What is the preferred retreatment regimen for a hepatitis C patient who failed a prior NS5A‑containing direct‑acting antiviral, considering liver disease stage (including decompensated cirrhosis) and renal function?

Retreatment of Hepatitis C After NS5A-Containing DAA Failure

For patients who failed prior NS5A-containing direct-acting antiviral therapy, the preferred retreatment regimen is sofosbuvir/velpatasvir/voxilaprevir for 12 weeks in those without cirrhosis or with compensated (Child-Pugh A) cirrhosis, achieving SVR rates >95%. 1, 2

Compensated Cirrhosis or No Cirrhosis (Child-Pugh A)

First-Line Retreatment (All Genotypes 1-6)

• Sofosbuvir/velpatasvir/voxilaprevir for 12 weeks is the standard retreatment for any genotype after NS5A inhibitor failure. 1, 2
• This triple combination achieved 96% SVR in a prospective Canadian registry of 128 DAA-experienced patients, including 44% with cirrhosis. 3
• The regimen includes sofosbuvir (high barrier to resistance), velpatasvir (NS5A inhibitor), and voxilaprevir (NS3 protease inhibitor), targeting all three drug classes simultaneously. 1, 2

Alternative for Difficult-to-Cure Cases

• Sofosbuvir + glecaprevir/pibrentasvir for 12 weeks can be used in patients with predictors of lower response (advanced liver disease, multiple prior DAA courses, complex NS5A resistance patterns) after multidisciplinary review. 1, 2
• Pibrentasvir has a higher barrier to resistance than other NS5A inhibitors, making this combination viable for complex resistance profiles. 1
• A phase II trial showed 96% SVR (22/23 patients) with this regimen in patients who previously failed glecaprevir/pibrentasvir. 1, 2

Very Difficult-to-Cure Patients

For patients with NS5A resistance who failed ≥2 prior DAA regimens:

• Either sofosbuvir/velpatasvir/voxilaprevir OR sofosbuvir/glecaprevir/pibrentasvir for 12 weeks. 1, 2
• Add weight-based ribavirin (1,000 mg if <75 kg; 1,200 mg if ≥75 kg) OR extend treatment duration to 16-24 weeks. 1, 2
• These modifications require expert multidisciplinary team decision-making considering liver disease severity, prior treatment history, and resistance profiles. 1

Sequential Failure After First-Line Triple Therapy

• If sofosbuvir/velpatasvir/voxilaprevir fails, retreat with sofosbuvir/glecaprevir/pibrentasvir for 24 weeks plus weight-based ribavirin. 2
• In the Canadian registry, patients who previously failed sofosbuvir/velpatasvir had lower SVR rates (88.5%) compared to those failing other regimens (99%). 3

Decompensated Cirrhosis (Child-Pugh B or C)

Critical Contraindication

• Protease inhibitor-containing regimens (voxilaprevir, glecaprevir) are absolutely contraindicated in decompensated cirrhosis due to risk of hepatic decompensation and death. 1, 2

Recommended Regimen

• Sofosbuvir/velpatasvir for 24 weeks plus weight-based ribavirin (1,000 mg if <75 kg; 1,200 mg if ≥75 kg). 2
• This is the only safe option for decompensated patients, as it avoids protease inhibitors entirely. 2
• Early retreatment before progression to decompensation is essential, as decompensated disease eliminates most therapeutic options. 1, 2

Genotype-Specific Considerations

Genotype 1 & 4

• After NS5A inhibitor failure, sofosbuvir/velpatasvir/voxilaprevir for 12 weeks achieves >95% SVR. 1, 2
• Glecaprevir/pibrentasvir alone (without sofosbuvir) is NOT recommended after NS5A failure—treatment failed in 7.3% of genotype 1a patients in randomized trials. 1, 4

Genotype 2

• Sofosbuvir/velpatasvir for 24 weeks with ribavirin achieves approximately 91% SVR after prior DAA failure. 2

Genotype 3

• Most challenging genotype, especially with cirrhosis and NS5A resistance. 1
• Sofosbuvir/velpatasvir for 24 weeks with ribavirin achieves approximately 90% SVR in cirrhotic patients with baseline NS5A resistance. 2
• Genotype 3b has particularly poor outcomes—only 70% SVR with glecaprevir/pibrentasvir in clinical trials. 4

