In an adult with chronic hepatitis C who experienced virologic failure after a prior direct‑acting antiviral regimen, what retreatment regimen is recommended based on genotype (1‑6), cirrhosis status (compensated vs decompensated), and prior NS5A inhibitor exposure?

Retreatment of Hepatitis C After Direct-Acting Antiviral Failure

For adults with chronic hepatitis C who failed prior DAA therapy, the preferred retreatment regimen is sofosbuvir/velpatasvir/voxilaprevir for 12 weeks in patients without cirrhosis or with compensated (Child-Pugh A) cirrhosis, regardless of genotype or prior NS5A inhibitor exposure. 1

Core Retreatment Principles

All patients who experience DAA treatment failure should be managed by a multidisciplinary team including experienced hepatologists and virologists, as retreatment strategies require specialized expertise. 1 The fundamental principle is to use a regimen containing sofosbuvir (which has a high barrier to resistance) combined with drugs from classes not previously used, ideally avoiding cross-resistance. 1

Resistance testing prior to retreatment is useful to guide therapy by predicting response probabilities based on the resistance profile, though specific algorithms cannot be derived from current data. 1

Compensated Cirrhosis or No Cirrhosis (Child-Pugh A)

First-Line Retreatment Option

Sofosbuvir/velpatasvir/voxilaprevir for 12 weeks is the recommended first-line retreatment for all genotypes (1-6) in patients who failed any prior DAA regimen (including NS5A inhibitor-containing regimens), achieving SVR rates >95%. 1 This triple combination overcomes the effect of baseline resistance-associated substitutions in both NS3 and NS5A regions. 1

Alternative for Difficult-to-Cure Patients

For patients with predictors of lower response—including advanced liver disease, multiple prior DAA treatment courses, or complex NS5A resistance patterns—sofosbuvir plus glecaprevir/pibrentasvir for 12 weeks can be used based on individual multidisciplinary decision. 1 In a phase II trial, this triple combination achieved SVR in 22 of 23 patients (96%) who had previously failed glecaprevir/pibrentasvir. 1

Very Difficult-to-Cure Patients

In patients with NS5A resistance-associated substitutions who have failed two or more prior DAA regimens containing protease and/or NS5A inhibitors, either sofosbuvir/velpatasvir/voxilaprevir OR sofosbuvir/glecaprevir/pibrentasvir can be administered for 12 weeks with weight-based ribavirin (1,000 mg if <75 kg or 1,200 mg if ≥75 kg), and/or treatment duration can be extended to 16-24 weeks. 1 These decisions must be individualized by expert teams considering severity of liver disease, prior treatment history, and resistance profiles. 1

Sequential Retreatment Failure

If a patient fails retreatment with sofosbuvir/velpatasvir/voxilaprevir, the next option is sofosbuvir/glecaprevir/pibrentasvir for 24 weeks with weight-based ribavirin (1,000 or 1,200 mg based on weight). 1

Decompensated Cirrhosis (Child-Pugh B or C)

Protease inhibitors are absolutely contraindicated in decompensated cirrhosis due to risk of hepatic decompensation and death. 1, 2 This eliminates voxilaprevir-containing and glecaprevir-containing regimens from consideration.

The recommended retreatment for decompensated cirrhosis after DAA failure is sofosbuvir/velpatasvir for 24 weeks with weight-based ribavirin (1,000 or 1,200 mg based on weight <75 kg or ≥75 kg). 1 This must be decided on an individual basis by expert teams. 1

Retreatment should be instituted as soon as possible before progression to decompensation, as the presence of decompensated cirrhosis severely limits therapeutic options. 1

Genotype-Specific Considerations

Genotypes 1 and 4

For patients who failed sofosbuvir-based regimens without NS5A inhibitors, retreatment with sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, or sofosbuvir/daclatasvir is appropriate. 1, 2

For patients who failed NS5A inhibitor-containing regimens, older data support using sofosbuvir plus ritonavir-boosted paritaprevir/ombitasvir/dasabuvir (genotype 1) or sofosbuvir plus ritonavir-boosted paritaprevir/ombitasvir (genotype 4) for 12-24 weeks with ribavirin, though this is now superseded by sofosbuvir/velpatasvir/voxilaprevir. 1 Real-world data show SVR rates of 94-95% with these older combinations. 3, 4

Genotype 2

Patients who failed sofosbuvir-based therapy can be retreated with sofosbuvir/velpatasvir for 24 weeks with ribavirin, achieving SVR rates of 91%. 1

Genotype 3

Genotype 3 represents a more challenging population, particularly with cirrhosis and NS5A resistance. 1 For NS5A inhibitor failures, sofosbuvir/velpatasvir for 24 weeks with ribavirin is recommended. 1 However, sofosbuvir/velpatasvir/voxilaprevir achieved only 90% SVR in genotype 3 patients with cirrhosis and baseline NS5A resistance. 1 Real-world data confirm lower SVR rates (69-76%) in genotype 3 cirrhotic patients with certain retreatment regimens. 1, 5

Genotypes 5 and 6

For NS5A inhibitor failures, sofosbuvir/velpatasvir for 24 weeks with ribavirin is recommended. 1

Critical Resistance Considerations

NS5A resistance-associated substitutions persist indefinitely after selection, unlike NS3 protease inhibitor resistance which declines over months to 2 years. 1 This makes prior NS5A inhibitor exposure the most important factor in retreatment planning. 1

Common NS5A resistance mutations include L31M/V/I and Y93H, and the presence of double mutations (both L31 and Y93) may reduce SVR rates compared to single mutations, though data are limited. 3 Glecaprevir/pibrentasvir is not recommended for retreatment after NS5A inhibitor failure, as SVR rates drop to 83-86% in genotype 1a patients, particularly with baseline NS3 plus NS5A resistance. 1, 6

Treatment Duration and Ribavirin

For patients without cirrhosis or with mild-moderate fibrosis (F0-F2) who failed prior DAA therapy, retreatment should be 12 weeks with ribavirin. 1 For patients with extensive fibrosis (F3) or compensated cirrhosis, extend to 24 weeks with ribavirin. 1

Weight-based ribavirin dosing is 1,000 mg daily if <75 kg or 1,200 mg daily if ≥75 kg. 1 In patients with contraindications to ribavirin, 24-week duration without ribavirin may be considered. 1

Common Pitfalls

• Do not use glecaprevir/pibrentasvir alone for retreatment after NS5A inhibitor failure—this regimen is specifically not indicated for this population due to high failure rates. 1, 6
• Do not delay retreatment in cirrhotic patients—progression to decompensation eliminates protease inhibitor options and significantly complicates management. 1
• Do not use protease inhibitors in any patient with decompensated cirrhosis—this can cause acute-on-chronic liver failure and death. 1, 2
• Do not assume all NS5A inhibitors have equal resistance profiles—pibrentasvir has a higher barrier to resistance than first-generation NS5A inhibitors, which is why sofosbuvir/glecaprevir/pibrentasvir can salvage some NS5A failures. 1