Hepatitis C Direct-Acting Antivirals
Medications listed in the tables and non-FDA approved indications included in these retrospective criteria are not indicative of Vendor Drug Program formulary coverage.
Note: This retrospective drug use criteria provides information from each respective therapies FDA approved package insert. Further guidance for patient specific treatments can be found within the continuously updated American Association for the Study of Liver Disease (AASLD) and the Infectious Diseases Society of America (IDSA) “HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C” guidelines at www.hcvguidelines.org. It is recommended to consult these guidelines prior to initiating therapy to treat hepatitis C infection.
- Revision history
- July 22, 2022
- Initially developed
- March 2018
1. Dosage
1.1. Adults
Direct acting antivirals (DAA) for hepatitis are FDA-indicated for treatment of chronic infections caused by hepatitis C virus (HCV). Individual agents have varying FDA indications and treatment durations based on genotype (1-6), subtype (1a vs. 1b), liver function, HIV co-infection and/or previous treatment history1.
Table 1 provides DAA information for treatment naïve patients with or without cirrhosis.
Drug Name | Dosage Form/Strength | Treatment Indication | Duration and Coadministration | Maximum Recommended Dosage |
---|---|---|---|---|
elbasvir/ grazoprevir (Zepatier®) | 50 mg/100 mg tablet |
Chronic HCV treatment:
|
16 weeks with ribavirin | 50 mg elbasvir and 100 mg grazoprevir once daily |
|
12 weeks | |||
|
12 weeks | |||
|
12 weeks | |||
glecaprevir/pibrentasvir (Mavyret®) | 100 mg/40 mg tablets |
Chronic HCV treatment:
|
8† weeks | 300 mg glecaprevir and 120 mg pibrentasvir once daily |
ledipasvir/ sofosbuvir (Harvoni®, generics) | 90 mg/400 mg tablet |
Chronic HCV treatment:
|
8* weeks or 12 weeks | 90 mg ledipasvir and 400 mg sofosbuvir once daily |
|
12 weeks | |||
|
12 weeks plus ribavirin | |||
|
12 weeks plus ribavirin | |||
genotype 4
|
12 weeks plus ribavirin | |||
|
12 weeks | |||
sofosbuvir/ velpatasvir (Epclusa®, generics) | 400 mg/100 mg tablets |
Chronic HCV treatment:
|
12 weeks | 400 mg sofosbuvir and 100 mg velpatasvir once daily |
|
12 weeks plus ribavirin | |||
sofosbuvir (Sovaldi®) | 400 mg tablet |
Chronic HCV treatment:
|
12 weeks plus ribavirin and peginterferon | 400 mg once daily |
|
12 weeks plus ribavirin | |||
|
24 weeks plus ribavirin |
Legend:
- HCV = hepatitis C virus;
- NS5A inhibitors = Nonstructural protein 5A (NS5A) inhibitors
- NS3/4A protease inhibitors = Nonstructural protein 3/4A protease inhibitors
- † = For HIV/HCV-coinfected patients, a treatment duration of 12 weeks is recommended with compensated cirrhosis (Child-Pugh A) for genotypes 1-4 and genotypes 5 and 6 regardless of liver status
- * = 8 weeks of treatment can be considered in treatment naïve genotype 1 patients without cirrhosis who have pretreatment HCV RNA less than 6 million IU/mL
Drug Name | Dosage Form/Strength | Treatment Indication | Duration and Coadministration | Maximum Recommended Dosage |
---|---|---|---|---|
elbasvir/grazoprevir (Zepatier®) | 50 mg/100 mg tablet |
Chronic HCV treatment:
|
12 weeks | 50 mg elbasvir and 100 mg grazoprevir once daily |
|
16 weeks plus ribavirin | |||
|
12 weeks plus ribavirin | |||
genotype 1b:
|
12 weeks | |||
|
12 weeks plus ribavirin | |||
|
16 weeks plus ribavirin | |||
glecaprevir/ pibrentasvir (Mavyret®) | 100 mg/40 mg tablets |
Chronic HCV treatment:
|
16 weeks | 300 mg glecaprevir and 120 mg pibrentasvir once daily |
|
12 weeks | |||
|
8 weeks | |||
|
12 weeks | |||
|
16 weeks | |||
ledipasvir/sofosbuvir (Harvoni®, generics) | 90 mg/400 mg tablet |
Chronic HCV treatment:
|
12 weeks | 90 mg ledipasvir and 400 mg sofosbuvir once daily |
|
24 weeks or 12 weeks in combination with ribavirin† | |||
|
12 weeks plus ribavirin | |||
|
12 weeks plus ribavirin | |||
|
12 weeks plus ribavirin | |||
|
12 weeks | |||
sofosbuvir/velpatasvir (Epclusa®, generics) | 400 mg/100 mg tablets |
Chronic HCV treatment:
|
12 weeks | 400 mg sofosbuvir and 100 mg velpatasvir once daily |
|
12 weeks plus ribavirin | |||
sofosbuvir (Sovaldi®) | 400 mg tablet |
Chronic HCV treatment:
|
12 weeks plus ribavirin | 400 mg once daily |
|
24 weeks plus ribavirin | |||
sofosbuvir, velpatasvir, and voxilaprevir (Vosevi®) | 400 mg/100 mg/100 mg |
Chronic HCV treatment:
|
12 weeks | 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir once daily |
|
12 weeks |
1.2. Pediatrics
Safety and efficacy of DAAs for use in children younger than 18 years of age has been established with sofosbuvir (Sovaldi®), sofosbuvir/velpatasvir (Epclusa®), glecaprevir/pibrentasvir (Mavyret®), elbasvir/grazoprevir (Zepatier®), and ledipasvir/ sofosbuvir (Harvoni®)2-8, 10-11. Safety and effectiveness of sofosbuvir/velpatasvir/voxilaprevir (Vosevi®) has not been established in pediatric patients less than 18 years of age9. Recommended DAA dosages in pediatric patients are summarized in Table 3.
Drug Name | Dosage Form/Strength | Treatment Indication | Duration and Coadministration | Maximum Recommended Dosage |
---|---|---|---|---|
elbasvir/grazoprevir (Zepatier®) | 50 mg/100 mg tablet |
Chronic HCV treatment in pediatric patients 12 years of age and older weighing at least 30kg with or without mild hepatic impairment (Child-Pugh A):
|
12 weeks | Patients 12-17 years of age: 50 mg elbasvir and 100 mg grazoprevir tablet once daily |
genotype 1a: treatment naïve or peginterferon and ribavirin experienced with baseline NS5A polymorphisms∆ | 16 weeks plus ribavirin* | |||
genotype 1b: treatment naïve or peginterferon and ribavirin experienced | 12 weeks | |||
genotypes 1a£ or 1b: Peginterferon, ribavirin, and NS3/4A protease inhibitor experienced | 12 weeks plus ribavirin* | |||
genotype 4: treatment naïve | 12 weeks | |||
genotype 4: treatment naïve or peginterferon and ribavirin experienced | 16 weeks plus ribavirin* | |||
glecaprevir/pibrentasvir (Mavyret®) |
100 mg/40 mg tablets 50 mg/20 mg oral pellet packets |
Chronic HCV treatment in pediatric patients 3 years of age and older:
|
8 weeks |
|
genotype 1 previously treated with an NS5A inhibitor (ledipasvir and sofosbuvir or daclatasvir with pegylated or nonpegylated interferon plus ribavirin) without prior NS3/4A treatment without cirrhosis or with compensated cirrhosis (Child-Pugh A) | 16 weeks | |||
genotype 1 liver or kidney transplant recipients previously treated with an NS5A inhibitor without prior NS3/4A treatment | 16 weeks | |||
genotype 1 previously treated with an NS3/4A protease inhibitor (containing simeprivir, and sofosbuvir, or simeprevir, boceprevir, or telaprevir with pegylated or nonpegylated interferon and ribavirin) without previous NS5A inhibitor treatment | 12 weeks | |||
genotypes 1, 2, 4, 5, or 6 previously treated with peginterferon, ribavirin, and/or sofosbuvir, but no prior treatment experience with an HCV NS3/4A PI or NS5A inhibitor without cirrhosis | 8 weeks | |||
