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

1.1. 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.

Table 1: DAAs for treatment of adult chronic HCV infection: Treatment naïve and patients with or without cirrhosis2-12
Drug Name Dosage Form/Strength Treatment Indication Duration and Coadministration Maximum Recommended Dosage
elbasvir/ grazoprevir (Zepatier®) 50 mg/100 mg tablet

Chronic HCV treatment:

  • genotypes 1a 
    • without cirrhosis or with compensated cirrhosis (Child-Pugh A) with baseline NS5A polymorphisms
16 weeks with ribavirin 50 mg elbasvir and 100 mg grazoprevir once daily
   
  • without cirrhosis or with compensated cirrhosis (Child-Pugh A) without baseline NS5A polymorphisms
12 weeks  
   
  • genotype 1b without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks  
   
  • genotype 4 without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks  
glecaprevir/pibrentasvir (Mavyret®) 100 mg/40 mg tablets

Chronic HCV treatment:

  • genotypes 1, 2, 3, 4, 5, and 6 without cirrhosis or with compensated cirrhosis (Child-Pugh A)    
8† weeks 300 mg glecaprevir and 120 mg pibrentasvir once daily
ledipasvir/ sofosbuvir (Harvoni®, generics) 90 mg/400 mg tablet

Chronic HCV treatment:

  • genotype 1
    • without cirrhosis
8* weeks or 12 weeks 90 mg ledipasvir and 400 mg sofosbuvir once daily
   
  • with compensated cirrhosis (Child-Pugh A)
12 weeks  
   
  • decompensated  cirrhosis (Child-Pugh B and C)
12 weeks plus ribavirin      
   
  • liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks plus ribavirin  
   

genotype 4

  • liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks plus ribavirin  
   
  • genotypes 4, 5, or 6 without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks  
sofosbuvir/ velpatasvir (Epclusa®, generics) 400 mg/100 mg tablets

Chronic HCV treatment:

  • genotypes 1, 2, 3, 4, 5, and 6 without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks 400 mg sofosbuvir and 100 mg velpatasvir once daily
   
  • genotypes 1, 2, 3, 4, 5, and 6 with decompensated cirrhosis (Child-Pugh B or C)
12 weeks plus ribavirin  
sofosbuvir (Sovaldi®) 400 mg tablet

Chronic HCV treatment:

  • genotypes 1 and 4 without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks plus ribavirin and peginterferon 400 mg once daily
   
  • genotype 2 without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks plus ribavirin  
   
  • genotype 3 without cirrhosis or with compensated cirrhosis (Child-Pugh A)
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
Table 2: DAAs for treatment of adult chronic HCV Infection: Treatment experienced patients with or without cirrhosis2-12
Drug Name Dosage Form/Strength Treatment Indication Duration and Coadministration Maximum Recommended Dosage
elbasvir/grazoprevir (Zepatier®) 50 mg/100 mg tablet

Chronic HCV treatment:

  • genotypes 1a:
    • that is peginterferon/ ribavirin experienced without baseline NS5A polymorphisms without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks 50 mg elbasvir and 100 mg grazoprevir once daily
   
  • that is peginterferon/ ribavirin experienced with baseline NS5A polymorphisms without cirrhosis or with compensated cirrhosis (Child-Pugh A)
16 weeks plus ribavirin  
   
  • that is peginterferon/ ribavirin and/or NS3/4A protease experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks plus ribavirin  
   

genotype 1b:

  • that is peginterferon/ ribavirin experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks  
   
  • that is peginterferon/ ribavirin and/or NS3/4A protease experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks plus ribavirin  
   
  • genotype 4 that is peginterferon/ribavirin experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A)
16 weeks plus ribavirin  
glecaprevir/ pibrentasvir (Mavyret®) 100 mg/40 mg tablets

Chronic HCV treatment:

  • genotype 1
  • who have previously been treated with a regimen containing an HCV NS5A inhibitor without cirrhosis
16 weeks 300 mg glecaprevir and 120 mg pibrentasvir once daily
   
  • who have previously been treated with a regimen containing an HCV or an NS3/4A protease inhibitor with or without compensated cirrhosis (Child-Pugh A)
12 weeks  
   
  • genotypes 1,2, 4, 5, or 6 with prior treatment with a peg interferon, ribavirin and/or sofosbuvir, but no prior treatment with an NS3/4A PI or NS5A inhibitor without cirrhosis
8 weeks  
   
  • genotypes 1,2, 4, 5, or 6 with prior treatment with a peg interferon, ribavirin and/or sofosbuvir, but no prior treatment with an NS3/4A PI or NS5A inhibitor with compensated cirrhosis (Child-Pugh A)
12 weeks  
   
  • genotype 3 with prior treatment with a peg interferon, ribavirin and/or sofosbuvir, but no prior treatment with an NS3/4A PI or NS5A inhibitor without cirrhosis or with compensated cirrhosis (Child-Pugh A)
16 weeks  
ledipasvir/sofosbuvir (Harvoni®, generics) 90 mg/400 mg tablet

Chronic HCV treatment:

  • genotype 1 who have failed peginterferon and/or ribavirin-based regimen with or without a protease inhibitor
    • without cirrhosis
12 weeks 90 mg ledipasvir and 400 mg sofosbuvir once daily
   
  • with compensated cirrhosis (Child-Pugh A)
24 weeks or 12 weeks in combination with ribavirin†  
   
  • decompensated cirrhosis (Child-Pugh B or C) plus ribavirin
12 weeks plus ribavirin  
   
  • liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks plus ribavirin      
   
  • genotype 4 who have failed peginterferon and/or ribavirin-based regimen with or without a protease inhibitor
    • in liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks plus ribavirin      
   
  • genotype 4, 5, or 6 without cirrhosis or with compensated cirrhosis (Child-Pugh A) who have failed peginterferon and/or ribavirin-based regimen with or without a protease inhibitor
12 weeks  
sofosbuvir/velpatasvir (Epclusa®, generics) 400 mg/100 mg tablets

Chronic HCV treatment:

  • genotype 1, 2, 3, 4, 5, or 6 treated with peginterferon/ribavirin and/or NS3/4A protease inhibitor
    • without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks 400 mg sofosbuvir and 100 mg velpatasvir once daily
   
  • with decompensated cirrhosis (Child-Pugh B or C)
12 weeks plus ribavirin  
sofosbuvir (Sovaldi®) 400 mg tablet

Chronic HCV treatment:

  • genotype 2 previously treated with an interferon-based regimen without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks plus ribavirin 400 mg once daily
   
  • genotype 3 previously treated with an interferon-based regimen without cirrhosis or with compensated cirrhosis (Child-Pugh A)
24 weeks plus ribavirin  
sofosbuvir, velpatasvir, and voxilaprevir (Vosevi®) 400 mg/100 mg/100 mg

Chronic HCV treatment:

  • genotypes 1, 2, 3, 4, 5, or 6 previously treated with an NS5A inhibitor without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir once daily
   
  • genotypes 1a or 3 previously treated with sofosbuvir without a NS5A inhibitor
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.

Table 3: Maximum recommended DAA dosages in pediatric chronic HCV infections2-12
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):

  • genotypes 1a: treatment naïve or peginterferon and ribavirin experienced without baseline NS5A polymorphisms
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: 

  • treatment naïve patients with any genotype without cirrhosis or with compensated cirrhosis (Child-Pugh A)
     
8 weeks
  • Patients 3-11 years of age: 
    • Less than 20 kg: one 150 mg/60 mg oral pellet pack once daily
    • 20 kg to less than 30 kg: one 200 mg/80 mg oral pellet pack once daily
    • 30 kg to less than 45 kg: one 250 mg/100 mg oral pellet pack once daily
    • 45 kg and greater: 300 mg/120 mg (three 100 mg/40 mg tablets once daily)
  • Patients 12-17 years of age:
    • three 100 mg/40 mg tablets once daily
    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:
  • genotype 1
    • treatment naïve without cirrhosis or with compensated cirrhosis (Child-Pugh A)
8¥ or 12 weeks
  • Patients 3-17 years of age: 
  • Less than 17 kg:
    • 3.75 mg/150 mg (one 33.75 mg/150 mg oral pellet packet) once daily
  • 17 kg to less than 35 kg:
    • 45 mg/200 mg (one 45 mg/200 mg tablet OR one 45 mg/200 mg oral pellet packet) once daily
  • 35 kg or more:
    • 90 mg/400 mg (one 90 mg/400 mg tablet OR two 45 mg/200 mg tablets0 OR two 45 mg/200 mg oral pellet packets) once daily
    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:

  • genotype 1, 2, 3, 4, 5, or 6 that are treatment naïve or experienced†† without cirrhosis or with compensated cirrhosis (Child-Pugh A)
12 weeks

Weight based dosing for patients 3-17 years of age: 

  • Less than 17 kg: one 150 mg/37.5 mg oral pellet packet once daily
  • 17 kg to less than 30 kg: one 200 mg/50 mg oral pellet packet OR one tablet once daily
  • 30 kg or greater: two 200 mg/50 mg oral pellet packets, two 200 mg/50 mg tablets, OR one 400 mg/100 mg tablet once daily
    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)

  • genotype 2 for treatment naïve or experienced# patients
12 weeks plus ribavirin*

Weight based dosing for patients 3-17 years of age: 

  • Less than 17 kg: one 150 mg oral pellet packet 
  • 17 kg to less than 35 kg: one 200 mg tablet or one 200 mg oral pellet packet once daily
  • 35 kg or greater: 400 mg tablet, two 200 mg tablets, or two 200 mg oral pellet packets once daily
    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. 

Table 14. DAA drug-drug interactions2,3
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

  1. 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&sectionid=224357874#1182438955. Accessed 10 June 2022. 
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc; 2022. Available at: http://www.clinicalpharmacology.com. Accessed June 11, 2022.
  3. 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). 
  4. Sofosbuvir (Sovaldi®) package insert. Gilead Sciences, Inc., Updated 5 March 2020.
  5. Ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets (Viekira Pak®) package insert. AbbVie Inc., November 2017.
  6. Ledipasvir and sofosbuvir (Harvoni®) package insert. Gilead Sciences, Inc., Updated 5 March 2020.
  7. Elbasvir/grazoprevir (Zepatier®) package insert. Merck & CO., Inc., Updated 19 December 2021.
  8. Sofosbuvir/velpatasvir (Epclusa®) package insert. Gilead Sciences, Inc., Updated 27 April 2022.
  9. Sofosbuvir/velpatasvir/voxilaprevir (Vosevi®) package insert. Gilead Sciences, Inc., Updated 15 November 2019.
  10. Glecaprevir/pibrentasvir (Mavyret™) package insert. AbbVie Inc., Updated 28 September 2021.
  11. Ribavirin (Rebetol®) package insert. Merck & Co., Inc., March 2022.
  12. AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed 28 June 2022. 
  13. 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.