Lesson 2. Retreatment of Patients with Prior HCV Treatment Experience

Hepatitis C virus (HCV) treatment failure can occur in a small percentage of individuals treated with direct-acting antivirals (DAAs) due to a variety of factors, including suboptimal adherence, advanced fibrosis, HCV genotype, and variable pharmacokinetic and/or host immune properties. Although there are options for retreatment in individuals in whom prior DAA therapy failed, the choices and clinical experience with these combinations are more limited than for treatment-naïve individuals. This lesson will review the recommended and alternative regimens for persons who are HCV treatment-experienced, as outlined by the American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA) HCV Guidance.[1]

The AASLD-IDSA HCV Guidance has organized pretreatment recommendations according to the following three prior treatment regimen groups: (1) sofosbuvir-containing DAA or elbasvir-grazoprevir, (2) glecaprevir-pibrentasvir, and (3) multiple DAA failures, including the salvage regimens of sofosbuvir-velpatasir-voxilaprevir or sofosbuvir plus glecaprevir-pibrentasvir.[2,3,4] Recommended regimens are considered preferred options due to their proven efficacy and a more robust evidence base, as well as their favorable side effect profile and pill burden.[1] Alternative regimens are also effective and may be the best choice for a specific patient, but they are considered secondary options due to greater dosing complexity, higher pill burden, or less clinical data.[1]

In contrast with persons receiving initial HCV DAA treatment, there are potential special considerations, as outlined below, that may arise or need to be addressed with retreatment.

Indications for Ordering HCV Genotype

Genotyping is recommended for treatment-experienced patients who previously failed a sofosbuvir-containing DAA regimen or elbasvir-grazoprevir because the presence of genotype 3 can have implications on retreatment in this population. Otherwise, genotype has little relevance for regimen selection when retreating HCV infection. This is also true for resistance testing, since the presence of resistance-associated variants has not been shown to influence treatment outcomes significantly. For further discussion about HCV resistance, see the AASLD/IDSA HCV Resistance Primer.[5]

Determination of Prior Treatment Failure or Reinfection

For persons with prior HCV treatment who have a detectable post-treatment HCV RNA level, there are three main possible scenarios:

1. They had treatment failure with the prior regimen and never achieved a sustained virologic response (SVR), or
2. They achieved an SVR but had a late virologic relapse, which is exceedingly rare), or
3. They achieved a virologic cure but have become reinfected with HCV.

The approach to HCV retreatment is different for individuals who experienced treatment failure versus those with reinfection. Virologic relapse after obtaining an SVR is very rare, and this scenario is unlikely to occur in clinical practice.[6,7] For persons with HCV reinfection, we recommend taking the same treatment approach as for treatment-naïve individuals, since there is no reason to expect they would be more difficult to treat than a person who has never received HCV treatment. For persons with true prior virologic failure (i.e., did not achieve an SRV), the approach to retreatment should be based on the prior treatment regimen, as outlined in this lesson. In addition, efforts should be made to identify any factors that may have contributed to the treatment failure, such as difficulty with medication adherence, unrecognized cirrhosis, or hepatocellular cancer. In the rare case of virologic relapse after achieving an SVR, the selection of the retreatment regimen should be guided by the prior treatment regimen.

Potential Use of Ribavirin and Safety Concerns

In the simplified treatment approach, ribavirin is not included in any of the recommended first-line regimens. For persons undergoing retreatment, ribavirin is a component of some of the regimens. Accordingly, clinicians should be aware of the main hematologic and teratogenic safety issues attributable to ribavirin.[8,9]

• Hematologic Toxicity: Ribavirin can cause severe hemolytic anemia, especially at higher doses. For persons taking ribavirin, regular monitoring of hemoglobin is recommended. Ribavirin can also cause leukopenia.
• Teratogenicity: Ribavirin is a teratogenic drug in rodents and may cause birth defects and fetal harm when administered to women who are pregnant.[10] It is therefore contraindicated in pregnant women and in men whose female partners are pregnant. In addition, extreme care must be taken to prevent pregnancy in females of reproductive age taking ribavirin and in female partners of male patients taking ribavirin. Women who may become pregnant should have a confirmed negative pregnancy test immediately before initiating ribavirin, and should be instructed to use at least two forms of effective contraception during treatment with ribavirin and for 6 months after treatment has been stopped.

