Hepatitis C Treatment Overview

Full update October 2017

The chart below provides hepatitis C treatment options for treatment-naive adults based on genotype and presence of compensated cirrhosis. A second chart reviews adverse effects, monitoring parameters, and select drug interactions of hepatitis C drugs. See http://www.hep-druginteractions.org/ or product labeling for detailed drug interaction information. Consider patient-specific factors (e.g., drug interactions, adverse effects, adherence, payor coverage) when choosing a regimen. Treatment guidelines from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America (AASLD/IDSA) are available at http://hcvguidelines.org/full-report-view. Note that the AASLD/IDSA guideline is a “living” document, and may have been updated since publication of this chart. Treatment options from the Canadian Association for the Study of the Liver (2015) are available at https://www.cag-acg.org/images/publications/hepatitis_c_2015.pdf. Information in chart may differ from product labeling. Information from Canadian labeling is included when it differs significantly (e.g., more conservative) from referenced U.S. labeling.

Abbreviations: ALT = alanine aminotransferase; BCRP = breast cancer resistance protein; CBC = complete blood count; GFR = glomerular filtration rate; INR = International Normalized Ratio; NS3 protease inhibitors = telaprevir, boceprevir, simeprevir; NS5A inhibitor = nonstructural protein 5A inhibitor (i.e., daclatasvir, ledipasvir, ombitasvir); P-gp = P-glycoprotein RAV = resistance-associated variants; TSH = thyroid stimulating hormone; wks = weeks

**Important: consult AASLD/IDSA guidelines at http://www.hep-druginteractions.org/ before prescribing for the most updated regimens, including those recommended for salvage/retreatment. Also consult guidelines for information on treatment of patients with renal impairment, decompensated cirrhosis, liver transplant, HIV co-infection, acute hepatitis C infection; treatment in children; and disease monitoring.**

Patient Population (treatment naive)

Regimens: frequency and duration (from ref 1 unless otherwise noted).

Genotype 1a (or unknown subtype), without cirrhosis

Daklinza once daily plus Sovaldi once daily x 12 wks

Epclusa once daily x 12 wks

Harvoni once daily x 12 wks (8 wks if non-Black, not HIV positive, and HCV RNA <6 million IU/mL1)

Mavyret (Maviret [Canada]) once daily x 8 wks14

Olysio (U.S.) or Galexos (Canada) once daily plus Sovaldi once daily x 12 wks

Viekira XR once daily plus ribavirin twice daily x 12 wks

Viekira Pak (U.S.) or Holkira Pak (Canada) plus ribavirin twice daily x 12 wks

Zepatier once daily x 12 wks (only for patients without baseline NS5A polymorphisms)

Alternative: Zepatier once daily plus ribavirin twice daily x 16 wks (for patients with baseline NS5A polymorphisms)

Genotype 1a (or unknown subtype), with compensated cirrhosis (Child-Pugh Class A)

Epclusa once daily x 12 wks

Harvoni once daily x 12 wks

Mavyret (Maviret [Canada]) once daily x 12 wks14

Zepatier once daily (only for patients without baseline NS5A polymorphisms) x 12 wks


Alternative Regimens

Daklinza once daily plus Sovaldi once daily with or without ribavirin twice daily x 24 wks

Olysio (U.S.) or Galexos (Canada) once daily plus Sovaldi once daily with or without ribavirin twice daily (only for patients without Q80K substitution) x 24 wks

Viekira XR once daily plus ribavirin twice daily x 24 wks

Viekira Pak (U.S.) or Holkira Pak (Canada) plus ribavirin twice daily x 24 wks

Zepatier once daily plus ribavirin twice daily (for patients with baseline NS5A polymorphisms) x 16 wks

Genotype 1b, without cirrhosis

Daklinza once daily plus Solvaldi once daily x 12 wks

Epclusa once daily x 12 wks

Harvoni once daily x 12 wks (8 wks if non-Black, not HIV positive, and HCV RNA <6 million IU/mL1)

Mavyret (Maviret [Canada]) once daily x 12 wks14

Olysio (U.S.) or Galexos (Canada) once daily plus Sovaldi once daily x 12 wks

Viekira XR once daily x 12 wks

Viekira Pak (U.S.) or Holkira Pak (Canada) x 12 wks

Zepatier once daily x 12 wks


Genotype 1b, with compensated cirrhosis (Child-Pugh Class A)

