What is the recommended antiviral therapy for a patient with Hepatitis C Virus (HCV) and a complex medical history, including Chronic Obstructive Pulmonary Disease (COPD)?

Antiviral Therapy in HCV

First-Line Treatment Recommendation

All patients with chronic HCV infection, including those with COPD or other comorbidities, should be treated with pangenotypic direct-acting antiviral (DAA) regimens: either sofosbuvir/velpatasvir 400mg/100mg once daily for 12 weeks or glecaprevir/pibrentasvir for 8-12 weeks depending on cirrhosis status. 1, 2

Treatment Selection Algorithm

Preferred Regimen

• Sofosbuvir/velpatasvir is the preferred pangenotypic option with 98% sustained virological response (SVR) rates across all genotypes 1, 2
• Administered as a single tablet once daily for 12 weeks regardless of genotype 1
• Effective in patients without cirrhosis and those with compensated cirrhosis (Child-Pugh A) 1, 2

Alternative Regimen

• Glecaprevir/pibrentasvir provides equally effective alternative therapy 1, 2
• Duration: 8 weeks for patients without cirrhosis 1, 3
• Duration: 12 weeks for patients with compensated cirrhosis (Child-Pugh A) 1, 3
• Administered as three tablets (300mg/120mg total) once daily with food 3

Pre-Treatment Assessment Requirements

Before initiating DAA therapy, the following mandatory testing must be completed: 1, 4, 2

• Hepatitis B screening: HBsAg and anti-HBc to detect current or prior HBV infection 3, 5
• HCV RNA quantitative testing to confirm active infection 1, 4
• HCV genotype and subtype determination 1, 4
• Fibrosis staging using non-invasive methods or liver biopsy if uncertainty exists 1, 2
• Comprehensive drug-drug interaction screening with all concurrent medications 1, 2

Critical Safety Consideration

HBV reactivation has been reported in HCV/HBV coinfected patients treated with DAAs, with some cases resulting in fulminant hepatitis, hepatic failure, and death. 3, 5 Monitor HCV/HBV coinfected patients for hepatitis flare during and after HCV treatment, and initiate HBV antiviral therapy as clinically indicated 3, 5

Treatment Prioritization for Immediate Therapy

The following patient groups require immediate treatment priority: 1, 2

• Patients with advanced fibrosis (≥F3) or any cirrhosis 1, 4, 2
• Pre- and post-liver transplant recipients 1, 2
• Patients with severe extrahepatic manifestations (symptomatic vasculitis, HCV immune complex nephropathy) 1, 2
• Patients with hepatocellular carcinoma 1, 2
• Individuals at high risk of transmission 2

Patients with minimal or no fibrosis (F0-F2) should still be scheduled for treatment rather than deferred, though timing may be more flexible. 2

Special Considerations for COPD Patients

COPD does not contraindicate DAA therapy or require treatment modifications. 6 The modern DAA regimens (sofosbuvir/velpatasvir and glecaprevir/pibrentasvir) have minimal side effects and excellent tolerability profiles, making them suitable for patients with complex medical histories including COPD 7

Key advantages of current DAA therapy: 7

• High efficacy (SVR rate >95%) with minimal side effects 7
• Good tolerability across diverse patient populations 7
• Easy drug administration with once-daily oral dosing 7
• Short treatment duration (8-12 weeks) 7

Critical Drug-Drug Interactions

Absolute contraindications for DAAs include: 1

• P-glycoprotein (P-gp) inducers 1
• Moderate-to-strong CYP inducers 1

These agents significantly decrease DAA concentrations and reduce efficacy 1. Screen all concurrent medications, including those commonly used for COPD management, before initiating therapy 1, 2

Treatment Monitoring Protocol

HCV RNA monitoring schedule: 1, 4

• Baseline HCV RNA quantitative testing 1, 4
• Week 4 during treatment 1
• Week 12 during treatment 1
• End of treatment 1
• 12 weeks post-treatment (SVR12) 1, 4

SVR12 (undetectable HCV RNA 12 weeks after treatment completion) represents viral cure in >99% of patients who achieve this endpoint. 1, 4 This is the primary measure of treatment success 1

Treatment Modifications by Clinical Scenario

Compensated Cirrhosis (Child-Pugh A)

• Use same pangenotypic regimens as non-cirrhotic patients 1, 2
• Extend glecaprevir/pibrentasvir duration to 12 weeks 1, 2, 3
• Monitor closely for side effects, which are increased compared to non-cirrhotic patients 2
• Exercise special care when albumin <3.5 g/dL or platelets <100,000 2

Liver or Kidney Transplant Recipients

• MAVYRET (glecaprevir/pibrentasvir) is recommended for 12 weeks in transplant recipients 3

Expected Clinical Outcomes and Benefits

Achieving SVR provides the following benefits: 2

• Prevention of cirrhosis complications 2
• Prevention of hepatocellular carcinoma 2
• Prevention of hepatic decompensation and death 2
• Improvement in liver histology 2
• Resolution of extrahepatic manifestations 2
• Improved quality of life and removal of stigma 2

Viral eradication significantly reduces non-liver related deaths in patients with HCV-related extrahepatic manifestations. 6

Post-SVR Follow-Up

For patients with advanced fibrosis or cirrhosis (F3-F4): 2

• Lifelong HCC surveillance required even after achieving SVR 2
• Ultrasound every 6 months indefinitely 2
• Risk of HCC is significantly reduced but not eliminated, with residual annual risk of 0.3-2.4% 4

For all patients post-SVR: 2

• Fibrosis reassessment 2
• Monitoring for reinfection in at-risk patients 2

Management of Treatment Failure

If DAA therapy fails (occurs in 1-5% of patients): 8, 7

First-Line Retreatment

• Voxilaprevir/velpatasvir/sofosbuvir (VOX/VEL/SOF) is first choice for second-line treatment following DAA failure 8
• Achieves viral eradication rates above 90% irrespective of resistance-associated substitutions (RASs) 8

Alternative Retreatment Strategies

• For patients who failed sofosbuvir alone or sofosbuvir plus ribavirin: retreatment with sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, or sofosbuvir/daclatasvir with ribavirin for 12 weeks (F0-F2) or 24 weeks (F3-F4) 1
• For patients who failed NS5A inhibitor-containing regimen: sofosbuvir with a protease inhibitor (grazoprevir/elbasvir or simeprevir) plus ribavirin for 12-24 weeks depending on genotype and cirrhosis status 1

Resistance Considerations

• Viral resistance is a major reason for virological failure 8
• NS3-4A variants often disappear gradually after DAA therapy is stopped 9
• NS5A variants tend to persist for more than 2 years 9
• For first-line therapy with glecaprevir/pibrentasvir or velpatasvir/sofosbuvir, no general baseline resistance analysis is required due to high antiviral activity and high barrier to resistance 8

Common Pitfalls and How to Avoid Them

Do not defer treatment due to COPD or other comorbidities - modern DAA regimens have excellent safety profiles and minimal drug interactions 6, 7

Do not skip HBV screening - failure to test for HBV before initiating DAA therapy can result in fatal HBV reactivation 3, 5

Do not use interferon-based regimens - these are outdated and have been replaced by highly effective, well-tolerated DAA regimens 6, 7, 10

Do not assume cure without SVR12 confirmation - fewer than 1% of patients relapse after achieving SVR12, but confirmation is essential 4

Do not discontinue HCC surveillance in cirrhotic patients post-SVR - residual HCC risk persists despite viral eradication 4, 2