In nearly all patients with or without compensated cirrhosis who have experienced treatment failure with a sofosbuvir-containing regimen, such as ledipasvir-sofosbuvir or sofosbuvir-velpatasvir, the AASLD-IDSA HCV Guidance recommends retreatment with the triple-class combination of sofosbuvir-velpatasvir-voxilaprevir for 12 weeks.[4] The only exception to this is in patients with cirrhosis and genotype 3; for these individuals, if they do not have a contraindication, the AASLD-IDSA HCV Guidance recommends treatment with sofosbuvir-velpatasvir-voxilaprevir with the addition of ribavirin.[4] The alternative option for patients who have experienced prior failure with sofosbuvir-containing DAAs is 16 weeks of glecaprevir-pibrentasvir.[4] This regimen may be indicated, for example, in patients who require higher-dose or twice-daily proton-pump inhibitor therapy for esophageal disease and therefore cannot take sofosbuvir-velpatasvir-voxilaprevir due to the drug interaction with velpatasvir.

For patients who have experienced treatment failure with elbasvir-grazoprevir, the AASLD-IDSA HCV Guidance recommends treatment with sofosbuvir-velpatasvir-voxilaprevir for 12 weeks.[4] Due to limited data and overlapping resistance pathways, the 16-week regimen of glecaprevir-pibrentasvir, which is an alternative regimen for prior failure with a sofosbuvir-containing regimen, is not recommended for prior treatment failure with elbasvir-grazoprevir.[4]

The following summarizes the evidence for these retreatment regimens, including the main trials that evaluated treatment-experienced individuals with the following salvage regimens.

Sofosbuvir-Velpatasvir-Voxilaprevir

• POLARIS-1: In this phase 3, placebo-controlled trial, investigators enrolled adults with chronic HCV genotypes 1, 2, 3, 4, 5, or 6 who had previously received treatment that included an NS5A inhibitor.[11] Participants with HCV genotype 1 were randomized in a 2:1 ratio to either the active arm, a fixed-dose combination of sofosbuvir-velpatasvir-voxilaprevir once daily for 12 weeks, or the placebo arm (participants received sofosbuvir-velpatasvir-voxilaprevir after follow-up).[11] Individuals with HCV genotypes 2, 3, 4, 5, or 6 were assigned to the active arm. Most participants were either ledipasvir- or daclatasvir-experienced (51% and 27%, respectively), and compensated cirrhosis was present in 46% of those in the active arm. The overall SVR12 rate was 96% by intent-to-treat analysis, with 1 virologic breakthrough and 6 viral relapses among those who received sofosbuvir-velpatasvir-voxilaprevir. An SVR12 occurred in 99% of those who were not cirrhotic and 93% of cirrhotic patients. The SVR12 rates were not associated with the presence of NS5A or other resistance-associated substitutions at baseline.[11]
• POLARIS-4: In this phase 3, active-comparator, open-label trial, 314 adults with chronic HCV genotypes 1, 2, or 3 with prior direct-acting antiviral therapy without an NS5A inhibitor were randomized to receive either sofosbuvir-velpatasvir-voxilaprevir or sofosbuvir-velpatasvir for 12 weeks.[11] Compensated cirrhosis was present in 46% of participants and prior sofosbuvir exposure in 80%. For participants with HCV genotype 1a, the SVR12 rates were 98% and 89% for the sofosbuvir-velpatasvir-voxilaprevir and sofosbuvir-velpatasvir arms, respectively. For HCV genotype 1b, the SVR12 rates were 96% for the sofosbuvir-velpatasvir-voxilaprevir arm and 95% for the sofosbuvir-velpatasvir arm.[11] Virologic relapse was confirmed at week 4 for 1 sofosbuvir-velpatasvir-voxilaprevir recipient and in 14 participants who received sofosbuvir-velpatasvir (5 of whom had genotype 1a).[11]
• VA Cohort of DAA-experienced Patients: This real-world observational cohort study evaluated 573 DAA-experienced patients from the VA system who received sofosbuvir-velpatasvir-voxilaprevir for retreatment of HCV infection.[12] Most (86%) participants had HCV genotype 1 infection and 35% had cirrhosis.[12] Nearly all were NS5A-experienced, many with prior exposure to ledipasvir-sofosbuvir (66%), elbasvir-grazoprevir (17%), or sofosbuvir-velpatasvir (9%).[12] Overall SVR rates were 91% for genotype 1, 90% for genotype 2, 91% for genotype 3, and 100% for genotype 4 when evaluated on an intent-to-treat basis.[12] Notably, lower SVR rates (79–87%) were observed in those with prior sofosbuvir-velpatasvir experience.[12] Resistance testing was not performed pre-treatment.
• Sofosbuvir-Velpatasvir-Voxilaprevir in Egypt: This clinical trial randomized 315 patients with prior treatment failure to either sofosbuvir-velpatasvir-voxilaprevir alone (n=158) or with ribavirin (n=157).[13] Most (96%) of the participants had received sofosbuvir and daclatasvir (with or without ribavirin) as their first-line DAA; 37% had a FIB-4 index greater than 3.25.[13] Genotyping or resistance testing was not performed. Ultimately, 17 individuals from each arm were lost to follow-up. The SVR12 rates were comparable in both arms (DAA alone versus DAA plus ribavirin), in both the intent-to-treat (87% versus 88%) or per protocol analysis (98% versus 99%).[13] Subgroup analysis did not suggest differences in SVR rates by cirrhosis status.[13]
• Meta-analysis of Sofosbuvir-Velpatasvir-Voxilaprevir: This meta-analysis included 24 studies of 2,887 patients who underwent retreatment with sofosbuvir-velpatasvir-voxilaprevir with or without ribavirin.[14] Among those included, 42% had cirrhosis, 17.2% had prior sofosbuvir-velpatasvir exposure, 24.8% received ribavirin in addition to sofosbuvir-velpatasvir-voxilaprevir, and 50% had pretreatment RAS testing performed.[14] The pooled SVR12 rates were 95% for the per-protocol analysis and 88% for the intent-to-treat analysis.[14] Predictors of retreatment failure were genotype 3, cirrhosis, active hepatocellular carcinoma, and prior sofosbuvir-velpatasvir therapy.[14]

