HEPATITIS C TREATMENT

• ACRONYMS AND DEFINITIONS

• AASLD - American Association for the Study of Liver Diseases
• ALT - Alanine aminotransferase
• GT - Genotype
• HBV - Hepatitis B virus
• HCC - Hepatocellular carcinoma
• HCV - Hepatitis C virus
• IDSA - Infectious Diseases Society of America
• MOA - Mechanism of action
• PegIFN - Pegylated interferon
• PI - Protease inhibitor
• RBV - Ribavirin

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• TREATMENT BY GENOTYPE

Genotype 1
Epclusa® (sofosbuvir + velpatasvir) ± ribavirin - no cirrhosis, cirrhosis (Child-Pugh A,B,C), and liver transplant Harvoni® (sofosbuvir + ledipasvir) ± ribavirin - no cirrhosis, cirrhosis (Child-Pugh A,B,C), and post-liver transplant Mavyret® (glecaprevir + pibrentasvir) - no cirrhosis, Child-Pugh A, and liver or kidney transplant recipients Viekira Pak™ (ombitasvir + paritaprevir + dasabuvir + ritonavir) - no cirrhosis, Child-Pugh A, and post-liver transplant Vosevi™ (sofosbuvir + velpatasvir + voxilaprevir) - retreatment in no cirrhosis and Child-Pugh A Zepatier™ (elbasvir + grazoprevir) - no cirrhosis and Child-Pugh A
Genotype 2
Epclusa® (sofosbuvir + velpatasvir) ± ribavirin - no cirrhosis, cirrhosis (Child-Pugh A,B,C), and liver transplant Mavyret® (glecaprevir + pibrentasvir) - no cirrhosis, Child-Pugh A, and liver or kidney transplant recipients Sofosbuvir (Sovaldi®) + ribavirin - no cirrhosis and Child-Pugh A Vosevi™ (sofosbuvir + velpatasvir + voxilaprevir) - retreatment in no cirrhosis and Child-Pugh A
Genotype 3
Epclusa® (sofosbuvir + velpatasvir) ± ribavirin - no cirrhosis, cirrhosis (Child-Pugh A,B,C), and liver transplant Mavyret® (glecaprevir + pibrentasvir) - no cirrhosis, Child-Pugh A, and liver or kidney transplant recipients Sofosbuvir (Sovaldi®) + ribavirin - no cirrhosis and Child-Pugh A Vosevi™ (sofosbuvir + velpatasvir + voxilaprevir) - retreatment in no cirrhosis and Child-Pugh A
Genotype 4
Epclusa® (sofosbuvir + velpatasvir) ± ribavirin - no cirrhosis, cirrhosis (Child-Pugh A,B,C), and liver transplant Harvoni® (sofosbuvir + ledipasvir) ± ribavirin - no cirrhosis, Child-Pugh A, and post-liver transplant Mavyret® (glecaprevir + pibrentasvir) - no cirrhosis, Child-Pugh A, and liver or kidney transplant recipients Zepatier™ (elbasvir + grazoprevir) - no cirrhosis and Child-Pugh A Vosevi™ (sofosbuvir + velpatasvir + voxilaprevir) - retreatment in no cirrhosis and Child-Pugh A
Genotype 5
Epclusa® (sofosbuvir + velpatasvir) ± ribavirin - no cirrhosis, cirrhosis (Child-Pugh A,B,C), and liver transplant Harvoni® (sofosbuvir + ledipasvir) ± ribavirin - no cirrhosis and Child-Pugh A Mavyret® (glecaprevir + pibrentasvir) - no cirrhosis, Child-Pugh A, and liver or kidney transplant recipients Vosevi™ (sofosbuvir + velpatasvir + voxilaprevir) - retreatment in no cirrhosis and Child-Pugh A
Genotype 6
Epclusa® (sofosbuvir + velpatasvir) ± ribavirin - no cirrhosis, cirrhosis (Child-Pugh A,B,C), and liver transplant Harvoni® (sofosbuvir + ledipasvir) ± ribavirin - no cirrhosis or Child-Pugh A Mavyret® (glecaprevir + pibrentasvir) - no cirrhosis, Child-Pugh A, and liver or kidney transplant recipients Vosevi™ (sofosbuvir + velpatasvir + voxilaprevir) - retreatment in no cirrhosis and Child-Pugh A

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• HEPATITIS C VIRUS MEDICATIONS

