Hepatology & Infectious Diseases & Family Medicine
Hepatitis C
Hepatitis C is a liver infection caused by the hepatitis C virus (HCV), a positive-strand single-stranded RNA flavivirus discovered in 1989 by Choo et al. (Science). Unlike hepatitis A and B, there is no vaccine against HCV—but hepatitis C is now the first chronic viral infection for which a curative treatment is available, without injections and lasting 8 to 12 weeks. Third-generation direct-acting antivirals (DAAs) achieve a sustained virologic response (SVR—virologic cure) in over 95% of cases, across all genotypes. In Canada, approximately 250,000 people live with chronic hepatitis C, a significant proportion of whom are unaware of their infection—as HCV can remain asymptomatic for decades before causing cirrhosis or hepatocellular carcinoma. In Quebec, the Régie de l'assurance maladie du Québec (RAMQ) has reimbursed first-line DAA treatments without fibrosis restrictions since 2018, and one-time universal screening is recommended for anyone born between 1945 and 1975 (the «baby boom» generation) as well as for anyone with risk factors. The WHO has set a goal to eliminate hepatitis C as a public health problem by 2030—reducing new infections by 80% and related mortality by 65%.
Virology, transmission, natural history, and screening
- HCV Virology - Genotypes and Therapeutic Implications: HCV structure: flavivirus — 9.6 kb positive-strand RNA → 3,011-amino-acid polyprotein cleaved into 10 structural (core + E1 + E2 + p7) and non-structural proteins (NS2 + NS3 + NS4A + NS4B + NS5A + NS5B) → replication via the NS5B RNA-dependent RNA polymerase (no error correction mechanism → high mutation rate → quasi-species + resistance); genotypes and subtypes: 8 genotypes (GT1–GT8) + numerous subtypes → variable geographic distribution → GT1: most common worldwide (46 %) + in North America (GT1a predominant in Quebec + Canada) + GT2 + GT3: North America + Europe + GT4: Africa + Middle East + GT5: South Africa + GT6: Southeast Asia + GT3: associated with faster fibrotic progression and increased risk of steatosis + HCC + importance of genotyping: guides the choice of DAA treatment (pangenotypic vs. genotype-specific) → treatment duration → need to add ribavirin; Hepatic replication and pathogenesis: HCV replicates exclusively in hepatocytes → no integration into the genome (unlike HBV) → liver damage is primarily immunological: inappropriate cytotoxic T-cell response → chronic inflammation → activation of stellate cells (Ito cells) → progressive fibrosis → cirrhosis + hepatocellular carcinoma (HCC) → HCV is not directly cytopathic → cure with DAAs halts the progression of fibrosis and may even allow regression of non-advanced fibrosis/cirrhosis
- Transmission, risk factors, and target populations for screening: Routes of transmission: percutaneous transmission (primary route): injection drug use (IDU): dominant route of transmission in North America and Canada — sharing of syringes, needles, spoons, cotton swabs, and water → a single instance of sharing is sufficient to transmit HCV → HCV is 10 times more transmissible than HIV via parenteral routes → tattooing and piercing under non-sterile conditions + blood transfusions prior to 1990–1992 (routine screening since 1990 by Héma-Québec/Canadian Blood Services) + contaminated blood products prior to 1985 (hemophiliacs ++) + blood exposure incidents (BEIs) in healthcare settings: transmission risk 1.8 % per percutaneous BEI (Alter 1990 — NEJM) + inadequately sterilized medical equipment (endoscopes + dental instruments) → rare in high-resource countries + sexual transmission: low but possible → higher in the presence of ulcerative sexually transmitted infections (STIs) + during traumatic intercourse + among men who have sex with men (MSM) + HIV co-infection → reassess screening regularly in these groups + vertical transmission (mother-to-child): risk 3–5 % + 10–15 % if HIV co-infection + no transmission through breastfeeding (if nipples are not damaged) + community transmission: sharing straws for nasal drug use (cocaine ++) → established risk but lower than injection; Screening — recommendations from Health Canada and the Canadian Society for Infectious Diseases (AMMI Canada 2018): one-time universal screening recommended for all individuals born between 1945 and 1975 (baby boom generation → exposure to medical procedures prior to routine HCV screening) + regular screening for individuals with persistent risk factors: current or former IDUs + MSM with multiple partners + prisoners (past or current incarceration) + individuals from endemic regions (sub-Saharan Africa + Southeast Asia + Egypt → HCV prevalence up to 10–15% of the general population) + sexual partners of HCV-positive individuals + children of HCV-positive mothers + healthcare workers with acute hepatitis symptoms → first-line screening: anti-HCV antibodies (anti-HCV) → if positive → HCV RNA by quantitative PCR → confirms active infection (distinguishes active infection from spontaneously resolved or post-treatment infection) → serological window for antibodies: 8–12 weeks post-exposure → in cases of high suspicion with negative antibodies → HCV RNA as early as 1–2 weeks
- Natural history of infection — phases and complications: Acute phase (6 months post-infection): symptomatic in only 15–25% of cases → jaundice + fatigue + nausea + right upper quadrant pain → in 75–85% of cases: asymptomatic infection → spontaneous clearance: 15–25% of patients spontaneously clear HCV during the acute phase (often young women + favorable IL28B CC genotype) → the majority progress to chronicity; chronic phase (after 6 months): most patients develop chronic hepatitis → fibrosis progression over 20–30 years: stage F0 (no fibrosis) → F1 → F2 → F3 → F4 (cirrhosis) [METAVIR score] → variable rate of progression → factors accelerating fibrosis: alcohol (the most significant — synergistic) + HIV or HBV co-infection + obesity + insulin resistance + age at the time of infection + male gender + GT3 (faster fibrotic progression) → 20–30% of chronic patients develop cirrhosis within 20–30 years + compensated cirrhosis → annual risk of decompensation 3–6% + of HCC 2–5% → decompensated cirrhosis → ascites + encephalopathy + variceal bleeding + hepatorenal syndrome → high mortality → liver transplantation; extrahepatic manifestations of chronic hepatitis C: mixed cryoglobulinemia (type II — monoclonal κ IgM + polyclonal IgG): vascular purpura + arthralgia + peripheral neuropathy + membranoproliferative glomerulonephritis → frequency 40–50% of HCV+ patients for biological cryoglobulins + symptomatic in 5–10% + non-Hodgkin B-cell lymphoma: 2–3 times higher risk in HCV-positive patients → autoimmune thyroiditis (Hashimoto’s) + type 2 diabetes + insulin resistance + lichen planus + Sjögren’s syndrome + chronic fatigue + impaired quality of life → all these manifestations may resolve after virological cure with AADs; assessment of liver fibrosis — non-invasive methods: liver elastography (FibroScan — Echosens): measurement of liver stiffness in kPa → threshold values (HCV): F0–F1: 7.0 kPa + F2: 7.0–9.5 kPa + F3: 9.5–12.5 kPa + F4 (cirrhosis): >12.5 kPa → sensitivity 84% and specificity 89% for cirrhosis (Castera 2005 — Gastroenterology) → FIB-4 index: (age × AST) / (platelet count × √ALT) → score <1.30 = mild fibrosis (VPN 90 %) + >3.25 = advanced fibrosis (VPP 65, %) → accessible as first-line testing without specialized equipment → liver biopsy: the gold standard but invasive → reserved for uncertain cases or when liver disease is present (steatohepatitis + HBV coinfection)
Treatment with direct-acting antivirals (DAAs) and post-treatment follow-up
| Situation / population | AAD Treatment and Clinical Data | Follow-up and special cases |
|---|---|---|
| First-line treatment — adults without cirrhosis or compensated Child-Pugh A cirrhosis Sofosbuvir/velpatasvir — glecaprevir/pibrentasvir — RVS >97 % — 8–12 weeks |