Glecaprevir-Pibrentasvir

• MAGELLAN-1 (Part 1): This was an open-label, phase 2 study evaluating the safety and efficacy of glecaprevir-pibrentasvir, with or without ribavirin, for 12 weeks in noncirrhotic individuals with HCV genotype 1 and who previously failed DAA therapy.[15] Fifty participants were enrolled, 6 of whom received low-dose glecaprevir 200 mg plus pibrentasvir 80 mg (arm A), 22 of whom received standard-dose glecaprevir-pibrentasvir plus ribavirin 800 mg (arm B), and 22 of whom received standard-dose glecaprevir-pibrentasvir without ribavirin (arm C).[15] Fifty percent of persons in the study were NS5A-naïve but protease inhibitor-experienced, 16% were NS5A treatment-experienced but protease inhibitor-naïve, and 34% were NS5A-experienced and protease inhibitor-experienced.[15] In an intention-to-treat analysis, 100% of participants in arm A, 95% in arm B, and 86% in arm C achieved an SVR12.[15]
• MAGELLAN-1 (Part 2): This was a randomized, open-label, phase 3 study evaluating the safety and efficacy of fixed-dose glecaprevir-pibrentasvir for 12 or 16 weeks in DAA treatment-experienced adults with HCV genotype 1 or 4.[16] Of the 91 participants enrolled, 30% had compensated cirrhosis, 30% were protease inhibitor treatment-experienced, 37% were NS5A treatment-experienced, and 33% were protease inhibitor and NS5A treatment-experienced.[16] Among individuals with prior protease inhibitor treatment experience, SVR12 was achieved in 100% in both the 12-week and 16-week arms.[16] Among those with prior NS5A treatment experience, SVR12 was obtained in 88% of those in the 12-week arm and 94% in the 16-week arm. [16] Only 79% and 81% of the NS5A and protease inhibitor treatment-experienced participants achieved an SVR12 in the 12-week and 16-week arms, respectively.[16]
• SURVEYOR-II (Part 3): In this partially randomized, open-label, phase 3 trial, the safety and efficacy of glecaprevir-pibrentasvir was evaluated in treatment-naïve and treatment-experienced adults with HCV genotype 3. Enrollment included 44 treatment-experienced adults with HCV genotype 3 infection without cirrhosis who were randomized 1:1 to receive either 12 or 16 weeks of glecaprevir-pibrentasvir. Patients with compensated cirrhosis were treated for 12 weeks if they were treatment naïve (n=40) or 16 weeks if treatment experienced (n = 47). Sustained virologic response (SVR12) was achieved in 98% of treatment-naïve persons with cirrhosis and 96% of treatment-experienced persons with cirrhosis who were treated with glecaprevir-pibrentasvir for 12 or 16 weeks, respectively. In the group without cirrhosis, 91% of treatment-experienced participants achieved SVR12 with 12 weeks of glecaprevir-pibrentasvir compared with 95% in the 16-week arm.
• HCV-TARGET: In this phase 3b, open-label pragmatic trial, the safety and efficacy of 12 or 16 weeks of glecaprevir-pibrentasvir was evaluated in treatment-experienced adults with HCV genotype 1 infection (80% genotype 1a) who experienced viral relapse after previous treatment with sofosbuvir plus an NS5A inhibitor (ledipasvir, velpatasvir or daclatasvir).[17] The study enrolled 177 participants and was stratified by cirrhosis status: 50 with compensated cirrhosis and 127 without cirrhosis.[17] Within each group, they were randomized to receive either 12 or 16 weeks of glecaprevir-pibrentasvir. Overall, an SVR12 was achieved in 91.5% (162 of 177) of participants.[17] The SVR12 rates were numerically higher in the 16-week arms of both groups: 94% (46 of 49) of noncirrhotic participants and 97% (28 of 29) of cirrhotic participants compared with 90% (70 of 78) and 86% (18 of 21), respectively, in the 12-week arm.[17]