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• RIBAVIRIN

• Overview
• Ribavirin is recommended in a number of HCV treatment regimens because it enhances their efficacy
• Ribavirin can have a number of serious side effects, the most important being hemolytic anemia. Because of this, extra lab monitoring is required with ribavirin therapy. See labs monitoring with ribavirin for more.
• Ribavirin also causes birth defects, and pregnant women or women hoping to become pregnant should not take ribavirin
• Ribavirin may be passed to female partners of ribavirin-treated males through intercourse. If these women become pregnant, the fetus may be exposed to ribavirin. Female partners of ribavirin-treated males should take precautions to avoid pregnancy.
• Pregnancy should also be avoided for 6 months after ribavirin has been stopped in both female patients and female partners of ribavirin-treated males [2]
• See ribavirin for a complete review of ribavirin

• Dosage forms
• Capsule
• Names: Rebetol®, Ribasphere®
• Dosage forms: 200 mg
• Generic/Cost: YES / $100 - $150 for 150 capsules
• Tablet
• Names: Copegus®
• Dosage forms: 200 mg
• Generic/Cost (200 mg): YES / $100 - $150 for 150 tablets

• Weight-based ribavirin dosing
• Regimen 1 (Daklinza, Epclusa, Harvoni, Sovaldi, Viekira Pak)
• < 165 lbs (75 kg): 1000 mg a day given in 2 divided doses
• > 165 lbs (75 kg): 1200 mg a day given in 2 divided doses
• A starting dose of 600 mg/day with titration as tolerated may be appropriate in patients with decompensated cirrhosis (Child-Pugh B and C)
• Take ribavirin with food. Food increases absorption.
• Regimen 2 (Zepatier)
• < 66 kg (145 pounds): 800 mg a day given in 2 divided doses
• 66 - 80 kg (145 - 176 pounds): 1000 mg a day given in 2 divided doses
• 81 - 105 kg (177 - 231 pounds): 1200 mg a day given in 2 divided doses
• > 105 kg (231 pounds): 1400 mg a day given in 2 divided doses
• A starting dose of 600 mg/day with titration as tolerated may be appropriate in patients with decompensated cirrhosis (Child-Pugh B and C)
• Take ribavirin with food. Food increases absorption.

• Lab monitoring
• One of the most concerning side effects of ribavirin is hemolytic anemia. The Rebetol PI recommends that a CBC be checked before the start of treatment and at Week 2 and Week 4 of therapy. Continued monitoring and/or more frequent checks may be appropriate in some patients.
• Recommendations for therapy adjustments based on lab results are presented below along with special precautions regarding pregnancy for both females and males

• Adjusting therapy
• Patients without cardiac disease
• Hemoglobin ≥ 10 g/dl: No dose adjustment necessary. If patient had prior dose reduction, may consider increasing ribavirin gradually in 200 mg increments.
• Hemoglobin 8.5 - 9.9 g/dl: Reduce ribavirin dose by 200 mg/day. If patient is receiving 1400 mg/day, reduce dose by 400 mg. Recheck hemoglobin within 2 weeks as clinically indicated.
• Hemoglobin < 8.5: Discontinue therapy


• Patients with stable coronary artery disease
• Hemoglobin reduction ≥ 2 g/dl during any 4 week period and hemoglobin is still ≥ 12 g/dl: Reduce ribavirin dose by 200 mg/day. If patient is receiving 1400 mg/day, reduce dose by 400 mg. Recheck hemoglobin within 2 weeks as clinically indicated.
• Hemoglobin 8.5 - 11.9 g/dl: Reduce ribavirin dose by 200 mg/day. If patient is receiving 1400 mg/day, reduce dose by 400 mg. Recheck hemoglobin within 2 weeks as clinically indicated. If hemoglobin remains < 12 g/dl despite 4 weeks at the reduced dose, discontinue therapy.
• Hemoglobin < 8.5: Discontinue therapy [14,15]

• Pregnancy (including female partners of males receiving ribavirin)
• Ribavirin causes birth defects, and pregnant women or women hoping to become pregnant should not take ribavirin
• Ribavirin may be passed to female partners of ribavirin-treated males through intercourse. If these women become pregnant, the fetus may be exposed to ribavirin. Female partners of ribavirin-treated males should take precautions to avoid pregnancy.
• Pregnancy should also be avoided for 6 months after ribavirin has been stopped in both female patients and female partners of ribavirin-treated males [2]

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• WHOM TO TREAT

• Current AASLD/IDSA guidelines
• The AASLD/IDSA guidelines currently recommend that all patients with HCV infection be treated as long as they do not have a short life expectancy that cannot be increased with HCV therapy, liver transplantation, or another directed therapy