Principles of DAAs — Mechanisms of therapeutic classes: NS5B (polymerase) inhibitors: sofosbuvir (SOF — Sovaldi): pyrimidine nucleotide analog → blocks viral RNA replication → high genetic barrier → most robust resistance class → NS5A (replication + assembly) inhibitors: velpatasvir (VEL) + pibrentasvir (PIB) + elbasvir + ledipasvir + ombitasvir + NS3/4A inhibitors (protease): glecaprevir (GLE) + grazoprevir + paritaprevir + simeprevir → sensitive to resistance-associated variants (RAVs) in NS3 → inhibited by CYP3A4 → significant drug interactions; standard pan-genotypic treatments (AASLD + EASL 2023 + AGHF Canada Guidelines): sofosbuvir/velpatasvir (SOF/VEL — Epclusa): 400/100 mg 1 tablet/day → effective against GT1–6 → SVR 97–99% % → duration 12 weeks in patients without cirrhosis and with compensated cirrhosis (Child A) → ASTRAL-1 trials (Feld 2015 — NEJM: HGT 1, 2, 4, 5, 6 — SVR 99% %) + ASTRAL-3 (Foster 2015 — NEJM: HGT3 — SVR 95% %) + ASTRAL-4 (Curry 2015 — NEJM: decompensated cirrhosis — SVR 83–94% % with ribavirin) → glecaprevir/pibrentasvir (GLE/PIB — Maviret): 100/40 mg 3 tablets/day with a meal → pan-genotypic → SVR 97–100 % → duration 8 weeks (no cirrhosis + treatment-naïve) + 12 weeks (compensated cirrhosis) → SURVEYOR I+II + ENDURANCE + EXPEDITION trials (Zeuzem 2018 — NEJM: 8 weeks for genotypes 1–6 without cirrhosis) → advantages: short duration (8 weeks) + favorable resistance profile + covered by RAMQ; sofosbuvir/ledipasvir (Harvoni): genotypes 1 + 4 → SVR 94–99% % → less commonly used since the advent of pan-genotypic regimens; criteria for choosing between SOF/VEL and GLE/PIB: GLE/PIB preferred if: severe CKD (eGFR <30) — sofosbuvir is contraindicated if eGFR <30 + short duration desired (8 weeks) + SOF/VEL preferred if: patient with moderate CKD (eGFR 30–60 — no dose adjustment required) + HIV co-infection on ART with drug interactions + hepatic decompensation (with or without ribavirin) → ribavirin (RBV): still used in certain cases of decompensated cirrhosis + GT3 with cirrhosis + relapsed patients on first-generation DAAs → weight-based dose 1,000–1,200 mg/day in 2 divided doses → side effects: hemolytic anemia + teratogenic → mandatory contraception for men and women for 6 months post-RBV | Reimbursement in Quebec (RAMQ 2024): sofosbuvir/velpatasvir (Epclusa) and glecaprevir/pibrentasvir (Maviret): listed on the RAMQ Drug List → covered without fibrosis score restriction since 2018 (previously restricted F2+) → prescription by family physician, general practitioner, or specialist → unit cost not covered by the patient if RAMQ drug insurance → special access program if not covered (private insurance or special status) → minimal pre-treatment assessment required: confirmed HCV serology (HCV Ab + HCV RNA) + genotype (if prescribing SOF/VEL: pangenotypic → optional genotype) + liver function tests: ALT + AST + bilirubin + albumin + INR (liver function assessment) + CBC (if ribavirin considered) + creatinine + eGFR (treatment choice if CKD) + fibrosis assessment: FibroScan or FIB-4 + antiviral resistance (AVR) tests: not necessary in 1st line with current pangenotypics → reserved for relapses or prior exposure to NS5A; definition of virological cure — SVR12: undetectable HCV RNA 12 weeks after treatment completion = sustained virological response (SVR12) → synonymous with virological cure → HCV cannot reactivate after an authentic SVR → except reinfection → SVR does not protect against reinfection → mandatory prevention of risky behaviors + annual screening if persistent exposure (IDU) |
| Special populations — CKD, HIV, decompensated cirrhosis, pregnancy, IVDU GLE/PIB if DFGe <30 — TAR VIH interactions — transplantation — reinfection |