For patients who have experienced treatment failure with glecaprevir-pibrentasvir, the AASLD-IDSA HCV Guidance recommends using either 16 weeks of glecaprevir-pibrentasvir with sofosbuvir and ribavirin (weight-based) or 12 weeks of sofosbuvir-velpatasvir-voxilaprevir.[2] The addition of weight-based ribavirin to the 12-week sofosbuvir-velpatasvir-voxilaprevir regimen is recommended for those patients with compensated cirrhosis, regardless of genotype.[2]

The following summarizes the evidence base for these retreatment regimens, including the main trials that evaluated treatment-experienced individuals.

Glecaprevir-pibrentasvir plus Sofosbuvir and Ribavirin

• MAGELLAN-3: This was an open-label, single-arm, phase 3 study that evaluated the safety and efficacy of 16 weeks of glecaprevir-pibrentasvir plus sofosbuvir with weight-based ribavirin for participants who experienced virologic failure with a standard 12-week course of glecaprevir-pibrentasvir in a parent trial.[18] Twenty-three enrolled in the study; 61% (14 of 23) had genotype 3 HCV, 30% (7 of 23) had genotype 1 HCV (all but 1 had 1a), and 9% (2 of 23) had genotype 2 HCV infection. Seven (30%) had compensated cirrhosis, and most 91% (21 of 23) had baseline resistance-associated substitutions in NS5A. Overall, 96% (22 of 23) achieved a sustained virologic response SVR. The retreatment regimen was well tolerated in this group, with no treatment discontinuations.[18]

Sofosbuvir-Velpatasvir-Voxilaprevir

• SOF-VEL-VOX in G/P Failure: This was a single-arm prospective study that enrolled 31 adults from three clinical centers with a history of treatment failure with glecaprevir-pibrentasvir to undergo 12 weeks of sofosbuvir-velpatasvir-voxilaprevir at standard dose.[19] For 90% (28 of 31) of the participants, glecaprevir-pibrentasvir was their first HCV treatment regimen. A majority of these participants had cirrhosis (58%) and/or genotype 3 infection (58%). Most (90%) had baseline resistance-associated substitutions to NS5A +/- NS3. Overall, SVR12 was achieved in 94% (29/31) of participants. Those with baseline RAS had an SVR12 rate of 93% while those without had 100%. The SVR12 rates were 94% and 92% for genotypes 3 and 1a, respectively. Treatment was well tolerated, with no early discontinuations. Of note, the addition of ribavirin was not evaluated in this study; however, the addition of ribavirin to sofosbuvir-velpatasvir-voxilaprevir is recommended for patients with compensated cirrhosis based on other treatment studies in patients who experienced DAA failure.[19]

There are very limited data to guide the retreatment of patients who experienced treatment failure with multiple DAA regimens, including treatment failure with the regimen of sofosbuvir-velpatasvir-voxilaprevir.[3] For prior treatment failure with sofosbuvir-velpatasvir-voxilaprevir, the AASLD-IDSA HCV Guidance recommends a longer treatment duration and incorporating ribavirin into the treatment regimen.[3]

The evidence base comprises small case series and reports and includes the following salvage regimen options.