Epclusa once daily x 12 wks

Harvoni once daily x 12 wks

Mavyret (Maviret [Canada]) once daily x 12 wks14

Viekira XR once daily x 12 wks

Viekira Pak (U.S.) or Holkira Pak (Canada) x 12 wks

Zepatier once daily x 12 wks


Alternative Regimens

Daklinza once daily plus Sovaldi once daily with or without ribavirin twice daily x 24 wks

Olysio (U.S.) or Galexos (Canada) once daily plus Sovaldi once daily with or without ribavirin twice daily x 24 wks

Genotype 2 (with or without compensated cirrhosis [Child-Pugh Class A])

Epclusa once daily x 12 wks

Mavyret (Maviret [Canada]) once daily x 8 wks (12 wks for compensated cirrhosis [Child-Pugh Class A])14

Alternative: Daklinza once daily plus Solvaldi once daily x 12 wks (16 to 24 wks for compensated cirrhosis [Child-Pugh Class A])


Genotype 3

Daklinza once daily plus Sovaldi once daily x 12 wks (without cirrhosis)

Daklinza once daily plus Sovaldi once daily with or without ribavirin twice daily x 24 wks (with compensated cirrhosis [Child-Pugh Class A])

Epclusa once daily x 12 wks (without cirrhosis, or with compensated cirrhosis [Child-Pugh Class A])

Mavyret (Maviret [Canada]) once daily x 8 wks (12 wks for compensated cirrhosis [Child-Pugh Class A])14


Genotype 4 (with or without compensated cirrhosis [Child-Pugh Class A])

Epclusa once daily x 12 wks

Harvoni once daily x 12 wks

Mavyret (Maviret [Canada]) once daily x 8 wks (12 wks for compensated cirrhosis [Child-Pugh Class A])14

Technivie once daily plus ribavirin twice daily x 12 wks

Zepatier once daily x 12 wks


Genotype 5 or 6 (with or without compensated cirrhosis [Child-Pugh Class A])

Epclusa once daily x 12 wks

Harvoni once daily x 12 wks

Mavyret (Maviret [Canada]) once daily x 8 wks (12 wks for compensated cirrhosis [Child-Pugh Class A])14




Therapeutic Considerations for use of Oral Hepatitis C Drugs

Selected Considerations Related to
DRUG INTERACTIONS
(see footnote a)

Common Adverse Effects

Monitoring (See guideline for information regarding quantitative HCV testing.)

All regimens

All may interact with certain anticonvulsants and HIV antivirals.

All but sofosbuvir can interact with certain statins


See individual agents.

Due to the risk of reactivation of hepatitis B by hepatitis C antivirals, screen patients for current or prior hep B infection before starting treatment. Monitor for hep B flare-ups or reactivation during and after hep C treatment.9

Within 12 weeks before starting: CBC, INR, liver function, GFR (calculated)

After four weeks and as clinically indicated: CBC, creatinine, GFR (calculated), liver function.

Discontinue treatment if ALT at week four increases tenfold, or increase is accompanied by symptoms, or increased bilirubin, alkaline phosphatase, or INR. Otherwise, asymptomatic increases in ALT at week four should prompt repeat ALT at weeks six and eight. Consider discontinuation in the event of persistent elevation.

Daclatasvir (Daklinza) (used with sofosbuvir)

Use with strong CYP344 inhibitors and moderate CYP3A4 inducers requires dose adjustment.6 See labeling.

