Hepatitis C

Hepatitis C is an infection caused by the hepatitis C virus (HCV), which attacks liver cells and causes liver inflammation. HCV is a bloodborne pathogen commonly transmitted through needlestick injuries in health care settings or through shared drug-injection needles. Screening plays a central role in detecting HCV infection because most infected individuals are asymptomatic or mildly symptomatic. Approximately 85% of individuals with an acute infection that is not recognized and treated will develop chronic hepatitis C, which is associated with cirrhosis, hepatocellular carcinoma, and increased mortality. The presence of HCV antibodies and HCV RNA confirm the diagnosis. HCV infection can be safely and effectively treated with direct-acting antivirals (DAAs), which have cure rates of over 95%. Simplified algorithms for the use of DAAs in treatment-naive patients without decompensated cirrhosis reduce the need for specialist-guided care.

• 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 individuals who use injection drugs
  • Needlestick injury (e.g., health care workers) ^[7]
  • Blood transfusion ^[8]
  • Dialysis
• Organ transplantation
• Sexual: rare (in contrast to HBV and HIV)
• Perinatal (vertical)

Risk factors for HCV infection

• Injection drug use (past or current, especially long-term use) ^[9]
• Hepatitis B virus or HIV positivity
• History of incarceration
• Individuals born between 1945 and 1965 ^[10]
• Individuals who received a blood transfusion or organ transplant before 1992

Patients at high risk of 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 of HCV (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

Individuals without risk factors for HCV infection ^[12][13][14]

• All individuals aged ≥ 18 years: at least once per lifetime ^[13][15]
• Pregnant individuals: once per pregnancy ^[14]

The CDC recommends against universal screening in settings where HCV disease prevalence is < 0.1%. ^[14]

Individuals with risk factors for HCV infection ^[14][15]

• One-time screening
  • Upon diagnosis with HIV
  • Individuals < 18 years of age with risk factors for HCV infection
  • Infants born to HCV-positive mothers
• Repeat screening
  • Screening after recent exposure to HCV (e.g., health care personnel exposure)
    • Initial screening: ideally within 48 hours of exposure
    • Repeat testing: ≥ 6 months after exposure (if the initial test is negative)
  • Annual screening
    • People who recreationally inject drugs
    • Men with HIV infection who have unprotected sex with men
    • Men who have sex with men taking HIV preexposure prophylaxis
• Other indications
  • Periodically based on individual risk factors for HCV infection
  • On patient request

General principles ^[15]

• Indications for hepatitis C testing
  • Screening for HCV in asymptomatic individuals
  • New diagnosis of hepatitis or cirrhosis
  • Extrahepatic features of HCV infection
• The same tests are used for both screening and diagnosis.
• For patients who test positive, obtain additional studies to guide management.
• Liver biopsy is not routinely recommended.

Individuals with hepatitis C are often asymptomatic or minimally symptomatic. Screening plays an essential role in the diagnosis of hepatitis C infection.

Hepatitis C tests ^[15]

• Anti-HCV antibodies (EIA/ELISA immunoassay): initial test for immunocompetent individuals who are HCV naïve
• HCV RNA (qualitative PCR):
  • If anti-HCV antibody test is positive
  • Alternatively, as the initial test in patients with the following
    • Prior HCV infection
    • Immunocompromise

Interpretation of hepatitis C tests

Additional evaluations ^[12]

Obtain prior to treatment to exclude liver cirrhosis and its complications and assess for comorbidities.

Laboratory studies

• Viral load determination: quantitative PCR for HCV RNA
• Routine studies
  • CBC, BMP
  • Hepatocellular enzymes
    • Normal or ↑ transaminases (10–20 × ULN) ^[16]
    • Fluctuating ALT peaks indicate acute HCV infection ^[15]
  • Cholestasis parameters
    • ↑ GGT
    • ↑ Alkaline phosphatase
    • ↑ Bilirubin
  • Liver synthetic function tests (alterations suggest cirrhosis)
    • ↓ Albumin
    • ↓ Total protein
    • ↑ PT/INR
• Evaluation of coinfection
  • HIV testing
  • Hepatitis B serology
  • Hepatitis A serology
• Serum pregnancy test (if applicable): ideally performed directly before initiating treatment

Cirrhosis assessment

• Presence of liver fibrosis: established with either of the following ^[15]
  • FIB-4 score > 3.25
  • Supportive findings during a previous assessment
    • Clinical features of liver cirrhosis
    • Serological tests (e.g., FibroSure®)
    • Liver elastography (e.g., FibroScan®)
    • Liver biopsy
• Patients with liver fibrosis or confirmed cirrhosis
  • Calculate the Child-Pugh score.
  • Obtain a liver ultrasound to screen for HCC.
  • Consider determining the HCV genotype .

Liver biopsy

• Consider when:
  • Etiology of hepatitis is unknown
  • Accurate liver fibrosis staging would alter treatment
• Supportive findings: See “Pathology.”

• Acute Phase ^[17]
  • 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 “Overview of viral hepatitis.”

The differential diagnoses listed here are not exhaustive.