genotypes 1, 2, 4, 5, or 6 previously treated with peginterferon, ribavirin, and/or sofosbuvir, but no prior treatment experience with an HCV NS3/4A PI or NS5A inhibitor with compensated cirrhosis (Child-Pugh A) | 12 weeks | |||
genotype 3 previously treated with peginterferon, ribavirin, and/or sofosbuvir, but no prior treatment experience with an HCV NS3/4A PI or NS5A inhibitor | 16 weeks | |||
genotype 3 liver or kidney transplant recipients previously treated with peginterferon, ribavirin, and/or sofosbuvir, but no prior treatment experience with an HCV NS3/4A PI or NS5A inhibitor | 16 weeks | |||
Liver or kidney transplant recipients | 12 weeks | |||
ledipasvir/sofosbuvir (Harvoni®, generics) |
33.75 mg/150 mg oral pellet packets 45 mg/200 mg oral pellet packets 45 mg/200 mg tablet 90 mg/400 mg tablet |
Chronic HCV treatment in pediatric patients 3 years of age and older:
|
8¥ or 12 weeks |
|
treatment experienced† without cirrhosis | 12 weeks | |||
treatment experienced† with compensated cirrhosis (Child-Pugh A) | 24 weeks** | |||
treatment naïve and treatment experienced† with decompensated cirrhosis (Child-Pugh B or C) | 12 weeks plus ribavirin | |||
genotype 1 or 4 treatment naïve and treatment experienced† liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh A) | 12 weeks plus ribavirin | |||
genotype 4,5, or 6 treatment naïve or experienced† patients without cirrhosis or with compensated cirrhosis (Child-Pugh A) | 12 weeks | |||
sofosbuvir/velpatasvir (Epclusa®, generics) |
150 mg/37.5 mg oral pellet packets 200 mg/50 mg oral pellet packets 200 mg/50 mg tablets 400 mg/100 mg tablets |
Chronic HCV treatment pediatric patients 3 years of age and older:
|
12 weeks |
Weight based dosing for patients 3-17 years of age:
|
genotype 1, 2, 3, 4, 5, or 6 that are treatment naïve or experienced†† with decompensated cirrhosis (Child-Pugh B and C) | 12 weeks plus ribavirin | |||
sofosbuvir (Sovaldi ®) |
150 mg oral pellet packet 200 mg oral pellet packet 200 mg tablet 400 mg tablet |
Chronic HCV genotype 2 or 3 treatment for pediatric patients 3 years of age and older without cirrhosis or with compensated cirrhosis (Child-Pugh A)
|
12 weeks plus ribavirin* |
Weight based dosing for patients 3-17 years of age:
|
genotype 3 for treatment naïve or experienced# patients | 24 weeks plus ribavirin* |
2. Duration of Therapy
Duration of therapy with hepatitis C DAAs is dependent on cirrhosis status, previous therapy, and hepatitis C virus genotype, with FDA-indicated treatment durations dependent on these factors. Treatment can be anywhere from 8 weeks to 24 weeks1-12. The goal of therapy is a sustained virologic response (SVR), defined as having non-detectable HCV RNA at least 12 weeks post completion of DAA course 1l, 13. Duration of therapy for current treatments can be found in Tables 1-3.
3. Duplicative Therapy
There are no FDA indications for duplicate therapy with multiple combination drug products (e.g. ledipasvir/ sofosbuvir (Harvoni®) with glecaprevir/pibrentasvir (Mavyret™))2-11.
Ribavirin combination therapy is indicated in patients with more advanced liver disease and HCV genotypes that are found to be more resistant (e.g. genotype 3)1,11.
For recommended combination therapies see Duration of Therapy tables above (Tables 1-3).
4. Drug-Drug Interactions
Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. The following drug-drug interactions are considered clinically relevant for DAAs. Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.
Target Drug | Interacting Drug | Interaction | Recommendation | Clinical Significance Level |
---|---|---|---|---|
elbasvir | Strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, St John’s wort, phenobarbital) | Concurrent use may decrease elbasvir plasma concentration | Use is contraindicated | 1-severe (CP), contraindicated (DrugReax) |
glecaprevir/ pibrentasvir | Strong or moderate dual CYP3A4 and p-glycoprotein inducers (e.g. rifampin, isoniazid) | Concurrent use may decrease glecepravir plasma concentration | Coadministration should be avoided | 1-severe (CP), major (DrugReax) |
grazoprevir | OTAP1B1/3 inhibitors (e.g. cyclosporine, eltrombopag) | Concurrent use can increase grazoprevir concentrations and elevate ALT. | Use is contraindicated | 1-severe (CP), contraindicated (DrugReax) |
grazoprevir | Protease inhibitors (e.g. saquinavir, ritonavir, darunavir) | Concurrent use can increase grazoprevir concentrations and elevate ALT. | Use is contraindicated | 1-severe (CP), contraindicated (DrugReax) |
ledipasvir | Proton pump inhibitors (PPIs) and histamine 2 receptor antagonists (H2RAs) (e.g. omeprazole, ranitidine) | Increased pH in stomach reduces ledipasvir solubility | Use cautiously; take H2RA simultaneously or 12 hours apart from ledipasvir; PPI dose should not exceed equivalent of omeprazole 20 mg/ day. H2RA should not exceed equivalent of famotidine 40 mg twice daily | 2-Major (CP), Major (DrugReax) |
ledipasvir | p-glycoprotein inducers (e.g. rifampin, St John’s wort) | Concurrent use can decrease ledipasvir concentrations, potentially resulting in loss of antiviral efficacy | Avoid coadministration of ledipasvir with potent p-glycoprotein inducers | 2-Major (CP), Contraindicated (DrugReax) |
sofosbuvir | rifampin | Concurrent use can decrease sofosbuvir concentrations | Avoid coadministration; contraindicated | 2-Major (CP), contraindicated (DrugReax) |
sofosbuvir | p-glycoprotein inducers (carbamazepine, phenytoin) | Concurrent use can decrease sofosbuvir concentrations | Avoid coadministration | 2-Major (CP), Major (DrugReax) |
sofosbuvir | amiodarone | Concurrent use may increase severe bradycardia risk | Avoid coadministration | 2-Major (CP), Major (DrugReax) |
velpatasvir | Strong or moderate dual CYP3A4 and CYP2B6 inducers (e.g., primidone, phenobarbital) | Concurrent use can decrease velpatasvir concentrations | Avoid coadministration | 2-major (CP), major (DrugReax) |
velpatasvir | PPIs and H2RAs (e.g. omeprazole, ranitidine) | Increased pH in stomach reduces velpatasvir solubility | Use cautiously; take H2RA simultaneously or 12 hours apart from velpatasvir; PPI dose should not exceed equivalent of omeprazole 20 mg/ day and should be taken 4 hours after administration of velpatasvir; H2RA should not exceed equivalent of famotidine 40 mg/ twice daily | 2-Major (CP), Major (DrugReax) |
voxilaprevir | Strong or moderate dual CYP3A4 and CYP2B6 inducers (e.g. primidone, phenobarbital) | Concurrent use can decrease voxilaprevir concentrations | Avoid coadministration | 2-major (CP), major (DrugReax) |
voxilaprevir | Strong or moderate dual CYP3A4 and p-glycoprotein inducers (e.g. phenytoin, St. John’s wort) | Concurrent use can decrease voxilaprevir concentrations | Avoid coadministration | 2-major (CP), major (DrugReax) |
voxilaprevir | Cyclosporine (P-glycoprotein inhibitor) | Concurrent use can increase voxilaprevir concentrations | Avoid coadministration | 2-major (CP), major (DrugReax) |
Legend:
- *CP= Clinical Pharmacology
5. References
- Deming P. Viral Hepatitis. In: DiPiro J, Yee G, Posey M, et al. Pharmacotherapy: a pathophysiologic approach, 11e New York, NY: McGraw-Hill. Available from: https://accesspharmacy-mhmedical-com.ezproxy.lib.utexas.edu/content.aspx?bookid=2577§ionid=224357874#1182438955. Accessed 10 June 2022.
- Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc; 2022. Available at: http://www.clinicalpharmacology.com. Accessed June 11, 2022.
- IBM Micromedex® DRUGDEX® (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com.libproxy.uthscsa.edu/ (cited: June 13th 2022).
- Sofosbuvir (Sovaldi®) package insert. Gilead Sciences, Inc., Updated 5 March 2020.
- Ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets (Viekira Pak®) package insert. AbbVie Inc., November 2017.
- Ledipasvir and sofosbuvir (Harvoni®) package insert. Gilead Sciences, Inc., Updated 5 March 2020.
- Elbasvir/grazoprevir (Zepatier®) package insert. Merck & CO., Inc., Updated 19 December 2021.
- Sofosbuvir/velpatasvir (Epclusa®) package insert. Gilead Sciences, Inc., Updated 27 April 2022.
- Sofosbuvir/velpatasvir/voxilaprevir (Vosevi®) package insert. Gilead Sciences, Inc., Updated 15 November 2019.
- Glecaprevir/pibrentasvir (Mavyret™) package insert. AbbVie Inc., Updated 28 September 2021.
- Ribavirin (Rebetol®) package insert. Merck & Co., Inc., March 2022.
- AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed 28 June 2022.
- Hepatitis C guidance 2018 update: AASLD-IDSA recommendations for testing, managing, and treating hepatitis C virus infection. Clinical Infectious Diseases 2018; 67(10): 1477-92.