HCV and chronic kidney disease (CKD): sofosbuvir: contraindicated if eGFR <30 (accumulation of the metabolite GS-331007 → safety not established + AASLD recommends avoiding) → GLE/PIB (Maviret): treatment of choice if eGFR <30 + in patients on hemodialysis → EXPEDITION-4 trial (Roth 2017 — NEJM): GLE/PIB × 12 weeks in patients on hemodialysis → SVR 98% % → excellent tolerability + sofosbuvir + velpatasvir + voxilaprevir (VOX — Vosevi): retreatment option if eGFR ≥30; HCV and HIV co-infection: drug interactions with antiretroviral therapy (ART) → NS3/4A inhibitors (glecaprevir) inhibited by CYP3A4 inducers (efavirenz + nevirapine → avoid) + ritonavir/cobicistat (pharmacological ARV boosters) → increase glecaprevir concentrations → drug interactions with certain ritonavir-boosted ARVs → check all interactions (hep-drug interactions: www.hep-druginteractions.org) → sofosbuvir/velpatasvir: fewer interactions → preferred for HIV co-infection + complex ART → SVR similar to HCV monotherapy (95–98% 1P3T) if HIV is controlled → treat HCV before optimizing ART → ION-4 trial (Naggie 2015 — NEJM): SOF/ledipasvir for HIV/HCV GT1 → SVR 96% 12-month sustained virologic response; HCV and decompensated cirrhosis (Child-Pugh B or C): protease inhibitors (glecaprevir): contraindicated → risk of hepatic decompensation (impaired hepatic metabolism → accumulation + toxicity) → SOF/VEL ± ribavirin → SVR 83–94% % (ASTRAL-4) → goal: achieve SVR before liver transplantation if possible → or treat post-transplantation (frequent relapse in the graft if pre-transplant viral load is high) + HCV and pregnancy: DAAs are NOT recommended during pregnancy (insufficient safety data — limited animal and human studies) → ribavirin: strictly contraindicated (Category X teratogen) → monitor HCV viremia + quarterly liver function tests during pregnancy → treat after delivery and the end of breastfeeding → vertical transmission: 3–5 % → no change in delivery method recommended + breastfeeding: no contraindication if nipples are intact (HCV is not transmitted through breast milk) → infant screening: HCV RNA at 2 months of age (maternal antibodies persist for up to 18 months → HCV antibodies cannot be interpreted before 18 months) | HCV and people who inject drugs (PWID) — public health issues: PWID represent the population with the highest HCV burden in Canada → HCV prevalence among active PWID: 50–70% in Quebec → treatment without abstinence requirements recommended (AASLD + EASL + AGHF): drug abstinence is NOT a prerequisite for treatment → active drug-using patients have the same SVR rates as abstinent patients (Grebely 2020 — Lancet Gastroenterology) → treatment in a harm reduction context → opioid use disorder treatment programs (OUDT — methadone + buprenorphine/naloxone) → supervised injection services → distribution of sterile equipment → education on reinfection prevention + reinfection after SVR among active IDUs: reinfection rate 2–5 %/year → retreatment indicated if reinfection confirmed → reinfection is not a contraindication to retreatment → annual HCV screening if persistent exposure → simplified community-based treatment program (task-shifting): nurse practitioners + pharmacists + harm reduction workers → delegated DAA prescriptions → increased access among marginalized populations in Quebec; retreatment of HCV relapses after first-line DAAs: SOF/VEL/VOX (Vosevi): sofosbuvir 400 mg + velpatasvir 100 mg + voxilaprevir 100 mg → 1 tablet/day × 12 weeks → pan-genotypic + high resistance barrier → POLARIS-1 and POLARIS-4 trials (Bourlière 2017 — NEJM): SVR 95–97% in patients who failed NS5A inhibitor therapy → standard of care for relapses following first-line pan-genotypic treatment |
| Post-treatment follow-up — residual cirrhosis and HCC surveillance RVS does not cure cirrhosis — residual HCC — ultrasound surveillance — reversible fibrosis |
Follow-up after achieving SVR — what does virological cure mean: undetectable HCV RNA = virological cure → HCV can no longer replicate + liver damage improves but does not disappear instantly → improvement in fibrosis: post-SVR liver elastography studies document a significant reduction in liver stiffness in 60–70% of patients after 1–3 years → partial regression of early cirrhosis is possible (F4 → F3 in 20–30% of patients according to Bachofner 2017 — Alimentary Pharmacology) → advanced cirrhosis does not regress completely → the risk of HCC persists after RLS in cirrhosis (reduced but not eliminated risk); HCC surveillance after SVR in the presence of cirrhosis: residual risk of HCC: 1–2 cases per year even after SVR in patients with cirrhosis (El-Serag 2012 — Gastroenterology → Kanwal 2017 — Gastroenterology: HCV-infected patients with cirrhosis undergoing SVR → HCC risk 0.9 %/year vs. 3.3 %/year without SVR) → mandatory lifelong monitoring if cirrhosis is documented → recommended protocol: liver ultrasound every 6 months (± alpha-fetoprotein AFP — AASLD: AFP optional + EASL: AFP recommended) → if liver nodule ≥1 cm → multi-protocol liver CT or MRI (LI-RADS) → biopsy if LI-RADS 4–5 inconclusive + complications of cirrhosis: monitoring of esophageal varices (gastroscopy every 2–3 years if compensated cirrhosis post-RVS) → if grade 2+ varices → non-selective propranolol or nadolol for primary prophylaxis → if decompensated cirrhosis: remain on the liver transplant list even if RVS + follow-up liver elastography: 1 year post-RVS → if liver stiffness normalized (<7 kPa) → discontinue HCC surveillance if AASLD criteria met (no documented histological cirrhosis) → resolution of extrahepatic manifestations: cryoglobulinemia → regression in 60–70% of cases after RLS + type 2 diabetes → improvement in insulin resistance + B-cell lymphoma → partial response | Major drug interactions with DAAs – systematic check required: Antacids (PPIs – esomeprazole + pantoprazole): reduce absorption of ledipasvir and velpatasvir → separate by 4 hours or avoid high doses of PPIs with SOF/VEL → no interaction with GLE/PIB Anticonvulsants (carbamazepine + phenytoin + oxcarbazepine + rifampicin): induce CYP3A4 and P-gp → drastic reduction of glecaprevir and velpatasvir concentrations → contraindicated with GLE/PIB → replace with levetiracetam or lamotrigine if possible Statins: glecaprevir inhibits OATP1B1/1B3 → increased concentrations of rosuvastatin + atorvastatin → risk of myopathy → reduce statin dose or substitute with pravastatin during treatment Amiodarone: absolute contraindication with any treatment containing sofosbuvir → risk of severe bradycardia (FDA black box warning) → replace amiodarone before treatment if possible St. John's Wort: P-gp inducer → major reduction in DAA concentrations → contraindicated Cyclosporine + tacrolimus (transplant recipients): inhibit CYP3A4 → increase glecaprevir → mandatory monitoring of immunosuppressant levels → interaction checker tool: www.hep-druginteractions.org (University of Liverpool) → check ALL interactions before prescribing |
| Hepatocellular Carcinoma (HCC) on HCV — screening and treatment LI-RADS — sorafenib — atezolizumab/bevacizumab — resection — ablation |
Surveillance and early detection of HCC: target population for surveillance: HCV-related cirrhosis (all Child-Pugh stages) + advanced F3 fibrosis with risk factors (alcohol + obesity + diabetes + associated steatohepatitis) → 6-month ultrasound protocol + optional AFP (AASLD) or recommended (EASL 2018) → nodules <1 cm: monitor at 4 months → if stable → return to 6-month protocol → if growth → MRI or CT → diagnostic imaging (without biopsy if criteria met): multiprotocol liver MRI or 4-phase CT → LI-RADS 2018 criteria: LI-RADS 5 = definite HCC (wash-in + wash-out + capsule + growth) → treat without biopsy → LI-RADS 4 = probable HCC → biopsy or treatment depending on context → LI-RADS 3 = intermediate → monitor at 3–6 months + AFP >200 ng/mL in the context of cirrhosis → very probable HCC; BCLC (Barcelona Clinic Liver Cancer) classification and treatment: BCLC 0 (very early — single tumor ≤2 cm + Child-Pugh A + PS 0) + BCLC A (early — 1–3 nodules ≤3 cm + Child-Pugh A-B + PS 0) → curative treatment: surgical resection (partial hepatectomy) + radiofrequency ablation (RFA) or microwave ablation + liver transplantation if Milan criteria (1 nodule ≤5 cm or 2–3 nodules ≤3 cm) → 5-year survival 50–70% % + BCLC B (intermediate — multifocal without vascular invasion + Child-Pugh A-B + PS 0) → transarterial chemoembolization (TACE) → palliative but improves survival vs. supportive care (Llovet 2002 — Lancet) + BCLC C (advanced — portal invasion or metastases + PS 1–2) → systemic: atezolizumab + bevacizumab (Atezo/Bev): IMbrave150 trial (Finn 2020 — NEJM) → median overall survival 19.2 