Hepatitis C

• incubation period of 14-180 days
• Usually transmitted parenterally. 
• Can be sexually transmitted in MSM, particularly if HIV
• Clinical
  • Asymptomatic infection common – 70%
  • Acute hepatitis  15% – lethargy, nausea, fever, anorexia, jaundice, pale stools, dark urine
    • similar to HBV but the inflammatory response is less and as a result symptoms are usually milder.

• Complications
  • Chronic persistent HCV hepatitis – 775%
    • HCV RNA in the bloodstream for at least 6 months. 
    • SSx: chronic fatigue 
    • cirrhosis 20% – 10-15 years
    • liver failure – 20% of – after 20 years. 
    • primary hepatocellular carcinoma – 5% of – 30 years.
  • Disease progression affected by
    • Age>40 at infection
    • duration
    • EtOH
    • coinfection HIV or HepB
    • male
    • marijuana use
    • obesity
  • 15% of those infected with HCV develop rapid onset cirrhosis of the liver.

Signs of cirrhosis

Peripheral	Palmar erythema Dupuytren contracture ClubbingLeukonychia Peripheral hair loss Asterixis Petechiae or ecchymoses Muscle wasting Ankle oedema
Face and chest	Jaundice Fetor hepaticus Gynaecomastia Parotid enlargement Spider naevi
Abdomen	Splenomegaly Ascites Caput medusae Hepatomegaly (only in alcoholic liver disease, haemochromatosis or with hepatocellular carcinoma)

Screening and Diagnosis of HCV Infection

Transmission Risk Factors

Populations to consider for HCV screening:

• People who inject or have injected drugs
• People in custodial settings
• Individuals with tattoos or body piercings
• Recipients of blood transfusions/organ transplants before 1990
• Individuals with coagulation disorders treated before 1993
• Children born to HCV-infected mothers
• People with HIV or HBV infection
• Sexual partners of HCV-infected individuals
  • (higher risk groups include MSM and those with HCV–HIV coinfection)
• Individuals with liver disease (persistently elevated ALT levels)
• People with a needle-stick injury
• Migrants from high-prevalence regions
  • (e.g., Egypt, Pakistan, Mediterranean, Eastern Europe, Africa, Asia)

Screening Test for HCV

• Serology (HCV Antibodies): Indicates exposure to HCV, whether current or past infection.
• Confirmation of Current HCV Infection:
  • Conducted using HCV RNA PCR assay.
  • Reflex testing for HCV RNA recommended if serology is positive; note request on pathology form.

Chronic Infection Diagnosis Criteria (PBS Eligibility)

• Evidence of chronic infection by repeated HCV antibody and RNA positivity.
• Chronic infection: HCV RNA detectable in plasma or blood and absence of acute hepatitis features (duration > 6 months is traditional but documentation of seropositivity is not mandatory).

Barriers to Testing and Alternative Testing Methods

• Venepuncture for whole blood sample collection presents challenges for people who inject drugs (PWID) with poor venous access.
• Dry Blood Spot (DBS) Testing:
  • Utilizes finger-prick sample collection for HCV RNA.
  • Not yet TGA-approved; requires confirmatory testing before DAAs.
• Point-of-Care Testing (POC):
  • Xpert® (Cepheid) for HCV RNA: Finger-prick sample, results <60 minutes.
  • Used in high-prevalence settings to improve screening and reduce loss to follow-up.
  • National program (2021) for scaling HCV POC testing with training, laboratory partnerships, and QA programs.

Barriers to Reimbursement for POC HCV RNA Testing

• Current MBS criteria require documentation of HCV seropositivity.
• High HCV seropositivity among PWID (>50% in high-prevalence settings).
• Challenges with tracking serology results due to inconsistent IT systems.
• Need for funding mechanisms to support POC HCV RNA testing without requiring HCV seropositivity documentation.