• Past AASLD/IDSA guidelines (prioritizing HCV treatment)
• Past AASLD/IDSA treatment recommendations prioritized treatment based on risk factors and medical conditions
• Those recommendations are presented below
• Highest priority for treatment owing to highest risk for severe complications
• Advanced fibrosis (Metavir F3) or compensated cirrhosis (Metavir F4)
• Liver transplant recipients or patients awaiting transplant
• Type 2 or 3 essential mixed cryoglobulinemia with end-organ manifestations (eg. vasculitis)
• Proteinuria, nephrotic syndrome, or membranoproliferative glomerulonephritis
• High priority for treatment owing to high risk for complications
• Fibrosis (Metavir F2)
• HIV coinfection
• Hepatitis B coinfection
• Other coexistent liver disease (eg, NASH)
• Debilitating fatigue
• Type 2 diabetes
• Porphyria cutanea tarda
• High hepatitis C transmission risk
• HIV-infected men who have sex with men
• IV drug abusers
• Incarcerated persons
• Persons on long-term hemodialysis [2]

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• TREATMENT RECOMMENDATIONS AND MONITORING

• AASLD simplified treatment recommendations
• The AASLD has published two simplified guidelines for the assessment and treatment of HCV in treatment-naïve adults. One guideline is for patients without cirrhosis and the other is for patients with compensated cirrhosis (Child-Pugh A). The guidelines provide a straightforward and simple approach to evaluating and treating most patients. Links to the guidelines are provided below.
• AASLD simplified HCV treatment in adults without cirrhosis
• AASLD simplified HCV treatment in adults with compensated cirrhosis (Child-Pugh A)

• Lab monitoring
• Recommendations for lab monitoring during HCV treatment are presented in the table below. The AASLD simplified treatment recommendations (see above) give slightly different recommendations.

Before treatment
Check anytime before start of therapy Hepatitis C genotype Hepatitis C viral load Baseline labs (within 12 weeks of starting therapy) Complete blood cell count including platelets (CBC) Liver function tests INR CrCl or GFR Pregnancy test - female patients of childbearing potential whose regimens will include ribavirin (see ribavirin monitoring below) Hepatitis B screening - HBsAg, Anti-HBs, and Anti-HBc (see hepatitis B serology for more) HIV
During treatment
Check the following after 4 weeks of therapy and as clinically indicated Complete blood cell count including platelets (CBC) - more frequent monitoring may be required in regimens that include ribavirin (see ribavirin below for more) Liver function tests (see ALT elevations below) CrCl or GFR Check a HCV viral load after 4 weeks of therapy and 12 weeks after the completion of therapy If viral load is detectable at 4 weeks, recheck in 2 weeks. If viral load increases by > 10-fold (> 1 log10IU/mL) from baseline at week 6 or thereafter, discontinue treatment. Successful treatment of HCV is defined as undetectable viral load by highly sensitive polymerase chain reaction assay (lower limit of detection <12 IU/mL) at 12 weeks after the completion of therapy. Risk of relapse from the original infection after successful treatment is < 1%. Patients receiving Viekira Pak (ombitasvir, paritaprevir, ritonavir ± dasabuvir) with Child-Pugh A Check liver function tests at 2 and 4 weeks after the start of therapy and as clinically indicated thereafter Patients with Child-Pugh A should be assessed for clinical signs of decompensated liver disease (eg, ascites, encephalopathy, or serum bilirubin > 3 mg/dL) Discontinue medication if signs develop. See Viekira Pak for more. Patients receiving Zepatier (elbasvir + grazoprevir) Check liver function tests at 8 weeks after the start of therapy. If patients are receiving 16 weeks of therapy, check again at 12 weeks. See Zepatier for more
ALT elevations
For a 10-fold increase in ALT at anytime during therapy Discontinue therapy For an increase in ALT less than 10-fold with symptoms of hepatitis Discontinue therapy Symptoms of hepatitis include any weakness, nausea, vomiting, jaundice, or significantly increased bilirubin, alkaline phosphatase, or INR For an increase in ALT less than 10-fold and no symptoms of hepatitis Recheck LFTs at 2 week intervals. If levels remain persistently elevated, consider stopping therapy. [2]
Ribavirin monitoring
See ribavirin lab monitoring above
Test of cure
Successful treatment of HCV is defined as undetectable viral load by highly sensitive polymerase chain reaction assay (lower limit of detection <12 IU/mL) at 12 weeks after the completion of therapy. Risk of relapse from the original infection after successful treatment is < 1%. Liver function tests should also be checked at the same time to confirm normalization

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• POST-TREATMENT SURVEILLANCE

• Overview
  • Successful treatment of HCV is defined as undetectable viral load by highly sensitive polymerase chain reaction assay (lower limit of detection <12 IU/mL) at 12 weeks after the completion of therapy. Risk of relapse from the original infection after successful treatment is < 1%.
  • Despite successful treatment, some patients are at continued risk for worsening cirrhosis and hepatocellular carcinoma (HCC)
  • The AASLD/IDSA recommendations for continued surveillance in patients who have been treated for HCV are detailed below. See Metavir scoring for a review of the Metavir system.
  
