Hepatitis C
Description
- Enveloped ssRNA flavivirus. No DNA intermediate, no integration, no nuclear reservoir
- Why HCV is curable and HBV is not
- Error-prone RNA polymerase -> quasispecies swarm -> immune escape, no effective vaccine
- 6 major genotypes (1-6)
- Genotype 1 commonest in Australia; genotype 3 = more steatosis, faster fibrosis, historically lower SVR
- Genotyping is no longer required before treatment - pan-genotypic DAAs
- Least likely hepatotropic virus to cause acute liver failure, most likely to become chronic
Epidemiology
- ~120,000 Australians with chronic HCV; falling steadily since unrestricted DAA access (2016)
- Australia is close to WHO elimination targets - the limiting step is diagnosis and linkage to care, not drug access
- PWID = 80-90% of Australian cases
- Other exposures: transfusion before 1990, tattoos/piercing, incarceration, birth in higher-prevalence country (Egypt, Pakistan, Italy, parts of Asia), needlestick, dialysis/iatrogenic, HIV-positive MSM, mother-to-child
- Perinatal ~5% - the commonest route in children; inc to ~10-20% with HIV co-infection
- Sexual transmission inefficient in heterosexual couples; significant in HIV-positive MSM
Aetiopathogenesis
- Injury is immune-mediated plus direct steatogenic effect (genotype 3)
- Insulin resistance, hepatic steatosis and iron loading accelerate fibrosis
Faster progression to cirrhosis
- Alcohol (dose-dependent, the biggest modifiable factor)
- HBV or HIV co-infection
- Male sex
- Older age at infection
- Obesity, insulin resistance, T2DM
- Immunosuppression (incl. post-transplant)
- Persistently raised ALT
- Fibrosis is non-linear - it accelerates in later decades
Diagnosis
Two-step, always
1. Anti-HCV antibody - >99% sens/spec
- Window ~6 weeks (range 2-26) before seroconversion
- Not protective - stays positive in active infection, and after cure
2. HCV RNA - confirms active infection
- Positive within days of exposure
- Antibody+/RNA- = cleared (spontaneously or treated), or window-period antibody. Reinfection is possible - re-test RNA on new exposure
- Reflex RNA on the same sample avoids a second visit - the main cause of loss to follow-up
- Point-of-care RNA testing now used in outreach/PWID settings
- Incubation 14-160 days
Before treatment
- HCV RNA (baseline), LFT, FBE, UEC, INR, eGFR
- Assess cirrhosis - the only thing that changes management
- APRI and FIB-4 first; transient elastography if available
- Cirrhosis if elastography >=12.5 kPa, or platelets <150 with splenomegaly, or clinical/imaging evidence
- HBsAg, anti-HBc, anti-HBs, HIV - HBV status is mandatory (reactivation)
- Vaccinate against HAV and HBV if non-immune
- Genotype no longer required
Cure
- SVR12 = undetectable HCV RNA 12 weeks after finishing = cure
Management
Verified against the Australian consensus statement on management of HCV infection (hepcguidelines.org.au, current edition) and PBS criteria.
Who to treat
- Everyone with chronic HCV infection, regardless of fibrosis stage, ALT, ongoing drug use or alcohol
- Active injecting drug use is not a contraindication and never a reason to defer
- Prescribable in Australia by GPs and nurse practitioners (with remote specialist consultation) - not just hepatologists
- No requirement for abstinence
Regimens - pan-genotypic
| Regimen | Duration | Notes |
|---|---|---|
| Sofosbuvir + velpatasvir | 12 weeks | Single daily tablet. Avoid if eGFR <30 (historically); NS5A inhibitor |
| Glecaprevir + pibrentasvir | 8 weeks (treatment-naive, incl. compensated cirrhosis) | 3 tablets daily with food. Safe in any degree of renal impairment incl. dialysis. Protease inhibitor - contraindicated in decompensated cirrhosis |
| Sofosbuvir + velpatasvir + voxilaprevir | 12 weeks | Salvage after DAA failure |
- SVR >95% across genotypes with either first-line regimen
- Decompensated cirrhosis (Child-Pugh B/C): no protease inhibitor - use sofosbuvir/velpatasvir + ribavirin, specialist-managed
Before prescribing - the three checks
1. HBV serology. HBsAg-positive -> risk of HBV reactivation during DAA therapy; prophylax or monitor closely
2. Drug interactions - DAAs are P-gp/CYP substrates
- Amiodarone + sofosbuvir -> severe bradycardia (contraindicated)
- Rifampicin, carbamazepine, phenytoin, St John's wort - inducers reduce DAA levels, avoid
- Statins (dose reduction), PPIs (with some regimens), some antiretrovirals
3. Cirrhosis? - determines regimen choice and whether surveillance continues after cure
After cure
- Cirrhosis at the time of cure -> lifelong 6-monthly liver ultrasound +/- AFP. SVR reduces but does not abolish HCC risk
- No cirrhosis: no surveillance needed
- Anti-HCV stays positive - monitor with RNA, not antibody
- Reinfection: re-test RNA at least annually in those with ongoing risk
Prevention
- No vaccine. Needle and syringe programs, opioid agonist therapy
- Universal precautions; test all donors
- Breastfeeding not contraindicated unless nipples cracked/bleeding
- Notifiable disease
Associations
Immune-complex and lymphoproliferative - far richer than HBV.
- Mixed cryoglobulinaemia - the strongest association
- Purpura, arthralgia, neuropathy, low C4, RF positive
- -> membranoproliferative GN
- Membranoproliferative glomerulonephritis
- Porphyria cutanea tarda
- Lichen planus
- Sjogren-like sicca / keratoconjunctivitis sicca
- RA-like non-erosive polyarthritis
- B-cell non-Hodgkin lymphoma, incl. splenic marginal zone lymphoma (may regress with DAA cure alone)
- Type 2 diabetes / insulin resistance
- Autoimmune thyroid disease
- HIV and HBV - shared transmission
Natural history & complications
Outcomes after acute infection
- ~25-35% clear spontaneously (higher if symptomatic, female, young, IL28B CC)
- ~65-75% become chronic
- Of chronic infection, ~1/3 progress to end-stage liver disease
Timeline if untreated
- Cirrhosis after ~20 years
- HCC after ~30 years
- Clinically silent until a complication appears - cirrhosis, small-vessel vasculitis, decompensation. The first presentation may be variceal bleed
- HCC in HCV arises almost exclusively on a background of cirrhosis (contrast HBV, where ~20% occur without)
- Acute liver failure very rare
After SVR
- Fibrosis regresses in many; portal hypertension improves slowly
- Residual HCC risk persists if cirrhotic at cure - surveillance is lifelong
- Extrahepatic manifestations usually improve
- Continued alcohol or metabolic liver disease will still progress - cure the virus, not the liver
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