Genotypes 5 & 6

• Sofosbuvir/velpatasvir for 24 weeks with ribavirin is recommended after NS5A inhibitor failure. 2

Resistance Testing and Management

Baseline Resistance Assessment

• HCV resistance testing prior to retreatment is useful to guide therapy by predicting response probabilities according to the resistance profile. 1
• All patients should be retreated in the context of a multidisciplinary team including experienced hepatologists and virologists. 1

Key Resistance Patterns

• NS5A resistance-associated substitutions (RAS) persist indefinitely, whereas NS3 protease inhibitor RAS wane over months to ~2 years. 2
• Common NS5A RAS include L31M/V/I and Y93H; double mutations may reduce SVR compared to single mutations. 2, 5
• For genotype 3, the Y93H mutation is particularly problematic and should prompt addition of ribavirin. 1

Impact on Treatment Selection

• Presence of NS5A RAS does not mean all drugs from the class are ineffective—pibrentasvir has higher barrier to resistance than ledipasvir or daclatasvir. 1, 2
• Complex NS5A RAS patterns warrant consideration of sofosbuvir/glecaprevir/pibrentasvir over sofosbuvir/velpatasvir/voxilaprevir. 1, 2

Renal Impairment Considerations

Severe Renal Impairment (CKD Stage 4-5)

• Glecaprevir/pibrentasvir requires no dose adjustment in severe renal impairment, including hemodialysis patients. 4
• In the EXPEDITION-4 trial, 98% SVR was achieved in 104 patients with CKD stages 4-5 (82% on hemodialysis). 4
• Sofosbuvir-containing regimens can be used in CKD stage 4-5, though glecaprevir/pibrentasvir is preferred for treatment-naive patients. 4

Retreatment in Renal Impairment

• For NS5A-experienced patients with severe renal impairment, sofosbuvir/velpatasvir/voxilaprevir remains the preferred option despite renal dysfunction. 2
• Ribavirin dosing must be adjusted for creatinine clearance when added to retreatment regimens. 2

Treatment Duration and Ribavirin Use

Standard Duration

• 12 weeks for patients without cirrhosis or with compensated (Child-Pugh A) cirrhosis receiving sofosbuvir/velpatasvir/voxilaprevir. 1, 2
• 24 weeks for decompensated cirrhosis receiving sofosbuvir/velpatasvir plus ribavirin. 2

Ribavirin Addition

• Weight-based ribavirin dosing: 1,000 mg daily if <75 kg; 1,200 mg daily if ≥75 kg. 1, 2
• Add ribavirin for: very difficult-to-cure patients, decompensated cirrhosis, or when extending treatment duration. 1, 2
• When ribavirin is contraindicated, extend treatment duration to 24 weeks without ribavirin. 1

Critical Pitfalls to Avoid

Do NOT Use Glecaprevir/Pibrentasvir Alone

• Glecaprevir/pibrentasvir without sofosbuvir is NOT recommended for retreatment after NS5A inhibitor failure. 1, 4
• SVR rates drop to 83-86% in genotype 1a patients with baseline NS3 + NS5A resistance. 1, 4
• The combination must include sofosbuvir to overcome NS5A resistance. 1, 2

Do NOT Delay Retreatment in Cirrhotic Patients

• Postponement can lead to decompensation, eliminating protease inhibitor options and leaving only sofosbuvir/velpatasvir with lower efficacy. 1, 2
• Retreatment should be instituted as soon as possible after virologic failure. 1

Do NOT Use Protease Inhibitors in Decompensated Cirrhosis

• Absolute contraindication due to risk of acute-on-chronic liver failure and death. 1, 2
• This includes voxilaprevir and glecaprevir—only sofosbuvir/velpatasvir is safe. 2

Do NOT Retreat with Same Failed Regimen

• Retreating with sofosbuvir/ledipasvir for 24 weeks after initial failure resulted in high frequency of failure predicted by NS5A RAS. 1
• Always switch to a regimen containing drugs from different classes than the failed regimen. 1, 2