  
• Surveillance after successful treatment
  • Patients with Metavir F0, F1, or F2: no special follow-up recommended
  • Patients with Metavir F3 or F4: twice yearly ultrasound to monitor for HCC
  • All patients with cirrhosis: baseline endoscopy to screen for varices. Patients in whom varices are found should be treated and followed as indicated.
  
  
• Surveillance after unsuccessful treatment
  • Monitor disease progression every 6 - 12 months with liver function tests, INR, and CBC
  • Twice yearly ultrasound to monitor for HCC in patients with Metavir F3 or F4
  • Endoscopy to screen for varices in patients with cirrhosis [2]

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• PEDIATRIC TREATMENT

• Epclusa
• Epclusa is FDA-approved for the treatment of all HCV genotypes in pediatric patients ≥ 3 years of age
• See Epclusa PI [sec 2] for dosing in pediatric patients


• Harvoni
• Harvoni is FDA-approved to treat pediatric patients 3 years of age and older with the following:
• Genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis
• Genotype 1 infection with decompensated cirrhosis, for use in combination with ribavirin
• Genotype 1 or 4 infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis, for use in combination with ribavirin
• See Harvoni PI [sec 2] for dosing recommendations in pediatric patients


• Mavyret
• Mavyret (glecaprevir + pibrentasvir) is FDA-approved for the treatment of all HCV genotypes in pediatric patients ≥ 3 years of age
• See Mavyret PI [sec 2] for pediatric dosing recommendations


• Sovaldi
• Sovaldi is FDA-approved in pediatric patients 3 years of age and older with genotype 2 or 3 chronic HCV infection without cirrhosis or with compensated cirrhosis in combination with ribavirin
• See Sovaldi PI [sec 2] for dosing recommendations in pediatric patients


• Zepatier
• Zepatier is FDA-approved for the treatment of HCV genotypes 1 and 4 in pediatric patients 12 years of age and older weighing at least 30 kg (66 lbs)
• Pediatric dosing is the same as adults. See Zepatier dosing for more.

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• AASLD / IDSA TREATMENT RECOMMENDATIONS

• The AASLD and IDSA have created a well-organized and comprehensive website that gives updated treatment recommendations for HCV
• The website is available at the link below


• AASLD / IDSA Hepatitis C treatment guidelines

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• HEPATITIS B COINFECTION

• Overview
• In October 2016, the FDA placed a boxed warning on all new hepatitis C drugs about the possible reactivation of hepatitis B infection in coinfected patients who are taking direct-acting antiviral hepatitis C drugs
• At the time of the warning, the FDA had identified 24 cases of hepatitis B reactivation in patients taking these drugs. Reactivation occurred in patients who were HBsAg positive and in those who were HBsAg negative and anti-HBc positive (see hepatitis B serology for more).
• AASLD recommendations for HBV coinfected patients are given below


• Patients who meet criteria for HBV treatment
• Begin treatment
• AASLD HBV treatment criteria


• Patients who do not meet criteria for HBV treatment
• Initiate prophylactic antiviral therapy for those with low or undetectable HBV DNA levels. If this course is elected, pending further data, prophylaxis should be continued until 12 weeks after completion of direct-acting antiviral therapy.
• Monitor HBV DNA levels during and immediately after direct-acting antiviral therapy for HCV. Antiviral treatment for HBV should be given in the event of a rise in HBV DNA > 10-fold above baseline or to a level > 1000 IU/mL in those with a previously undetectable or unquantifiable HBV DNA level.
• AASLD HBV treatment criteria

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• BIBLIOGRAPHY

• 1 - Manufacturer's package insert
• 2 - AASLD hepatitis C website
• 3 - Rebetol PI
• 4 - PMID 24795200 - ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV, NEJM (2014)
• 5 - PMID 15880505
• 6 - PMID 5904286
• 7 - PMID 9250851
• 8 - PMID 9347849
• 9 - PMID 17486049