Hepatitis C virus

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Background

Microbiology

  • Enveloped single-stranded RNA virus in the genus Hepacivirus and family Flaviviridae
  • NS5A and NS5B are important non-structural proteins

Life Cycle

  • Involves protease, polymerase, and non-structural proteins (NS5A/NS5B)

Epidemiology

  • Worldwide about 70 million cases
  • Genotype varies by geography
    • Genotype 1 most common worldwide
    • Genotype 1a and 1b common in Canada
      • Disproportionate burden in Indigienous Canadian population in the North
      • Very high burden of disease in Canada, causing more years of life lost in Ontario than any other infectious disease
    • Genotype 3 more common south-east Asia and in injection drug use
    • Genotype 4 common in Egypt (15% prevalence); Egypt has the highest burden in the world
  • In Canada, about 245,000 chronic hepatitis C, about half are undiagnosed
    • Risk factors: injection drug use (highest risk), prior transfusion, and hemophilia
    • Increasing burden of disease as patients age and progress to cirrhosis
  • Modes of transmission
    • Injection drug use (most important population, highest risk)
    • Tattoos
    • Blood transfusions before 1992
    • Cocaine use from blood on the straws
    • Rarely, sexual transmission especially HIV-infected MSM
    • Vertical transmission rare (3-5%)
    • Iatrogenic or medical transmission, from multi-use vials

Pathophysiology

  • In the acute phase, the viral load and liver enzymes fluctuate over months
    • Anti-HCV-Ab develops at 12 weeks
    • Acute phase lasts 6 months to 2 years
  • Spontaneous clearance is rare after 2 years
    • Anti-HCV-Ab positive and HCV RNA negative
    • Repeat to confirm, but no need to follow it
    • No complications, though it is a surrogate for risk behaviours
    • Not protected from reinfection
  • If it isn't cleared, it becomes chronic
    • Lifetime risk of cirrhosis is 50-60%, with 20% having cirrhosis at 20 years
    • Liver cancer develops in 1-4%

Clinical Manifestations

  • After exposure, may clear infection, but 70-80% become chronically infected
  • Progresses slowly and asymptomatically until they develop liver fibrosis, compensated cirrhosis, then decompensated cirrhosis
    • ~20-25% progress to end-stage liver disease within 20 years

Diagnosis

  • Screening with serology for anti-HCV antibodies followed by RNA PCR to confirm ongoing infection
    • The window period for serology is about 5 to 10 weeks before antibodies are detectable
  • Anti-HCV antibodies appear to be lifelong but not protective against reinfection, so need to check RNA PCR to rule out reinfection

Management

Decision to Treat

  • All individuals should be considered for antiretroviral treatment
  • Assess readiness for treatment, as good adherence is necessary
  • Alcohol, drug use, and mental health disorders are not containdications to treatment

Initial Investigations

  • Confirm active infection with HCV RNA then get genotype and subtype
    • Two positive HCV RNA tests 6 months apart documents chronic infection, only needed in Ontario
    • May need resistance testing
    • Genotype only actually matters for cirrhosis (since we can otherwise pick a pan-genotypic regimen)
  • Baseline bloodwork, including CBC, liver enzymes, liver function, and creatinine
  • Serology to exclude HIV and HBV
  • Transferrin saturation to exclude hemochromatosis, and IgG levels to exclude autoimmune hepatitis
  • Baseline liver ultrasound
  • If not clearly cirrhotic, assess liver fibrosis

Antivirals

  • Include nonstructural 3/4A (NS3/4A) serine protease (­-previr), the NS5B RNA­ dependent RNA poly­merase (-buvir) and the NS5A protein (­-asvir)
  • Assess drug-drug interactions with www.hep­druginteractions.org
    • PPIs interact with Epclusa and Harvoni
    • Statins require dose reduction; avoid atorvastatin with Maviret
    • Notable interactions with most anti-epileptics, except leviteracetam
    • Sofosbuvir increases TDF levels
  • Choice of treatment regimen depends on genotype, previously-failed treatments, and cirrhosis
    • All protease inhibitors (-previr) are contraindicated in decompensated cirrhosis, which refers to ascites, esophageal variceal hemorrhage, jaundice, or hepatic encepha­lopathy
    • Sofosbuvir/velpatasvir/voxilaprevir (Vosevi) is indicated for previously-treated patients
Regimen Duration by Genotype Notes
1a 1b 2 3 4 5 6
Ledipasvir/sofosbuvir (Harvoni) 12 wk ± ribavirin 12 wk – 12 wk + ribavirin 12 wk 12 wk 12 wk
Elbasvir/grazoprevir (Zepatier) 12-16 wk ± ribavirin 12 wk – 12 wk + sofosbuvir 12 wk – – rule out resistance first in G1a
Sofosbuvir/velpatasvir (Epclusa) 12 wk 12 wk 12 wk 12 wk 12 wk 12 wk 12 wk
Glecaprevir/pibrentasvir (Maviret) 8 wk 8 wk 8 wk 8 wk 8 wk 8 wk 8 wk
Sofosbuvir/velpatasvir/voxilaprevir for treatment failure
  • Durations are typically between 8 and 12 weeks
    • Epclusa 12 weeks for most, now covered by ODB
    • Zepatier 12 weeks for G1 and G4
    • Maviret 8 weeks for most; 12 weeks for cirrhosis
    • Harvoni 8 weeks if uncomplicated

Treatment-Experienced Patients

  • Changes the options, mostly longer courses of treatment

Non-Pharmacologic Management

  • Counsel to avoid sharing products like needles or razors, safe sex, avoid alcohol
  • Vaccinate for hepatitis A and B

Follow-Up

  • Need to confirm sustained virologic response (SVR)

Screening

  • Majority of cases of chronic hepatitis C occur in baby boomers (born 1945 to 1975), though screening for this population appears to be controversial

Populations to Screen

  • History of injection drug use, ever
  • History of incarceration
  • Received healthcare where there is a lack of IPAC
  • Blood products or organ transplantation before 1992 in Canada
  • Born or resided in a country where prevalence of HCV is >3%
    • Central, East and South Asia
    • Australasia and Oceania
    • Eastern Europe
    • Subsaharan Africa
    • North Africa or the Middle East
  • Born to HCV positive mother
  • History of sharing personal care items or sex with an HCV-positive person
  • HIV infection
  • Received hemodialysis
  • Elevated ALT
  • Born between 1945 and 1975 (baby boomers)
    • Recommended in the US and by CASL but not by CTFPHC

Opportunistic Screening

  • Emergency rooms
  • Hospital inpatients
  • Substance use treatment clinics

Screening Procedure

  • Anti-HCV antibody
    • Serum serology gold standard
    • There are some quick point-of-care tests, like from saliva
    • Also cheap options like dried blood spot testing, which can have RNA testing as well
  • If positive, proceed to HCV RNA
    • May be able to do it as reflex testing
  • Should be done annually in patients who have ongoing high-risk exposures

Further Reading

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