Inhibits P-gp.6

Contraindicated with strong CYP3A4 inducers (e.g., rifampin, St. John’s wort, etc).6

Reduce digoxin dose by 15% to 30% or extend dosing interval.6

See dabigatran labeling for dosing with P-gp inhibitors.6


With sofosbuvir, ≥10% of patients: headache, fatigue.6


See “All regimens,” above

Elbasvir/grazoprevir (Zepatier)

Contraindicated with OATP1B1/3 inhibitors (e.g., cyclosporine, atazanavir, darunavir, lopinavir, saquinavir, tipranavir).21

Contraindicated with strong CYP3A inducers (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort, efavirenz).21

Use with moderate CYP3A inducers (e.g., bosentan, etravirine, modafinil, nafcillin) is not recommended.21

Use with certain strong CYP3A inhibitors (e.g., cobicistat, ketoconazole) is not recommended.21

Statins: max daily atorvastatin dose is 20 mg. Max daily rosuvastatin dose is 10 mg.21 Max daily fluvastatin, lovastatin, or simvastatin dose is 20 mg (Canada; U.S.: use lowest necessary dose).21,24


>5% of patients: fatigue, headache, nausea with ribavirin, moderate to severe headache and anemia.21


See “All regimens,” above. Also check liver function tests at week 8 (and week 12 if receiving a 16-week course), and as clinically indicated.21

Glecaprevir/pibrentasvir (Mavyret, Maviret [Canada])

May increase plasma concentrations of substrates of P-gp (e.g., dabigatran), BCRP, OATP1B1, or OATP1B3.14

Weakly inhibits CYP3A, CYP1A2, and UGT1A1.14

Drugs that inhibit P-gp, BCRP, OATP1B1, or OATP1B3 may increase plasma concentrations of glecaprevir and/or pibrentasvir.14

Drugs that induce P-gp and CYP3A4 may decrease glecaprevir and/or pibrentasvir concentrations.14,16

Contraindicated drugs: atazanavir, rifampin, dabigatran (Canada), ethinyl estradiol (Canada), atorvastatin (Canada), simvastatin (Canada).14,16

Not recommended for use with ethinyl estradiol (Canada: contraindicated), darunavir, lopinavir, ritonavir, efavirenz, carbamazepine, phenobarbital (Canada), phenytoin (Canada), St. John’s wort, atorvastatin (Canada: contraindicated), lovastatin, simvastatin (Canada: contraindicated), and stable cyclosporine doses >100 mg/day.14,16

Statins: reduce pravastatin dose by 50%. Do not exceed rosuvastatin 10 mg/day (Canada: 5 mg/day). Use the lowest necessary dose of fluvastatin or pitavastatin.14,16

Reduce digoxin dose by 50% or extend dosing interval.14

See dabigatran labeling for dosing with P-gp inhibitors (U.S.; [Canada: contraindicated with Maviret].14,16


>10% of patients: headache, fatigue.14

See “All regimens,” above.

Note: may increase direct and indirect bilirubin via OATP1B1/3 and UGT1A1 inhibition.14

Ledipasvir (component of Harvoni, with sofosbuvir)

Separate from antacids by four hours. H2-blockers can be given with or 12 hours apart from Harvoni at a dose not greater than famotidine 40 mg twice daily, or equivalent. Proton pump inhibitors can be taken with Harvoni, on an empty stomach, if the dose does not exceed omeprazole 20 mg daily or equivalent.8

Use of Harvoni with amiodarone may result in serious bradycardia, and is not recommended.8

Does not affect CYP450 enzymes.8

Substrate and inhibitor of P-gp.8 Use with P-gp inducers (e.g., St. John’s wort, rifampin, rifabutin, rifapentine, carbamazepine, phenytoin, phenobarbital, oxcarbazepine) is not recommended.8

Substrate and inhibitor of BCRP.8

Use with rosuvastatin is not recommended.8

Use with tipranavir/ritonavir, or elvitegravir/cobicistat/emtricitabine/tenofovir is not recommended.8

Monitor digoxin levels.8


With sofosbuvir (in Harvoni), ≥10% of patients: headache, weakness, fatigue;8 ≥5% of patients may have nausea or insomnia with
12 weeks of treatment.8


See “All regimens,” above.

Paritaprevir/ritonavir/ombitasvir/dasabuvir (Viekira Pak, Viekira XR [U.S.], Holkira Pak [Canada], Technivie [does not contain dasabuvir])

Has the most potential drug interactions.

  • Ombitasvir, paritaprevir, and dasabuvir are inhibitors of UGT1A1.10
  • Ritonavir is an inhibitor of CYP3A4.10
  • Paritaprevir is an inhibitor of OATP1B1 and OATP1B3.10
  • