What is the recommended treatment regimen for a patient with hepatitis C to achieve Sustained Virologic Response (SVR)?

Hepatitis C Treatment for Sustained Virologic Response (SVR)

Modern direct-acting antiviral (DAA) regimens achieve SVR rates exceeding 95-97% across all HCV genotypes, with sofosbuvir/velpatasvir for 12 weeks or glecaprevir/pibrentasvir for 8-12 weeks (depending on cirrhosis status) representing first-line pangenotypic therapy. 1, 2, 3

Definition of Treatment Success

• SVR is defined as undetectable HCV RNA at 12 weeks post-treatment (SVR12), which represents permanent viral eradication in more than 99% of patients 4, 1, 2
• SVR12 is equivalent to cure, with fewer than 1% of patients experiencing late relapse after achieving this endpoint 1
• SVR24 (24 weeks post-treatment) can also be used but is no longer routinely necessary given the high concordance with SVR12 4, 5

First-Line Treatment Regimens

For Patients Without Cirrhosis (Treatment-Naïve)

• Sofosbuvir/velpatasvir 400mg/100mg once daily for 12 weeks achieves 98% SVR across all genotypes 1, 3
• Glecaprevir/pibrentasvir for 8 weeks is an equally effective alternative for non-cirrhotic patients 4, 1, 3, 6
• Both regimens are pangenotypic and do not require genotype-specific adjustments 1, 3

For Patients With Compensated Cirrhosis (Child-Pugh A)

• Sofosbuvir/velpatasvir for 12 weeks remains the standard duration 4, 3
• Glecaprevir/pibrentasvir duration extends to 12 weeks (not 8 weeks) in cirrhotic patients 4, 3
• Patients with cirrhosis require closer monitoring for adverse effects, which occur more frequently than in non-cirrhotic patients 3

For Recently Acquired Hepatitis C

• Sofosbuvir/velpatasvir for 8 weeks is recommended as first-line 1
• Glecaprevir/pibrentasvir for 8 weeks serves as an alternative first-line option 1

Pre-Treatment Assessment Requirements

Before initiating DAA therapy, the following assessments are mandatory:

• HCV RNA quantitative testing to confirm active viremia 1, 3
• HCV genotype and subtype determination (though modern pangenotypic regimens minimize the clinical impact of this) 1, 3
• Fibrosis staging using non-invasive methods (FibroScan, APRI, FIB-4) or liver biopsy if uncertainty exists 3
• Comprehensive drug-drug interaction screening with all concurrent medications, as P-glycoprotein inducers and moderate-to-strong CYP inducers are absolute contraindications 1, 3
• Baseline resistance-associated substitutions (RAS) testing is recommended for HCV genotype 1a and genotype 3 with specific mutations (A30K, Y93H, P53del) that reduce DAA effectiveness 7

Treatment Prioritization

Immediate treatment should be prioritized for:

• Patients with advanced fibrosis (≥F3) or any degree of cirrhosis (F4), as they face the highest risk of hepatic decompensation and hepatocellular carcinoma 1, 2, 3
• Patients with severe extrahepatic manifestations including symptomatic vasculitis or HCV immune complex nephropathy 3
• Pre- and post-liver transplant patients 3
• Individuals at high risk of HCV transmission: people who inject drugs, men who have sex with men with high-risk practices, women of childbearing age wishing to conceive, and hemodialysis patients 2

Patients with minimal or no fibrosis (F0-F2) should still be scheduled for treatment rather than deferred, though timing may be more flexible 3

Treatment Monitoring Protocol

• HCV RNA levels should be checked at baseline, weeks 4 and 12 during treatment, end of treatment, and 12 weeks post-treatment 3
• SVR12 confirmation is mandatory via undetectable HCV RNA using a sensitive molecular assay 1, 2, 6
• For most patients on DAA regimens with expected high SVR rates, checking SVR is optional except in patients at risk of reinfection 1
• Routine testing for HCV RNA beyond 48 weeks post-treatment to evaluate for late virologic relapse is not supported by evidence 1

Special Populations and Considerations

HIV/HCV Coinfection

• HIV/HCV coinfected patients can be treated with identical HCV regimens as HCV mono-infected patients, with equivalent virological outcomes 3
• The safety profile in coinfected subjects is similar to mono-infected subjects 8
• Elevated total bilirubin occurs in 94% of subjects receiving atazanavir as part of antiretroviral therapy, though without concomitant transaminase increases 8

Treatment-Experienced Patients

For patients who failed prior DAA therapy:

• If 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) 3
• If failed NS5A inhibitor-containing regimen: 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) 3
• Glecaprevir/pibrentasvir for 16 weeks can be used for retreatment in genotype 3 treatment-experienced patients 4

Liver Transplant Recipients

• Sofosbuvir/velpatasvir plus ribavirin for 12 weeks is recommended for both pre- and post-transplant settings 3

Clinical Benefits of Achieving SVR

• Prevents complications of chronic liver disease including cirrhosis, hepatic decompensation, hepatocellular carcinoma, and death 2
• Resolution of liver disease in non-cirrhotic patients 4, 3
• Regression of hepatic fibrosis and reduced risk of hepatic failure and portal hypertension in cirrhotic patients 4
• Significant reduction (>70%) but not elimination of HCC risk in cirrhotic patients, with residual annual risk of 0.3-2.4% 1
• Improvement in extrahepatic manifestations: DAAs effectively treat HCV-associated mixed cryoglobulinemia, improve insulin resistance in 90% of patients, increase glomerular filtration rate, decrease proteinuria and hematuria, and reduce major cardiovascular events 7
• Improvement in quality of life, physical function, fatigue, and cognitive impairment 7

Critical Post-SVR Considerations

Patients with established cirrhosis (F4) or advanced fibrosis (F3) require indefinite hepatocellular carcinoma surveillance with ultrasound every 6 months even after achieving SVR, as they retain a reduced but ongoing HCC risk 1, 2

Common Adverse Effects

The most common adverse events with sofosbuvir-based regimens include:

• Fatigue (30-38%) and headache (24-30%) with sofosbuvir/ribavirin for 12-24 weeks 8
• Anemia (6-10%) with interferon-free regimens, though significantly less than interferon-containing regimens (21-23%) 8
• The majority of adverse events are grade 1 in severity 8
• Serious symptomatic bradycardia can occur when coadministered with amiodarone, requiring careful monitoring 8

Risk Factors for Treatment Failure

• Old age, male sex, and cirrhosis are associated with lower SVR rates 7
• Presence of resistance-associated substitutions (RAS) in the region targeted by the received DAAs, particularly for HCV genotype 3 with baseline RAS like A30K, Y93H, and P53del 7
• Significant liver fibrosis remains an impediment to achieving SVR with short-duration DAA therapy, as demonstrated by only 76% SVR with 6-week triple DAA therapy in patients with stage 3-4 fibrosis 9

Historical Context (No Longer Recommended)

Older interferon-based regimens achieved SVR rates of only 40-50% for genotype 1 and up to 80% for genotypes 2 and 3 4. First-generation protease inhibitors (telaprevir, boceprevir) with peginterferon and ribavirin achieved 65-75% SVR but should no longer be used due to inferior efficacy and tolerability compared to modern DAAs 4.