24]

• Vertical transmission: approx. 5–15% ^[25]
  • C-section does not lower risk of transmission
  • Avoid amniocentesis or the use of fetal scalp electrode (due to increased risk of transmission)
  • HCV-infected patients (without HIV coinfection) may breastfeed as normal
• Prenatal screening (Anti-HCV antibody testing): recommended for all pregnant women during the initial examination (∼ 10 weeks of gestation)
• Postpartum treatment
  • The medication regimens currently available are all contraindicated.
  • Infants should receive vaccinations for hepatitis A and B.

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3. How many new HCV infections occur annually in the United States?. https://www.cdc.gov/hepatitis/hcv/hcvfaq.htm#a2. Updated: April 9, 2019. Accessed: June 7, 2019.
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8. Ronald E. Engle, Jens Bukh, Robert H. Purcell. Transfusion-associated hepatitis before the screening of blood for hepatitis risk factors. Transfusion. 2014 .
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10. Recommendations for the Identification of Chronic Hepatitis C Virus Infection Among Persons Born During 1945–1965. https://www.cdc.gov/mmwr/preview/mmwrhtml/rr6104a1.htm. Updated: August 17, 2012. Accessed: July 3, 2019.
11. The ABCs of Hepatitis. https://www.cdc.gov/hepatitis/Resources/Professionals/PDFs/ABCTable.pdf. Updated: January 1, 2016. Accessed: March 27, 2017.
12. Barrera JM, Bruguera M, Ercilla MG, Gil C, Celis R, Gil MP, del Valle Onorato M, Rodés J, Ordinas A. Persistent hepatitis C viremia after acute self-limiting posttransfusion hepatitis C.. Hepatology. 1995 .
13. Kowdley KV, Belt P, Wilson LA, et al. Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease. Hepatology. 2011; 55 (1): p.77-85. doi: 10.1002/hep.24706 . | Open in Read by QxMD
14. Dhingra S. Liver pathology of hepatitis C, beyond grading and staging of the disease. World Journal of Gastroenterology. 2016; 22 (4): p.1357. doi: 10.3748/wjg.v22.i4.1357 . | Open in Read by QxMD
15. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. https://www.hcvguidelines.org/sites/default/files/full-guidance-pdf/AASLD-IDSA_HCVGuidance_August_27_2020.pdf. Updated: August 27, 2020. Accessed: December 3, 2020.
16. Initial Treatment of HCV Infection. https://www.hcvguidelines.org/treatment-naive. Updated: August 27, 2020. Accessed: December 3, 2020.
17. Hepatitis C FAQs for Health Professionals. https://www.cdc.gov/hepatitis/hcv/hcvfaq.htm. Updated: January 27, 2017. Accessed: March 27, 2017.
18. Yasir Waheed. Ledipasvir and sofosbuvir: Interferon free therapy for hepatitis C virus genotype 1 infection. World Journal of Virology. 2015 .
19. Clark V, Nelson DR. The role of ribavirin in direct acting antiviral drug regimens for chronic hepatitis C. Liver Int. 2012; 32 (Suppl 1): p.103-107. doi: 10.1111/j.1478-3231.2011.02711.x . | Open in Read by QxMD
20. Chu C-J, Lee S-D. Hepatitis B virus/hepatitis C virus coinfection: epidemiology, clinical features, viral interactions and treatment. J Gastroenterol Hepatol. 2008; 23 (4): p.512-520. doi: 10.1111/j.1440-1746.2008.05384.x . | Open in Read by QxMD
21. Tsoulfas G, Goulis I, Giakoustidis D, et al. Hepatitis C and liver transplantation. Hippokratia. 2009; 13 (4): p.211-215.
22. Yeung CY, Lee HC, Chan WT, Jiang CB, Chang SW, Chuang CK. Vertical transmission of hepatitis C virus: Current knowledge and perspectives. World J Hepatol. 2014; 6 (9): p.643-651. doi: 10.4254/wjh.v6.i9.643 . | Open in Read by QxMD
23. Chung RT, Ghany MG, et al. Hepatitis C Guidance 2018 Update: AASLD-IDSA Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection. Clinical Infectious Diseases. 2018; 67 (10): p.1477-1492. doi: 10.1093/cid/ciy585 . | Open in Read by QxMD
24. Hepatitis C Virus Infection in Adolescents and Adults: Screening. https://www.uspreventiveservicestaskforce.org/uspstf/document/RecommendationStatementFinal/hepatitis-c-screening. Updated: March 2, 2020. Accessed: January 28, 2021.
25. CDC Recommendations for Hepatitis C Screening Among Adults in the United States. https://www.cdc.gov/hepatitis/hcv/guidelinesc.htm#:~:text=CDC%20Recommendations%20for%20Hepatitis%20C,is%20less%20than%200.1%25*. Updated: July 29, 2020. Accessed: January 28, 2021.