Annual Testing Recommendations

• Seronegative Individuals with Risk Factors: Annual HCV serological testing.
• Seropositive Individuals with Undetectable HCV RNA: Annual HCV RNA testing only if ongoing risk factors exist.
• Use venepuncture or POC finger-prick testing as appropriate.
• Note: Positive HCV serological results are lifelong; repeat serological testing unnecessary post-treatment.

Pre-treatment Assessment for Chronic HCV Infection

• Consideration for Treatment:
  • All individuals with HCV should be considered for treatment, except those with a life expectancy <12 months due to unrelated or non-HCV comorbidities.
• Comprehensive Pre-Treatment Assessment:
  • Establish a therapeutic and collaborative relationship.
  • Provide access to peer and social support, psychological, alcohol and drug counseling, and information on preventing HCV transmission and reinfection.

Key Elements of Pre-Treatment Assessment

• History
  • Estimated duration of HCV infection
  • identify underlying risk factors for HCV
  • Previous HCV treatment details: date, regimen, response
  • Cofactors for liver disease progression:
    • Alcohol intake, marijuana use
    • Virological cofactors (HIV, HBV)
    • Diabetes, obesity
  • Ribavirin use history (for patients planned to receive it): cardiovascular risk assessment
  • Vaccinations against HBV and HAV
  • Detailed drug history
    • drug-drug interactions
    • prescription, over-the-counter, and recreational substances.
  • Physical and psychiatric comorbidities
  • Risk factors for viral transmission and reinfection
  • Social issues (potential barriers to adherence)
  • Document HCV treatment history.
• Medication Assessment
  • Review of concomitant medications (prescription, OTC, illicit)
• Physical Examination
  • Cirrhosis indicators: hard liver edge, spider naevi, leukonychia
  • Features of decompensation/portal hypertension: jaundice, ascites, oedema, etc.
  • Body weight and BMI
• Investigations
  • Full blood count
  • liver function tests
  • eGFR
  • INR (synthetics function)
  • Pregnancy test for women of childbearing potential
  • Virological Evaluation:
    • HCV PCR
    • HCV genotype (if considered) –
      • HCV genotype is no longer required by the PBS criteria for pan-genotypic regimens:
        • sofosbuvir + velpatasvir (first-line, treatment-naive)
        • glecaprevir + pibrentasvir (first-line, treatment-naive)
        • sofosbuvir + velpatasvir + voxilaprevir (NS5A inhibitor-experienced).
      • Testing HCV genotype is recommended that HCV genotype be determined as this can help in differentiating relapse from reinfection among people with a high risk of reinfection
    • Co-Infection Evaluation:
      • HBV (HBsAg, anti-HBc, anti-HBs) serology
      • HIV serology
      • HAV serology
• Liver fibrosis assessment:
  • Elastography (FibroScan®, ARFI, SWE)
  • Serum biomarker (APRI, FIB-4, Hepascore, ELF test‡)
    • APRI – AST to platelet ratio index
      • <0.5 indicating significant fibrosis
      • >1.0 indicates significant fibrosis or cirrhosis
    • Hepascore
      • score based on age, sex and biochemical serum markers
  • If fibrosis assessment cannot be organised in a timely fashion, people should immediately start hepatitis C treatment, especially when there is concern about loss to follow-up.
• For people with cirrhosis
  • Liver ultrasound  to exclude hepatocellular carcinoma (should be performed within 3 months before starting DAAs)
  • Screening for clinically significant portal hypertension and osteoporosis

Immune responses and immunopathology in acute and chronic viral hepatitis Eui-Cheol Shin, Pil Soo Sung & Su-Hyung Park Nature Reviews Immunology volume 16, pages509–523 (2016

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Treatment

• Direct anti-viral therapy
  • curative in > 95%
  • Three pan-genotypic DAA regimens are listed on the PBS
  • two of which are suitable for treatment of patients by GPs
  • Don’t have to do genotype anymore – but may be helpful to identify for reinfection
  • Can still use if previously failed interferon therapy