vs. 13.4 months vs. sorafenib → standard first-line treatment since 2020 → sorafenib (Nexavar): previous first-line treatment → SHARP trial (Llovet 2008 — NEJM) → second-line: regorafenib + cabozantinib + ramucirumab (if AFP >400) | Liver transplantation for hepatitis C: Indications: decompensated HCV cirrhosis (Child-Pugh B-C + MELD ≥15) + HCC meeting the Milan criteria → HCV treatment prior to transplantation is strongly recommended (RVS → improvement in liver function → may remove the patient from the transplant list if sufficient improvement is achieved) → HCV treatable in the graft if post-transplant recurrence (SOF/VEL or GLE/PIB) → excellent results → Canada: liver transplant waiting list: CHUM Montreal + Montreal Jewish General Hospital + London Health Sciences Centre + Toronto General Hospital → MELD criteria + regional allocation; prevention of HCV transmission — public health: harm reduction: needle exchange programs (NEPs) + supervised consumption rooms + over-the-counter naloxone (Narcan) + MUSE Canada → treatment as prevention (TAP): treated patients in sustained virologic response (SVR) no longer transmit HCV → mathematical models: treating IDUs with high prevalence reduces community incidence by 50–80 % over 10 years (Martin 2013 — Lancet) → WHO 2030 goal: elimination → 80% reduction in new HCV infections + 65% reduction in HCV mortality → Quebec Hepatitis C Elimination Plan (INSPQ 2022): expanded screening + universal treatment + harm reduction + routine HBV vaccination |
ℹ️
Hepatitis C is curable in 8 to 12 weeks — and reimbursed in Quebec without any conditions: Direct-acting antivirals (Maviret or Epclusa) achieve virological cure in more than 97% of cases, with one or two daily doses, and no injections. In Quebec, the RAMQ has reimbursed these medications without restrictions based on fibrosis stage since 2018. Any primary care physician can prescribe them. The only test required before starting treatment is a blood test confirming active infection (detectable HCV RNA). Screen and treat = cure.
Situations requiring urgent medical assessment
Known HCV cirrhotic patient + hematemesis or abundant melena + hypotension → acute variceal hemorrhage → call 911 + emergency hospitalization → IV terlipressin or octreotide + antibiotic prophylaxis (norfloxacin or ceftriaxone) + urgent endoscopic elastic band ligation → transfer to intensive care unit → prognosis related to speed of management.
Cirrhotic patient, HCV positive, confusion, asterixis, ammonia odor, distended abdomen Acute hepatic encephalopathy + ascites → medical emergency → lactulose + rifaximin + search for precipitating factor (infection + gastrointestinal bleeding + medications) + diagnostic paracentesis (PMNs >250/mm³ = spontaneous bacterial peritonitis → IV cefotaxime).
Liver nodule ≥1 cm discovered on surveillance ultrasound in a HCV cirrhotic patient. → Exclude CHC → Urgent (within 4 weeks) multiprotocol liver MRI (or 4-phase CT scan) → Do not biopsy without hepatology consultation → Refer to hepatology/digestive oncology for BCLC assessment and therapeutic decision.
Discovery of anti-HCV antibodies in a pregnant woman → confirm with HCV-RNA → if active infection: hepatological + obstetrical follow-up → no treatment during pregnancy → newborn screening by HCV-RNA at 2 months + anti-HCV at 18 months → breastfeeding is allowed if nipples are not damaged.
Consult at Clinique Omicron
Clinique Omicron physicians provide hepatitis C screening, prescription of direct-acting antivirals reimbursed by the RAMQ, liver fibrosis assessment, and post-treatment follow-up. Telemedicine consultations are available to facilitate access to treatment at several service points in Quebec. To make an appointment, visit cliniqueomicron.ca.
The content of this page is for informational purposes only and does not replace the advice of a doctor or hepatologist. Any treatment decision for hepatitis C should take into account the patient's complete clinical profile, drug interactions, and stage of liver disease.
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