General principles ^[15]

• Recommend early antiviral therapy unless life expectancy is too short for the patient to benefit.
• Determine patient eligibility for simplified treatment or specialist-guided treatment regimens.
• The goal of treatment is sustained virologic response (SVR).
• Refer patients with end-stage liver disease for liver transplantation evaluation.

Patients who are treatment-naive and have no history of decompensated cirrhosis are eligible for simplified treatment. ^[15]

Antiviral therapy ^[15]

HCV infection is always treated with a multidrug approach (no antivirals are approved as monotherapy).

• Direct-acting antivirals (DAAs)
  • Antivirals target and inhibit HCV-encoded proteins that are essential for the HCV replication cycle.
  • Example regimens
    • Glecaprevir PLUS pibrentasvir (all 6 genotypes)
    • Sofosbuvir PLUS velpatasvir (all 6 genotypes)
    • Ledipasvir PLUS sofosbuvir (genotypes 1, 4, 5, and 6)
• Interferon PLUS ribavirin ^[18]
  • Was the preferred treatment before the development of DAAs
  • Associated with severe adverse effects (e.g., arthralgias, thrombocytopenia, leukopenia, depression, anemia) and teratogenicity
  • Contraindicated in patients with decompensated cirrhosis (high risk of worsening cirrhosis decompensation)

DAAs have superior efficacy and safety profiles compared with interferon or ribavirin-based regimens and are thus preferred.

Acute and chronic HCV are treated with the same antiviral regimens.

Treatment regimens

Simplified treatment ^[12]

Simplified treatment regimens may be provided by nonspecialists.

• Indications: treatment-naive patients with none of the following
  • Current pregnancy
  • Current or prior decompensated cirrhosis (Child-Pugh class B or C)
  • Compensated cirrhosis (Child-Pugh class A) with end-stage renal disease
  • Hepatitis B coinfection
  • Hepatocellular carcinoma
  • History of liver transplant
• Regimen examples
  • Glecaprevir PLUS pibrentasvir ^[15]
  • Sofosbuvir PLUS velpatasvir : not recommended in patients with compensated cirrhosis with HCV genotype 3 ^[15]
• Monitoring
  • All patients
    • Assess for potential drug-drug interactions between pharmacotherapy and current medications.
    • Monitor for sequelae of increased hepatic drug metabolism.
  • Patients with cirrhosis
    • Monitor for signs of decompensated cirrhosis.
    • Consider obtaining serial liver chemistries to monitor for liver injury.

Refer for specialty care if clinical findings and/or laboratory studies indicate hepatic decompensation (e.g., jaundice, hepatic encephalopathy, ↑ bilirubin, ↑ transaminases)

Specialist-guided treatment ^[15]

• Indications
  • Ineligible for simplified treatment (e.g., patients with decompensated cirrhosis)
  • Did not achieve SVR after initial treatment
• Regimen examples
  • DAAs in combination with ribavirin (e.g., ledipasvir PLUS sofosbuvir PLUS ribavirin ) ^[15]
  • If ribavirin is contraindicated (e.g., during pregnancy): Extend DAA treatment to 24 weeks.

Posttreatment care ^[12][19]

Assess for sustained virologic response with a quantitative PCR for HCV RNA ≥ 12 weeks after completion of therapy.

• SVR achieved: i.e., viral load is undetectable
  • Ongoing risk factors for HCV infection: Screen for reinfection periodically.
  • No cirrhosis: No further liver-related monitoring is required.
  • Cirrhosis: Continue to screen for liver-related complications (e.g., HCC, esophageal varices).
• SVR not achieved: i.e., persistent viremia (unsuccessful treatment) or viremia after initially achieving SVR (relapse or reinfection)
  • Refer to specialist care.
  • Assess for disease progression every 6–12 months.

If hepatocellular enzymes remain elevated after achieving SVR, test for other etiologies of liver disease. ^[19]

Supportive care

• All individuals with HCV
  • Avoid hepatotoxic drugs (e.g., acetaminophen) and alcohol use.
  • Counsel about HIV and hepatitis B prevention.
  • Counsel regarding adherence, reinfection prevention, and medication risks.
• Hepatitis A and B seronegative individuals: Offer hepatitis A vaccination and/or hepatitis B vaccination.
• People who inject drugs
  • Counsel on harm reduction strategies.
  • Refer for treatment of substance use disorder.

Monitor for complications of HCV infection in individuals who decline antiviral treatment or do not achieve SVR.

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

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

• Primary prevention
  • There is currently no effective preexposure or postexposure prophylaxis and no vaccine against HCV infection.
  • Use standard precautions for bloodborne pathogens in healthcare settings.
  • Educate individuals with HCV infection about preventing transmission, e.g.:
    • Do not donate blood, semen, etc.
    • Do not share personal items that might have blood on them (e.g., needles, razors, toothbrushes).
    • Cover open cuts and sores.
• Secondary prevention: See “Screening for hepatitis C virus infection.”

Spontaneous resolution of HCV and successful treatment of infection do not confer immunity to reinfection.

Considerations in pregnancy ^[23]

• Vertical transmission: approx. 5–15% ^[24]
  • 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.

• One-Minute Telegram 57-2022-3/3: HCV reinfection rates low among drug users receiving opioid agonists

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