What is the management of Hepatitis C (HCV)?

Management of Hepatitis C

First-Line Treatment: Direct-Acting Antivirals

All patients with chronic hepatitis C should be treated with pangenotypic direct-acting antiviral (DAA) regimens, specifically sofosbuvir/velpatasvir 400mg/100mg once daily for 12 weeks or glecaprevir/pibrentasvir for 8-12 weeks depending on cirrhosis status. 1, 2

Preferred Regimen

• Sofosbuvir/velpatasvir is the preferred first-line option, achieving 98% sustained virologic response (SVR) rates across all genotypes 1, 2
• Administered as a single tablet (400mg/100mg) once daily for 12 weeks, with or without food 3, 4
• Effective for genotypes 1,2,3,4,5, and 6 1, 2

Alternative Regimen

• Glecaprevir/pibrentasvir is equally effective with treatment duration of 8 weeks for patients without cirrhosis and 12 weeks for compensated cirrhosis (Child-Pugh A) 2

Pre-Treatment Assessment Requirements

Before initiating DAA therapy, mandatory testing must include:

• HCV RNA quantitative testing to confirm active infection 2
• HCV genotype and subtype determination 5, 2
• Hepatitis B testing (HBsAg and anti-HBc) in all patients to identify risk of HBV reactivation 3, 4
• Fibrosis staging using non-invasive methods (transient elastography, serum biomarkers) or liver biopsy if uncertainty exists 5, 6
• Comprehensive drug-drug interaction screening 2

Critical Safety Consideration

HBV reactivation has resulted in fulminant hepatitis, hepatic failure, and death in HCV/HBV coinfected patients treated with DAAs. 3, 4 Monitor these patients for hepatitis flare during and after HCV treatment, and initiate HBV antiviral therapy as clinically indicated 4

Treatment Prioritization Algorithm

Immediate treatment priority should be given to:

1. Patients with advanced fibrosis (≥F3) or any cirrhosis due to higher risk of complications 6, 2
2. Decompensated cirrhosis (Child-Pugh B and C) requiring urgent interferon-free regimens 6
3. Pre- and post-liver transplant patients 2
4. Patients with severe extrahepatic manifestations (symptomatic vasculitis, HCV immune complex nephropathy) 5, 6
5. Patients with hepatocellular carcinoma 2

For patients with minimal or no fibrosis (F0-F2), treatment should still be scheduled rather than deferred, though timing may be more flexible 5

Treatment Modifications by Clinical Scenario

Compensated Cirrhosis (Child-Pugh A)

• Use same pangenotypic regimens as non-cirrhotic patients 2
• Extend glecaprevir/pibrentasvir duration to 12 weeks 2
• Monitor closely as side effects are increased compared to non-cirrhotic patients 5

Decompensated Cirrhosis (Child-Pugh B/C)

• Sofosbuvir/velpatasvir plus ribavirin for 12 weeks is recommended 1
• Risk factors for hepatic decompensation during treatment include: albumin <35 g/L (HR 3.11), MELD score ≥14 (HR 1.63), and HCV genotype 3 (HR 2.05) 7
• Patients with these risk factors require close monitoring or treatment deferral until after transplantation 7
• Treatment should be performed with special care when albumin <3.5 g/dl or platelets <100,000 5

Liver Transplant Recipients

• Sofosbuvir/velpatasvir plus ribavirin for 12 weeks in both pre- and post-transplant settings 2
• For patients awaiting transplant, administer up to 48 weeks or until transplantation to prevent post-transplant reinfection 3

HIV/HCV Coinfection

• Use the same HCV treatment regimens as HCV mono-infected patients with identical virological outcomes 2
• Dose adjustments may be needed for drug interactions with antiretroviral drugs 1
• Daclatasvir requires dose adjustment to 30 mg with ritonavir/cobicistat-boosted protease inhibitors and to 90 mg with efavirenz 1

Renal Impairment

• No dosage adjustment required for sofosbuvir/velpatasvir in any degree of renal impairment, including dialysis patients 4
• Ribavirin requires dose reduction when CrCl ≤50 mL/min 3, 4

Critical Drug-Drug Interactions

Absolute contraindications - do not use with DAAs:

• P-glycoprotein (P-gp) inducers 2, 4
• Moderate-to-strong CYP inducers (CYP2B6, CYP2C8, CYP3A4) including rifampin, St. John's wort, and carbamazepine 2, 4
• These agents significantly decrease DAA concentrations and reduce efficacy 4

Amiodarone coadministration is not recommended due to risk of serious symptomatic bradycardia, including fatal cardiac arrest 4

• If no alternative exists, require 48-hour inpatient cardiac monitoring followed by daily outpatient heart rate monitoring for 2 weeks 4
• Bradycardia can occur within hours to 2 weeks after starting treatment 4

Monitoring Protocol

HCV RNA monitoring schedule:

• Baseline before treatment 2
• Week 4 during treatment 2
• Week 12 during treatment 2
• End of treatment 2
• 12 weeks post-treatment (SVR12) - primary measure of cure 1, 2

SVR12 (undetectable HCV RNA 12 weeks after treatment completion) represents viral eradication and is achieved in >99% of patients who reach this endpoint. 2

Post-SVR Surveillance

Patients with cirrhosis require continued HCC surveillance with ultrasound every 6 months indefinitely, even after achieving SVR, as the risk of HCC is significantly reduced but not eliminated 6, 1

Treatment Outcomes and Goals

Expected outcomes with modern DAA regimens:

• SVR rates exceeding 95% in most patient populations 1, 2, 8
• Improvement in liver histology 2
• Decreased risk of cirrhotic complications 2
• Reduced occurrence of hepatocellular carcinoma 2
• Improved survival rates 2
• Resolution of extrahepatic manifestations 2

The primary goal is HCV eradication, preventing cirrhosis complications, hepatocellular carcinoma, extrahepatic manifestations, and death. 2

Retreatment Strategies for DAA Failure

For patients who fail initial sofosbuvir-based therapy:

• Retreatment with sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, or sofosbuvir/daclatasvir with ribavirin for 12 weeks (F0-F2) or 24 weeks (F3-F4) 2

For patients who fail NS5A inhibitor-containing regimens:

• Use sofosbuvir with a protease inhibitor (grazoprevir/elbasvir or simeprevir) plus ribavirin for 12 weeks (genotype 1b or 4 without cirrhosis) or 24 weeks (genotype 1a or cirrhosis) 2

Common Pitfalls to Avoid

• Failing to test for HBV before treatment - can result in fatal HBV reactivation 3, 4
• Inadequate fibrosis staging - leads to missing disease progression and incorrect treatment duration 6
• Overlooking drug-drug interactions - particularly with P-gp/CYP inducers and amiodarone 2, 4
• Discontinuing HCC surveillance after SVR in cirrhotic patients - HCC risk persists despite cure 6, 1
• Treating decompensated cirrhosis patients with high-risk features without close monitoring - albumin <35 g/L, MELD ≥14, and genotype 3 predict decompensation during treatment 7