Treatment regimens for hepatitis C virus in people who are treatment naive
Drug regimen	Dosing	Duration (treatment naive)		Comments
		No cirrhosis	Cirrhosis
Epclusa – Sofosbuvir plus velpatasvir	One tablet, once daily	12 weeks	12 weeks	Consider adding weight-based ribavirin for patients with genotype 3 hepatitis C virus (HCV) who have compensated cirrhosis. Side effects include headache, fatigue, nausea and nasopharyngitis. Of note, renal dose adjustment is no longer required.
				Ribavirin – S/E: Haemolytic anaemia, nausea, rashRibavirin is teratogenic
Mavyret – Glecaprevir plus pibrentasvir	Three tablets, once daily with food	Eight weeks	Eight weeks	Side effects include headache, fatigue and nausea. No renal dose adjustment is required. Not recommended for individuals with decompensated cirrhosis (Child–Pugh B and C).

• (www.hep-druginteractions.org) Some common drug interactions include:
  • proton pump inhibitors
  • statins
  • St John’s wort
  • ethinyloestradiol-containing contraceptives
  • anti-epileptics
  • amiodarone.

Patients who are not suitable for hepatitis C virus treatment in general practice

1. Children
2. Adult patients who have any of the following characteristics:
   1. current or prior episode of decompensated cirrhosis, defined as Child–Pugh score ≥7
   2. prior hepatitis C virus infection and treatment (excluding failed peginterferon/ribavirin regimens)
   3. end-stage renal disease
   4. human immunodeficiency virus or hepatitis B surface antigen
   5. current pregnancy
   6. hepatocellular carcinoma
   7. liver transplantation

• sustained virological response (SVR)
  • HCV RNA viral load performed 12 weeks after completion of treatment
  • rate of >95% have been reported for all HCV genotypes
  • HCV antibody remains positive in cured individuals and should not be used to assess treatment response or to assess for reinfection.
  • There is no protection against reinfection
  • HCV eradication is associated with
    • normalisation of liver enzymes
    • improvement or regression of liver necroinflammation and fibro
    • improvement in liver function. 
  • risk of HCC, although not eliminated, is also significantly reduced
• Non-responders
  • = serum HCV RNA after treatment.
  • may be due to breakthrough or relapse related to medication resistance, or due to non-adherence or reinfection.
  • should be referred to a specialised gastroenterology
  • if reinfection is confirmed, treatment can be undertaken as for a treatment-naive patient. 
• Other
  • Vaccinate for hep A and B
  • Other STI testing
  • Notifiable
  • Risk of transmission baby – should have testing
  • Reduce other liver risks – medications, EtOH

Recommended education for patients with hepatitis C virus

Transmission Information

• Mode of Transmission:
  • HCV is a blood-borne virus transmitted through direct blood-to-blood contact.
• Blood Donation Restriction:
  • HCV-positive individuals should not donate blood.
• Personal Hygiene Items:
  • Toothbrushes and razors should not be shared to prevent HCV transmission.

HCV and Pregnancy

• Mother-to-Baby Transmission Risk:
  • Low risk of transmission (5–7%).
• Testing for Infants:
  • Maternal HCV antibodies may persist in infants for up to 18 months; testing should be performed after this period.
• Mode of Delivery:
  • Caesarean section does not reduce the risk of mother-to-child transmission.
• Breastfeeding Recommendations:
  • Breast milk can be given, but should be discarded if the nipples are bleeding or cracked to minimize the risk of transmission.

