Sign In

Treatment of Chronic Hepatitis C Infection

Treatment of HCV Genotype 5 or 6

Lesson 5. Treatment of HCV Genotype 5 or 6

CME/CNE Earn CE credit for this module  PDF Share

Learning Objective Performance Indicators

  • List the preferred therapies for the initial treatment of adults with HCV genotype 5 or 6 chronic infection
  • Discuss the preferred approach to retreatment of adults with HCV genotype 5 or 6 chronic infection who have failed prior therapy
Last Updated: October 12th, 2020
Authors:
Maria A. Corcorran, MD, MPH
Maria A. Corcorran, MD, MPH
Assistant Professor
Division of Allergy & Infectious Diseases
University of Washington
,
H. Nina Kim, MD
H. Nina Kim, MD
Professor of Medicine
Division of Allergy & Infectious Diseases
University of Washington
Disclosures: Grant to institution: Gilead Sciences
Reviewer:
David H. Spach, MD
David H. Spach, MD
Professor of Medicine
Division of Allergy & Infectious Diseases
University of Washington
Disclosures: None
Table of Contents

Introduction

Background

In the United States, fewer than 2% of hepatitis C virus (HCV) infections involve genotype 5 or 6 infection.[1] In contrast, infection with HCV genotype 5 is endemic in South Africa, where up to 40% of individuals with chronic HCV have genotype 5 infection.[2,3,4] Scattered pockets of HCV genotype 5 have also been isolated from regions in Europe and North and Eastern sub-Saharan Africa.[4,5,6] There is only one subtype of HCV genotype 5 (subtype 5a).[3] Little is known about the natural history of individuals with genotype 5 HCV. Infection with HCV genotype 6 has primarily occurred in China, Hong Kong, Korea, Taiwan, and Southeast Asia, including Thailand, Vietnam, Singapore, and Malaysia.[7,8,9] Almost all cases of HCV genotype 6 in the United States have involved immigrants from Asia and Southeast Asia.[10] Available data suggest that adults with HCV genotype 6 infection have a similar natural history as those with genotype 1.[11] Because of the low prevalence of HCV genotype 5 or 6 in clinical trials, less is known about the optimal treatment of HCV genotype 5 or 6 infection compared with the more common genotypes. The following discussion regarding initial treatment and retreatment of adults with genotype 5 or 6 chronic HCV assumes the person and their clinician have already made the decision to initiate HCV therapy. This topic review does not address the treatment of HCV genotype 5 or 6 in persons with decompensated cirrhosis, severe renal impairment (or end-stage renal disease), or post-liver transplantation.

Medications used to Treat Hepatitis C

The HCV Medications section on this website provides detailed information for each of the Food and Drug Administration (FDA)-approved medications listed in the treatment recommendations, including links to the full prescribing information and to patient assistance programs. The direct-acting antiviral (DAA) agents exert their action at specific steps in the HCV life cycle. There are three major classes of DAA medications: (1) nonstructural proteins 3/4A (NS3/4A) protease inhibitors, (2) NS5A inhibitors, and (3) NS5B polymerase inhibitors (Figure 1); the NS5B polymerase inhibitors include the nucleoside analogs and nonnucleoside analogs.[12,13] Adherence with the treatment regimen is extremely important. Thus, patients should receive detailed counseling regarding the importance of adherence prior to starting therapy, as well as intensive monitoring and follow-up during therapy.

Approach to Choosing HCV Genotype 5 or 6 Treatment Regimens

For adults with HCV genotype 5 or 6 chronic infection, two key factors influence the choice and duration of therapy: cirrhosis status and prior treatment experience. In addition, the cost of the regimen, insurance coverage, and patient or provider preference can play a major role in the regimen choice. The following treatment recommendations are based on the AASLD-IDSA HCV Guidance for initial treatment of adults with HCV genotypes 5 or 6 and for retreatment of adults in whom prior therapy failed, including those with HCV genotypes 5 or 6.[14,15]

HCV Genotype 5 or 6: Initial Treatment

Background

There are relatively few studies dedicated to the treatment of persons with HCV genotype 5 or 6 chronic infection, particularly for DAA therapy. Older studies in treatment-naïve patients with genotype 5 infection that have examined the combination of interferon (or peginterferon) with ribavirin for 48 weeks have reported sustained virologic response rates at 12 weeks (SVR12) post-treatment of approximately 55 to 70%.[5,16,17,18,19] Most of the older studies of initial treatment of persons with HCV genotype 6 were observational (with small sample sizes) and have reported SVR12 rates of 70 to 80% with peginterferon plus ribavirin when given for 48 weeks (and only slightly lower when given for 24 weeks).[20,21,22,23] Available data suggest SVR12 rates can exceed 95% with glecaprevir-pibrentasvir, sofosbuvir-velpatasvir, or ledipasvir-sofosbuvir for the initial therapy of HCV genotype 5 or 6 infection.[24,25,26,27,28]

Factors to Consider Prior to Choosing Treatment Regimen

For individuals with HCV genotype 5 or 6 chronic infection, little is known regarding baseline factors that may predict response to therapy, but as with other genotypes, cirrhosis and treatment experience probably play a role.

AASLD-IDSA HCV Guidance for Initial Treatment of HCV Genotype 5 and 6

The following is a summary of the AASLD-IDSA HCV Guidance for initial treatment of adults with HCV genotype 5 or 6 infection, including those with compensated cirrhosis.[29] For individuals with cirrhosis, the AASLD-IDSA HCV Guidance defines compensated cirrhosis as Child-Turcotte-Pugh class A and decompensated cirrhosis as Child-Turcotte-Pugh class B or class C. The recommended regimens are listed by evidence level; when the evidence level is considered equivalent, the regimens are listed alphabetically.

Table 1. AASLD-IDSA HCV Guidance for Genotype 5 or 6: Initial Treatment
Treatment-Naïve Genotype 5 or 6 Patients With and Without Compensated Cirrhosis^

Recommended regimens listed by evidence level and alphabetically
^For treatment of patients with decompensated cirrhosis, see the AASLD-IDSA Guidance: Unique Populations—Patients with Decompensated Cirrhosis.
Source: AASLD-IDSA. HCV Guidance: Recommendations for testing, management, and treating hepatitis C. Initial treatment of HCV infection: treatment-naive genotype 5 or 6. [AASLD-IDSA Hepatitis C Guidance] - Accessed October 11, 2020.

Studies of Initial Treatment of Adults with HCV Genotype 5 or 6

The following key studies support the recommendations for treatment of patients with chronic hepatitis C and genotype 5 or 6 infection who are treatment naïve.

Glecaprevir-Pibrentasvir

  • ENDURANCE-4: In this single-arm, phase 3 trial, 121 adults with HCV genotype 4, 5, or 6 infection (without cirrhosis) were enrolled to receive treatment with a 12-week course of glecaprevir-pibrentasvir.[25] Among those who were enrolled 32% were treatment experienced (all of whom had previously received either interferon plus ribavirin or peginterferon plus ribavirin).[25] Of the 121 participants included in the trial, 21% (26 of 121) had genotype 5 and 16% (19 of 126) had genotype 6. All participants with genotype 5 or 6 achieved an SVR12.[25]
  • ENDURANCE-5,6: This phase 3b, open-label trial examined the safety and efficacy of glecaprevir-pibrentasvir in treatment-naïve and treatment-experienced adults with HCV genotype 5 or 6.[30] The duration of treatment was 8 weeks in participants without cirrhosis (n = 75) and 12 weeks in those with compensated cirrhosis (n = 9). Overall, 97.6% (82 of 84) of individuals who received treatment achieved an SVR12; treatment success occurred in 96% (22 of 23) of participants with HCV genotype 5 and in 98% (60 of 61) of those with HCV genotype 6. High efficacy was noted across 14 different HCV genotype 6 subtypes.[30]
  • EXPEDITION-1: This phase 3, single-arm, open-label trial evaluated the safety and efficacy of 12 weeks of glecaprevir-pibrentasvir in treatment-naïve and treatment-experienced adults with compensated cirrhosis and HCV genotype 1, 2, 4, 5, or 6 infection.[26] All (100%) of participants with genotype 5 (n = 2) or genotype 6 (n = 7) achieved an SVR12.[26]
  • EXPEDITION-8: This single-arm, phase 3b study evaluated the efficacy of glecaprevir-pibrentasvir for 8 weeks in treatment-naïve adults with compensated cirrhosis and HCV genotypes 1, 2, 3, 4, 5, or 6.[31] Among all participants enrolled, only 1 had HCV genotype 5 and 9 had HCV genotype 6; all participants with HCV genotype 5 or 6 achieved an SRV12.[31]
  • SURVEYOR-I and SURVEYOR-II: The SURVEYOR-I (HCV genotype 1, 4, 5, or 6) and SURVEYOR-II (HCV genotypes 2 or 3) were phase 2, open-label trials of treatment-naïve and treatment-experienced adults without cirrhosis.[32] In the SURVEYOR-I trial, participants with HCV genotype 4, 5, or 6 received 12 weeks of glecaprevir-pibrentasvir. Among those enrolled and treated, one had HCV genotype 5 and 11 had HCV genotype 6.[32] For the participants with HCV genotype 5 or 6, 100% (12 of 12) achieved an SVR12 (data not provided for number of treatment-naïve versus treatment-experienced patients with HCV genotype 5 or 6).[32]
  • SURVEYOR-II (Part 4): This phase 2, open-label, single-arm trial evaluated the efficacy of 8 weeks of glecaprevir-pibrentasvir in treatment-naïve and treatment-experienced adults without cirrhosis who had HCV genotype 2, 4, 5, or 6.[25] Treatment-experienced participants had previously received (1) peginterferon (or interferon), with or without ribavirin, or (2) sofosbuvir plus ribavirin, with or without peginterferon.[25] Of the 2 individuals with HCV genotype 5 who were enrolled, both achieved an SVR-12; 90% (9 of 10) of participants with HCV genotype 6 achieved an SVR12, and one was lost to follow up.[25]

Ledipasvir-Sofosbuvir

  • Ledipasvir-Sofosbuvir for HCV Genotype 5: In a phase 2, open-label study conducted in France, investigators enrolled 21 treatment-naïve and 20 treatment-experienced adults with HCV genotype 5 infection to receive a 12-week course of ledipasvir-sofosbuvir.[28] For the treatment-naïve individuals with HCV genotype 5 infection, 95% (20 of 21) achieved an SVR12. For individuals with cirrhosis, 89% (8 of 9) achieved an SVR12 compared with 97% (31 of 32) without cirrhosis who achieved an SVR12.[28]
  • New Zealand Genotype 3 and 6 Trial: In this open-label, phase 2 study performed at two centers in New Zealand, investigators enrolled treatment-naïve and treatment-experienced adults with HCV genotype 3 or 6 infection.[24] One arm of this study enrolled 25 participants with HCV genotype 6 to receive a 12-week course of ledipasvir-sofosbuvir. Overall, 96% (24 of 25) of individuals with HCV genotype 6 achieved an SVR12; the one person in this cohort who did not achieve an SVR12 withdrew from the study at week 8.[24] Only two of the treatment-naïve individuals with HCV genotype 6 had cirrhosis.[24]
  • Systematic Review of HCV Genotype 6 Treatment: In a 2019 systematic review of response to DAA therapy among persons with genotype 6 HCV, there was significant variability in SVR rates observed following ledipasvir-sofosbuvir therapy.[33] In this review, authors found HCV treatment SVR12 rates varied from a low of 64.1% in a Myanmar study to 100% in a study out of Vietnam.[33] Although factors influencing these discrepant results are felt to be multiple, a variable distribution of genotype 6 subtypes, with a higher prevalence of genotype 6e (a subtype without in vitro activity against ledipasvir-sofosbuvir) in Myanmar, may have contributed to these findings.[33,34] Pending further data, the AASLD/IDSA guidance recommends against the use of ledipasvir-sofosbuvir in persons with known genotype 6e.
  • United States-Based HCV Genotype 6 Study: This open-label, prospective study enrolled noncirrhotic individuals with HCV genotype 6 at 4 United States health centers to receive treatment with ledipasvir-sofosbuvir.[35] The noncirrhotic participants received an 8-week treatment course and those with cirrhosis (or prior treatment experience) received a 12-week course.[35] In the 8-week arm, 95% (19/20) achieved an SVR12. Similarly, in the 12-week arm 90% (38/40) achieved an SVR12.[35]

Sofosbuvir-Velpatasvir

  • ASTRAL-1: In the phase 3 ASTRAL-1 trial, investigators randomized treatment-naïve and treatment-experienced adults with chronic HCV genotype 1, 2, 4, 5, or 6 infection in a 5:1 ratio to receive a 12-week course of either sofosbuvir-velpatasvir or placebo.[27] The study enrollment included 34 individuals with HCV genotype 5 infection and 41 with HCV genotype 6.[27] Among the treatment-naïve participants treated with sofosbuvir-velpatasvir, 96% (23 of 24) with HCV genotype 5 infection achieved an SVR12 and 100% (38 of 38) with HCV genotype 6 achieved an SVR12.[27]
  • POLARIS-2: This open-label, phase 3 trial compared 12 weeks of sofosbuvir-velpatasvir versus 8 weeks of sofosbuvir-velpatasvir-voxilaprevir in DAA-naïve persons with HCV genotype 1, 2, 3, 4, 5, or 6.[36] There were no participants with HCV genotype 5 who received sofosbuvir-velpatasvir, but, 94% (17 of 18) with HCV genotype 5 who received 8 weeks of sofosbuvir-velpatasvir-voxilaprevir achieved an SVR12.[36] All participants with HCV genotype 6 achieved an SRV12, including 9 in the sofosbuvir-velpatasvir arm and 30 in the sofosbuvir-velpatasvir-voxilaprevir arm.[36]

HCV Genotype 5 or 6: Retreating Persons who Failed Prior Therapy

Background

Given the very low prevalence of genotypes 5 and 6 in settings where HCV therapy is accessible, limited data and experience exist with retreatment of patients with genotype 5 or 6. Recommendations are primarily based on available data in small numbers of treatment-experienced individuals with genotype 5 or 6 from clinical studies, and by extrapolating from experience with other HCV genotypes.

Factors to Consider Prior to Choosing Treatment Regimen

For patients chronically infected with genotype 5 or 6 hepatitis C, insufficient data exist regarding the impact of cirrhosis on the optimal retreatment regimen or duration of therapy given the small numbers of patients in these trials. The retreatment of genotype 5 or 6 patients with decompensated cirrhosis, severe renal impairment (or end-stage renal disease),  or post-liver transplantation is not addressed in this lesson.

Baseline Resistance Testing

Baseline resistance testing is not routinely recommended for treatment-experienced patients with HCV genotype 5 or 6 infection.

AASLD-IDSA HCV Guidance for Retreatment of HCV Genotype 5 or 6

The following is a summary of the AASLD-IDSA HCV Guidance for retreatment of adults with hepatitis C genotype 5 or 6 infection, including those without cirrhosis and those with compensated cirrhosis.[14,37,38,39] For individuals with cirrhosis, compensated cirrhosis is defined as Child-Turcotte-Pugh class A and decompensated cirrhosis as Child-Turcotte-Pugh class B or class C. The AASLD-IDSA HCV Guidance for retreatment is no longer genotype specific, but instead emphasizes a pangenotypic approach to retreatment based on the prior treatment regimen. In addition, the AASLD-IDSA HCV Guidance no longer includes recommendations for the retreatment of persons who experienced prior treatment failure with interferon-based therapy, including interferon plus first-generation protease inhibitors (telaprevir, boceprevir); these individuals have robust cure rates with modern DAA regimens similar to that observed with treatment-naïve persons. The major exception is that retreatment of persons with HCV genotype 5 or 6 with compensated cirrhosis with glecaprevir-pibrentasvir should be given for 12 weeks as opposed to only 8 weeks in treatment-naive persons with compensated cirrhosis. In the following tables, the recommended regimens are based on prior regimen failure and are listed by evidence level; when the evidence level is considered equivalent, the regimens are listed alphabetically.

Table 2. AASLD-IDSA HCV Guidance: Retreatment
Sofosbuvir-Based Treatment Failures, With or Without Compensated Cirrhosis^

^For patients with decompensated cirrhosis, refer to a liver specialist and see the AASLD-IDSA Guidance: Unique Populations—Patients with Decompensated Cirrhosis.
Source: AASLD-IDSA. HCV Guidance: Recommendations for testing, management, and treating hepatitis C. Retreatment of persons in whom prior therapy failed: Sofosbuvir-Based and Elbasvir/Grazoprevir Treatment Failures. [AASLD-IDSA Hepatitis C Guidance] - Accessed September 18, 2023.

Table 3. AASLD-IDSA HCV Guidance: Retreatment
Elbasvir-Grazoprevir Treatment Failures, With or Without Compensated Cirrhosis^

^For patients with decompensated cirrhosis, refer to a liver specialist and see the AASLD-IDSA Guidance: Unique Populations—Patients with Decompensated Cirrhosis.
Source: AASLD-IDSA. HCV Guidance: Recommendations for testing, management, and treating hepatitis C. Retreatment of persons in whom prior therapy failed: Sofosbuvir-Based and Elbasvir/Grazoprevir Treatment Failures. [AASLD-IDSA Hepatitis C Guidance] - Accessed September 18, 2023.

Table 4. AASLD-IDSA HCV Guidance for All Genotypes: Retreatment
Glecaprevir-Pibrentasvir Treatment Failures (All Genotypes), With or Without Compensated Cirrhosis^

^For patients with decompensated cirrhosis, refer to a liver specialist and see the AASLD-IDSA Guidance: Unique Populations—Patients with Decompensated Cirrhosis.
Source: AASLD-IDSA. HCV Guidance: Recommendations for testing, management, and treating hepatitis C. Retreatment of persons in whom prior therapy has failed: glecaprevir/pibrentasvir treatment failure (all genotypes). [AASLD-IDSA] - Accessed September 18, 2023.

Table 5. AASLD-IDSA HCV Guidance for All Genotypes: Retreatment
Multiple DAA Treatment Failures (All Genotypes), Including Sofosbuvir-Velpatasvir-Voxilaprevir or Sofosbuvir Plus Glecaprevir-Pibrentasvir^

^For patients with decompensated cirrhosis, refer to a liver specialist and see the AASLD-IDSA Guidance: Unique Populations—Patients with Decompensated Cirrhosis.
Source: AASLD-IDSA. HCV Guidance: Recommendations for testing, management, and treating hepatitis C. Retreatment of persons in whom prior therapy has failed: sofosbuvir/velpatasvir/voxilaprevir treatment failure (all genotypes) [AASLD-IDSA] - Accessed September 18, 2023.

Studies of Retreatment of Adults with HCV Genotype 5 or 6

There are limited data from studies that adequately address the retreatment of adults with HCV genotype 5 or 6 infection who failed prior therapy.

Glecaprevir-Pibrentasvir

  • Combination Analysis: This combined analysis of phase 2 and 3 studies evaluating 8 weeks or 12 weeks of glecaprevir-pibrentasvir included 30 individuals with HCV genotype 5 and 44 with HCV genotype 6.[40] No participants had cirrhosis and 22% had prior interferon-based treatment failure. Among individuals with HCV genotype 5, 2 received 8 weeks of glecaprevir-pibrentasvir and 28 received 12 weeks; all participants with HCV genotype 5 achieved an SVR12.[40] Among participants with HCV genotype 6, 92% (12/13) of those receiving 8 weeks and 100% (31/31) of those receiving 12 weeks of glecaprevir-pibrentasvir achieved an SVR12. In addition, the single treatment failure in the 8-week group was a nonvirologic failure.[40]
  • ENDURANCE-5,6: This phase 3b, open-label trial examined the safety and efficacy of glecaprevir-pibrentasvir exclusively in treatment-naïve and treatment-experienced adults with HCV genotype 5 or 6.[30] Duration of treatment was 8 weeks in participants without cirrhosis (n = 75) and 12 weeks in those with compensated cirrhosis (n = 9). Overall, 97.6% (82 of 84) of individuals enrolled achieved an SVR12; treatment success occurred in 96% (22 of 23) of participants with HCV genotype 5 and in 98% (60 of 61) of those with HCV genotype 6.[30] High efficacy was noted across 14 different HCV genotype 6 subtypes.[30]
  • EXPEDITION-1: This phase 3, single-arm, open-label trial evaluated the safety and efficacy of 12 weeks of glecaprevir-pibrentasvir in treatment-naïve and treatment-experienced adults with compensated cirrhosis and HCV genotype 1, 2, 4, 5, or 6 HCV infection.[26] All (100%) of participants with HCV genotype 5 (n=2) or HCV genotype 6 (n=7) achieved an SVR12 (data not provided for number of treatment-naïve versus treatment-experienced individuals with HCV genotype 5 or 6).[26]
  • SURVEYOR-I and SURVEYOR-II: The SURVEYOR-I (HCV genotypes 1, 4, 5 and 6) and SURVEYOR-II (HCV genotypes 2 and 3) were phase 2, open-label trials that enrolled treatment-naïve and treatment-experienced adults without cirrhosis.[32] In the SURVEYOR-I trial, participants with HCV genotype 4, 5, or 6 received 12 weeks of glecaprevir-pibrentasvir.[32] Among those enrolled and treated, one had HCV genotype 5 and the other 11 had HCV genotype 6.[32] All (100%) with HCV genotype 5 or 6 achieved an SVR12 (data not provided for number of treatment-naïve versus treatment-experienced patients with HCV genotype 5 or 6).[32]

Ledipasvir-Sofosbuvir

  • Ledipasvir-Sofosbuvir for Genotype 5 Infection: In a small, open-label study conducted in France, investigators enrolled 21 treatment-naïve adults and 20 treatment experienced adults with HCV genotype 5 to receive a 12-week course of ledipasvir-sofosbuvir.[28] For the treatment-experienced participants with HCV genotype 5 infection, 95% (19 of 20) achieved an SVR12; cirrhosis status did not impact the SVR12 rates.[28] Analysis of treatment response by cirrhosis status showed SVR12 rates of 89% (8 of 9) for participants with cirrhosis compared with 97% (31 of 32) for those without cirrhosis.[28]
  • New Zealand Genotype 3 and 6 Trial: In this open-label, phase 2 study performed at two centers in New Zealand, investigators enrolled treatment-naïve and treatment-experienced adults with HCV genotype 3 or 6 infection.[24] One arm of this study enrolled 25 participants with HCV genotype 6 to receive a 12-week course of ledipasvir-sofosbuvir.[24] Overall, 96% (24 of 25) of the individuals with HCV genotype 6 achieved an SVR12; the one person in this cohort who did not achieve an SVR12 withdrew from the study at week 8. Only two of the treatment-naïve individuals with HCV genotype 6 had cirrhosis.[24]

Sofosbuvir-Velpatasvir

  • ASTRAL-1: In the phase 3 ASTRAL-1 trial, investigators randomized treatment-naïve and treatment-experienced adults with HCV genotype 1, 2, 4, 5, or 6 infection in a 5:1 ratio to receive a 12-week course of either sofosbuvir-velpatasvir or placebo.[27] The study included 34 individuals with HCV genotype 5 and 41 with HCV genotype 6. The SVR12 rates for the treatment-experienced participants treated with sofosbuvir-velpatasvir were 100% (11 of 11) in those with HCV genotype 5 and 100% (3 of 3) with HCV genotype 6.[27]

Sofosbuvir-Velpatasvir-Voxilaprevir

  • POLARIS-1: In this phase 3, placebo-controlled trial, investigators enrolled adults with HCV genotype 1, 2, 3, 4, 5, or 6 who had previously received treatment that included an NS5A inhibitor to receive sofosbuvir-velpatasvir-voxilaprevir for 12 weeks.[41] Individuals with HCV genotype 2, 3, 4, 5, or 6 were all 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 individuals in the active arm.[41] For the participants with HCV genotype 5 (n = 1) or HCV genotype 6 infection (n = 6), all (100%) achieved an SRV12.[41]

Summary Points

  • Infection with HCV genotype 5 is uncommon in the United States, but endemic in South Africa.
  • Infection with HCV genotype 6 is also uncommon in the United States and is primarily found in China, Korea, Taiwan, and Southeast Asia.
  • Recommendations for initial treatment or retreatment of individuals with HCV genotype 5 or 6 are based on in vitro data, limited data from clinical trials, and observational studies.
  • The recommended regimens for initial treatment of adults with HCV genotype 5 or 6, with or without compensated cirrhosis, are: glecaprevir-pibrentasvir for 8 weeks (extend to 12 weeks in persons with HIV infection), sofosbuvir-velpatasvir for 12 weeks, or ledipasvir-sofosbuvir for 12 weeks.
  • The recommended regimens for retreatment of peginterferon plus ribavirin-experienced adults with HCV genotype 5 or 6 infection, with or without cirrhosis, are the same as for initial treatment, except that glecaprevir-pibrentasvir should be given for 12 weeks in persons with compensated cirrhosis as opposed to 8 weeks with treatment-naïve persons with compensated cirrhosis.
  • The recommended regimen for retreatment of DAA-experienced adults with HCV genotype 5 or 6 depends on the prior regimen that was taken.
  PDF Share

Citations

  1. 1.Manos MM, Shvachko VA, Murphy RC, Arduino JM, Shire NJ. Distribution of hepatitis C virus genotypes in a diverse US integrated health care population. J Med Virol. 2012;84:1744-50.
  2. 2.Antaki N, Abboud D, Antaki F, Craxi A. HCV genotype 5: an orphan virus. Antivir Ther. 2013;18:263-9.
  3. 3.Al Naamani K, Al Sinani S, Deschênes M. Epidemiology and treatment of hepatitis C genotypes 5 and 6. Can J Gastroenterol. 2013;27:e8-12.
  4. 4.Messina JP, Humphreys I, Flaxman A, et al. Global distribution and prevalence of hepatitis C virus genotypes. Hepatology. 2015;61:77-87.
  5. 5.Legrand-Abravanel F, Sandres-Sauné K, Barange K, et al. Hepatitis C virus genotype 5: epidemiological characteristics and sensitivity to combination therapy with interferon-alpha plus ribavirin. J Infect Dis. 2004;189:1397-400.
  6. 6.Abergel A, Ughetto S, Dubost S, et al. The epidemiology and virology of hepatitis C virus genotype 5 in central France. Aliment Pharmacol Ther. 2007;26:1437-46.
  7. 7.Prescott LE, Simmonds P, Lai CL, Chan NK, Pike I, Yap PL, Lin CK. Detection and clinical features of hepatitis C virus type 6 infections in blood donors from Hong Kong.J Med Virol. 1996;50:168-75.
  8. 8.Thong VD, Akkarathamrongsin S, Poovorawan K, Tangkijvanich P, Poovorawan Y. Hepatitis C virus genotype 6: virology, epidemiology, genetic variation and clinical implication. World J Gastroenterol. 2014;20:2927-40.
  9. 9.Bunchorntavakul C, Chavalitdhamrong D, Tanwandee T. Hepatitis C genotype 6: A concise review and response-guided therapy proposal. World J Hepatol. 2013;5:496-504.
  10. 10.Nguyen NH, Vutien P, Trinh HN, et al. Risk factors, genotype 6 prevalence, and clinical characteristics of chronic hepatitis C in Southeast Asian Americans. Hepatol Int. 2010;4:523-9.
  11. 11.Seto WK, Lai CL, Fung J, et al. Natural history of chronic hepatitis C: genotype 1 versus genotype 6. J Hepatol. 2010;53:444-8.
  12. 12.Manns MP, Buti M, Gane E, et al. Hepatitis C virus infection. Nat Rev Dis Primers. 2017;3:17006.
  13. 13.Scheel TK, Rice CM. Understanding the hepatitis C virus life cycle paves the way for highly effective therapies. Nat Med. 2013;19:837-49.
  14. 14.AASLD-IDSA. HCV Guidance: Recommendations for testing, management, and treating hepatitis C. Retreatment of persons in whom prior therapy failed.
  15. 15.AASLD-IDSA. HCV Guidance: Recommendations for testing, management, and treating hepatitis C. Treatment-Naive Genotype 5 or 6.
  16. 16.D'Heygere F, George C, Van Vlierberghe H, et al. Efficacy of interferon-based antiviral therapy in patients with chronic hepatitis C infected with genotype 5: a meta-analysis of two large prospective clinical trials. J Med Virol. 2011;83:815-9.
  17. 17.Bonny C, Fontaine H, Poynard T, et al Effectiveness of interferon plus ribavirin combination in the treatment of naive patients with hepatitis C virus type 5. A French multicentre retrospective study. Aliment Pharmacol Ther. 2006;24:593-600.
  18. 18.Antaki N, Hermes A, Hadad M, Ftayeh M, Antaki F, Abdo N, Kebbewar K. Efficacy of interferon plus ribavirin in the treatment of hepatitis C virus genotype 5. J Viral Hepat. 2008;15:383-6.
  19. 19.Devaki P, Jencks D, Yee BE, Nguyen MH. Sustained virologic response to standard interferon or pegylated interferon and ribavirin in patients with hepatitis C virus genotype 5: systematic review and meta-analysis of ten studies and 423 patients. Hepatol Int. 2015;9:431-7.
  20. 20.Lam KD, Trinh HN, Do ST, et. al. Randomized controlled trial of pegylated interferon-alfa 2a and ribavirin in treatment-naive chronic hepatitis C genotype 6. Hepatology 2010;52:1573-80.
  21. 21.Thuy PT, Bunchorntavakul C, Tan Dat H, Rajender Reddy K. A randomized trial of 48 versus 24 weeks of combination pegylated interferon and ribavirin therapy in genotype 6 chronic hepatitis C. J Hepatol. 2012;56:1012-8.
  22. 22.Wang X, Liu F, Wei F, Ren H, Hu H. Efficacy and safety of pegylated interferon plus ribavirin therapy for chronic hepatitis C genotype 6: a meta-analysis. PLoS One. 2014;9:e100128.
  23. 23.Nguyen MH, Trinh HN, Garcia R, Nguyen G, Lam KD, Keeffe EB. Higher rate of sustained virologic response in chronic hepatitis C genotype 6 treated with 48 weeks versus 24 weeks of peginterferon plus ribavirin. Am J Gastroenterol. 2008;103:1131-5.
  24. 24.Gane EJ, Hyland RH, An D, et al. Efficacy of ledipasvir and sofosbuvir, with or without ribavirin, for 12 weeks in patients with HCV genotype 3 or 6 infection. Gastroenterology. 2015;149:1454-1461.e1.
  25. 25.Asselah T, Kowdley KV, Zadeikis N, et al. Efficacy of Glecaprevir/Pibrentasvir for 8 or 12 Weeks in Patients With Hepatitis C Virus Genotype 2, 4, 5, or 6 Infection Without Cirrhosis. Clin Gastroenterol Hepatol. 2018;16:417-26.
  26. 26.Forns X, Lee SS, Valdes J, et al. Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial. Lancet Infect Dis. 2017;17:1062-1068.
  27. 27.Feld JJ, Jacobson IM, Hézode C, et al. Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection. N Engl J Med. 2015;373:2599-607.
  28. 28.Abergel A, Asselah T, Metivier S, et al. Ledipasvir-sofosbuvir in patients with hepatitis C virus genotype 5 infection: an open-label, multicentre, single-arm, phase 2 study. Lancet Infect Dis. 2016;16:459-64.
  29. 29.AASLD-IDSA. HCV Guidance: Recommendations for testing, management, and treating hepatitis C. Initial treatment of HCV infection: treatment-naive genotype 5 or 6.
  30. 30.Asselah T, Lee SS, Yao BB, et al. Efficacy and safety of glecaprevir/pibrentasvir in patients with chronic hepatitis C virus genotype 5 or 6 infection (ENDURANCE-5,6): an open-label, multicentre, phase 3b trial. Lancet Gastroenterol Hepatol. 2019;4:45-51.
  31. 31.Brown RS Jr, Buti M, Rodrigues L, et al. Glecaprevir/pibrentasvir for 8 weeks in treatment-naïve patients with chronic HCV genotypes 1-6 and compensated cirrhosis: The EXPEDITION-8 trial. J Hepatol. 2020;72:441-9.
  32. 32.Kwo PY, Poordad F, Asatryan A, et al. Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1-6 without cirrhosis. J Hepatol. 2017;67:263-271.
  33. 33.Mettikanont P, Bunchorntavakul C, Reddy KR. Systematic review: epidemiology and response to direct-acting antiviral therapy in genotype 6 chronic hepatitis C virus infection. Aliment Pharmacol Ther. 2019;49:492-505.
  34. 34.Cheng G, Tian Y, Doehle B, et al. In Vitro Antiviral Activity and Resistance Profile Characterization of the Hepatitis C Virus NS5A Inhibitor Ledipasvir. Antimicrob Agents Chemother. 2016;60:1847-53.
  35. 35.Nguyen MH, Trinh H, Do S, Nguyen T, Nguyen P, Henry L. Open Label Study of 8 vs. 12 Weeks of Ledipasvir/Sofosbuvir in Genotype 6 Treatment Naïve or Experienced Patients. Am J Gastroenterol. 2017;112:1824-31.
  36. 36.Jacobson IM, Lawitz E, Gane EJ, et al. Efficacy of 8 Weeks of Sofosbuvir, Velpatasvir, and Voxilaprevir in Patients With Chronic HCV Infection: 2 Phase 3 Randomized Trials. Gastroenterology. 2017;153:113-22.
  37. 37.AASLD-IDSA. HCV Guidance: Recommendations for testing, management, and treating hepatitis C. Retreatment of persons in whom prior therapy failed: Sofosbuvir-Based and Elbasvir/Grazoprevir Treatment Failures.
  38. 38.AASLD-IDSA. HCV Guidance: Recommendations for testing, management, and treating hepatitis C. Retreatment of persons in whom prior therapy failed: Multiple DAA Treatment Failures (All Genotypes), Including Sofosbuvir/Velpatasvir/Voxilaprevir or Sofosbuvir Plus Glecaprevir/Pibrentasvir.
  39. 39.AASLD-IDSA. HCV Guidance: Recommendations for testing, management, and treating hepatitis C. Retreatment of persons in whom prior therapy failed: Glecaprevir/Pibrentasvir Treatment Failures.
  40. 40.Puoti M, Foster GR, Wang S, et al. High SVR12 with 8-week and 12-week glecaprevir/pibrentasvir therapy: An integrated analysis of HCV genotype 1-6 patients without cirrhosis. J Hepatol. 2018;69:293-300.
  41. 41.Bourlière M, Gordon SC, Flamm SL, et al. Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection. N Engl J Med. 2017;376:2134-46.

Additional References

  • European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C: Final update of the series☆. J Hepatol. 2020:S0168-8278(20)30548-1.
    [EASL] -
  • Kowdley KV, Lawitz E, Crespo I, et al. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet. 2013;381:2100-7.
  • Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368:1878-87.
  • Lenz O, Vijgen L, Berke JM, et al. Virologic response and characterisation of HCV genotype 2-6 in patients receiving TMC435 monotherapy (study TMC435-C202). J Hepatol. 2013;58:445-51.
  • Mauss S, Berger F, Vogel M, et al. Treatment results of chronic hepatitis C genotype 5 and 6 infections in Germany. Z Gastroenterol. 2012;50:441-4.
  • McOmish F, Yap PL, Dow BC, et al. Geographical distribution of hepatitis C virus genotypes in blood donors: an international collaborative survey. J Clin Microbiol. 1994;32:884-92.
  • Nguyen MH, Keeffe EB. Prevalence and treatment of hepatitis C virus genotypes 4, 5, and 6. Clin Gastroenterol Hepatol. 2005;3(10 Suppl 2):S97-S101.
  • Nguyen NH, Nguyen MH. Current Treatment Options in Patients with Hepatitis C Virus Genotype 6. Gastroenterol Clin North Am. 2015;44:871-81.
  • Papastergiou V, Skorda L, Lisgos P, et. al. Hepatitis C virus genotype 5: prospective evaluation of peginterferon/ribavirin treatment efficacy and predictive value of on-treatment virological responses for sustained virological response. J Clin Gastroenterol. 2014;48:160-5.
  • Smuts HE, Kannemeyer J. Genotyping of hepatitis C virus in South Africa. J Clin Microbiol 1995;33:1679-81.
  • Wantuck JM, Ahmed A, Nguyen MH. Review article: the epidemiology and therapy of chronic hepatitis C genotypes 4, 5 and 6. Aliment Pharmacol Ther. 2014;39:137-47.

Figures

Note that all medications in gray boxes have been discontinued and are no longer manufactured in the United States.
Figure 1. Classes of Direct-Acting Antiviral Agents Used to Treat HCV
Note that all medications in gray boxes have been discontinued and are no longer manufactured in the United States.

Tables

Table 1. AASLD-IDSA HCV Guidance for Genotype 5 or 6: Initial Treatment
Treatment-Naïve Genotype 5 or 6 Patients With and Without Compensated Cirrhosis^

Recommended regimens listed by evidence level and alphabetically
^For treatment of patients with decompensated cirrhosis, see the AASLD-IDSA Guidance: Unique Populations—Patients with Decompensated Cirrhosis.
Source: AASLD-IDSA. HCV Guidance: Recommendations for testing, management, and treating hepatitis C. Initial treatment of HCV infection: treatment-naive genotype 5 or 6. [AASLD-IDSA Hepatitis C Guidance] - Accessed October 11, 2020.

Table 2. AASLD-IDSA HCV Guidance: Retreatment
Sofosbuvir-Based Treatment Failures, With or Without Compensated Cirrhosis^

^For patients with decompensated cirrhosis, refer to a liver specialist and see the AASLD-IDSA Guidance: Unique Populations—Patients with Decompensated Cirrhosis.
Source: AASLD-IDSA. HCV Guidance: Recommendations for testing, management, and treating hepatitis C. Retreatment of persons in whom prior therapy failed: Sofosbuvir-Based and Elbasvir/Grazoprevir Treatment Failures. [AASLD-IDSA Hepatitis C Guidance] - Accessed September 18, 2023.

Table 3. AASLD-IDSA HCV Guidance: Retreatment
Elbasvir-Grazoprevir Treatment Failures, With or Without Compensated Cirrhosis^

^For patients with decompensated cirrhosis, refer to a liver specialist and see the AASLD-IDSA Guidance: Unique Populations—Patients with Decompensated Cirrhosis.
Source: AASLD-IDSA. HCV Guidance: Recommendations for testing, management, and treating hepatitis C. Retreatment of persons in whom prior therapy failed: Sofosbuvir-Based and Elbasvir/Grazoprevir Treatment Failures. [AASLD-IDSA Hepatitis C Guidance] - Accessed September 18, 2023.

Table 4. AASLD-IDSA HCV Guidance for All Genotypes: Retreatment
Glecaprevir-Pibrentasvir Treatment Failures (All Genotypes), With or Without Compensated Cirrhosis^

^For patients with decompensated cirrhosis, refer to a liver specialist and see the AASLD-IDSA Guidance: Unique Populations—Patients with Decompensated Cirrhosis.
Source: AASLD-IDSA. HCV Guidance: Recommendations for testing, management, and treating hepatitis C. Retreatment of persons in whom prior therapy has failed: glecaprevir/pibrentasvir treatment failure (all genotypes). [AASLD-IDSA] - Accessed September 18, 2023.

Table 5. AASLD-IDSA HCV Guidance for All Genotypes: Retreatment
Multiple DAA Treatment Failures (All Genotypes), Including Sofosbuvir-Velpatasvir-Voxilaprevir or Sofosbuvir Plus Glecaprevir-Pibrentasvir^

^For patients with decompensated cirrhosis, refer to a liver specialist and see the AASLD-IDSA Guidance: Unique Populations—Patients with Decompensated Cirrhosis.
Source: AASLD-IDSA. HCV Guidance: Recommendations for testing, management, and treating hepatitis C. Retreatment of persons in whom prior therapy has failed: sofosbuvir/velpatasvir/voxilaprevir treatment failure (all genotypes) [AASLD-IDSA] - Accessed September 18, 2023.
  PDF Share

Share by e-mail

Check
-On-
Learning
Questions
The Check-on-Learning Questions are short and topic related. They are meant to help you stay on track throughout each lesson and check your understanding of key concepts.

You must be signed in to customize your interaction with these questions.

Since you've received 80% or better on this quiz, you may claim continuing education credit.

You seem to have a popup blocker enabled. If you want to skip this dialog please Always allow popup windows for the online course.