Glecaprevir-Pibrentasvir plus Sofosbuvir and Ribavirin

Glecaprevir and pibrentasvir each appear to retain antiviral activity in vitro against the more common amino acid substitutions known to confer resistance to the earlier-generation NS5A inhibitors and NS3/4A protease inhibitors.[20,21] For this reason, it is considered in retreatment regimens even when patients have failed glecaprevir-pibrentasvir.

• In MAGELLAN-3, the open-label, single-arm trial, investigators evaluated the safety and efficacy of glecaprevir-pibrentasvir with sofosbuvir and ribavirin (weight-based) for 16 weeks in patients who had virologic failure with glecaprevir-pibrentasvir.[18] They enrolled 23 such patients, 30% of whom had compensated cirrhosis and 91% of whom had baseline resistance-associated substitutions for NS5A. Ninety-one percent (21 of 23) of the participants achieved an SVR12.[18]
• In a report from Europe, the same combination (glecaprevir-pibrentasvir with sofosbuvir and weight-based ribavirin) was one of the most commonly used rescue therapies in 40 individuals who experienced viral relapse with sofosbuvir-velpatasvir-voxilaprevir.[22] Most of them had HCV genotype 3 or 1a infection, and 70% had cirrhosis. Of the 15 individuals who received glecaprevir-pibrentasvir with sofosbuvir (with or without ribavirin, n=8 and n=7 respectively) forof varying durations (12, 16, or 24 weeks), 73% (11 of 15) achieved an SVR12.[22]

Extended duration of therapy may need to be considered in some individuals who are experienced with multiple DAA regimens. How best to identify these individuals who may benefit from extended therapy is unclear, but those with multiple poor prognostic factors (e.g., HCV genotype 3 and cirrhosis) may be candidates. One case report described a patient with genotype 3 infection and advanced fibrosis who did not achieve an SVR12 with sofosbuvir and daclatasvir (first regimen), sofosbuvir-velpatasvir and ribavirin (second regimen) and finally sofosbuvir-velpatasvir-voxilaprevir.[23] She ultimately achieved SVR12 after a 24-week course of glecaprevir-pibrentasvir with sofosbuvir and ribavirin.[23]

Sofosbuvir-Velpatasvir-Voxilaprevir plus Ribavirin

At this time, there are no published reports of the efficacy of extending the duration to 24 weeks with sofosbuvir-velpatasvir-voxilaprevir and ribavirin in patients who have experienced treatment failure with multiple DAA regimens. The AASLD-IDSA HCV Guidance for using sofosbuvir-velpatasvir-voxilaprevir with ribavirin in this setting is based largely on extrapolated data from a multicenter, single-arm study that examined the efficacy of 24 weeks of sofosbuvir-velpatasvir plus weight-based ribavirin in patients who had prior experience with NS5A-NS5B combination therapy with or without an NS3/4 protease inhibitor.[24] In this study, the SVR rate with this treatment combination was 91% (63 of 69), with higher rates observed in persons with HCV genotype 1 (97%) and genotype 2 (93%), compared with genotype 3 (78%).[24]

• Retreatment options exist for patients who experience DAA failure, but these options are more limited than those available for treatment-naïve individuals.
• For most patients who experience treatment failure with a sofosbuvir-containing regimen such as ledipasvir-sofosbuvir or sofosbuvir-velpatasvir, the recommended option for retreatment is the triple-class combination of sofosbuvir-velpatasvir-voxilaprevir for 12 weeks.
• Patients with cirrhosis and genotype 3 who experience treatment failure with a sofosbuvir-containing regimen should receive sofosbuvir-velpatasvir-voxilaprevir with ribavirin.
• For patients who have experienced treatment failure with glecaprevir-pibrentasvir, the recommended regimens include either 16 weeks of glecaprevir-pibrentasvir with sofosbuvir and ribavirin (weight-based) or 12 weeks of sofosbuvir-velpatasvir-voxilaprevir. The addition of weight-based ribavirin to the 12-week regimen is recommended for those patients with compensated cirrhosis.
• There are limited data to guide the retreatment of patients who experience treatment failure with multiple DAA treatment regimens, including sofosbuvir-velpatasvir-voxilaprevir. Recommended options in this setting include triple-class combinations of an NS5A inhibitor, an NS5B inhibitor, and NS3/4A protease inhibitor with ribavirin for an extended duration of 16 or 24 weeks. Expert consultation is advised in these cases.