Sexual Transmission

• Risk Among Long-Term Monogamous Heterosexual Partners:
  • Very low risk of sexual transmission (0–0.6% per year).
• Higher Risk Groups:
  • Sexual transmission is relatively common among GBMSM (gay, bisexual, and other men who have sex with men, including cis and trans individuals) living with HIV and has also been reported in GBMSM not living with HIV.
• Infection Likelihood in Long-Term Partners:
  • Risk of infection in long-term sexual partners is <5% if there are no other risk factors.
• Condom Use:
  • Condoms likely offer protection against HCV transmission.
• Oral Sex Transmission:
  • Rare occurrence.
• Sexual Activity During HCV Treatment:
  • Safe Practices: To minimize any potential risk during treatment:
    • Use condoms consistently, especially with new or multiple partners.
    • Avoid sexual activities that may involve blood exposure.
    • Communicate openly with partners about HCV status and any concerns.
  • Post-Treatment: After successful treatment and achieving a sustained virological response (SVR), the virus is typically undetectable, significantly reducing the risk of transmission. However, maintaining safe practices is advisable to prevent reinfection.

Management of Contacts

• Counseling and Testing:
  • Antibodies may take up to 6 months to develop; testing should be conducted accordingly.
  • Referral for investigation and treatment if HCV antibody-positive and HCV RNA-positive.
  • Adhere to the National HCV Testing Policy.
• Testing Recommendations:
  • Sex or injecting partners of HCV-infected individuals should be encouraged to be tested.

Contact Tracing Priority

• Priority Groups:
  • Needle-sharing contacts.
  • Current blood donors within 12 months prior to positive HCV antibody testing.
  • Blood donor recipients before 1990.

Injecting Drug Use

• Referral to Needle and Syringe Programs:
  • HCV-positive patients with ongoing intravenous drug use should be referred to harm reduction services.
• Reinfection Risk:
  • Previous HCV infection does not confer immunity, so reinfection is possible.

Alcohol Consumption

• Abstinence Recommendations:
  • Advise abstinence from alcohol if possible.
  • Individuals consuming >40g/day are at increased risk of accelerated liver disease progression and should receive counseling and potential referral to alcohol services.

Vaccination

• No Vaccine for HCV:
  • Currently, there is no vaccine available for HCV.
• Hepatitis A and B Vaccination:
  • Patients should be tested for immunity and vaccinated if not immune.

Herbal Remedies

• Silymarin (Milk Thistle):
  • No evidence supports its efficacy in improving ALT levels, HCV RNA levels, or clinical outcomes in chronic hepatitis C.

Disclosure and Legal Obligations in Australia:

• Sexual Partners: In Queensland, individuals living with Hep C or HIV are not legally required to disclose their status to sexual partners. However, they have a responsibility under Section 143 of the Public Health Act 2005 to “not recklessly put someone else at risk of contracting a controlled notifiable condition.” This means taking reasonable precautions, such as practicing safe sex, to prevent transmission
• General Employment: In most professions, there is no legal requirement to disclose HCV status to employers or colleagues. Disclosure is a personal choice and should be based on individual circumstances and the nature of the work.
• Healthcare Professionals: For those performing exposure-prone procedures (EPPs), such as certain surgical or dental procedures where there is a risk of injury resulting in exposure to a patient’s open tissues, specific guidelines apply:
  • Healthcare workers are advised to know their HCV status.
  • If HIV/HCV-positive, they should seek advice from an expert panel or occupational health physician regarding the scope of their practice.
  • Disclosure to patients is generally not required unless there’s a significant risk of transmission.
• Legal Framework: The Communicable Diseases Network Australia (CDNA) provides guidelines for healthcare workers regarding blood-borne viruses, emphasizing the importance of risk assessment and appropriate management without mandating disclosure

When to refer patients with hepatitis C to a specialist or liver clinic

• Cirrhosis *
• Hepatitis B co-infection
• HIV co-infection †
• Complex comorbidities and medication requirements 
• Chronic kidney disease (eGFR <50 mL/min/1.73 m2) 
• Under 18 years of age
• Failure of treatment with all-oral therapy (sustained virologic response not achieved)
• Ongoing evidence of liver disease despite achieving sustained virologic response
• Preference not to treat hepatitis C in primary care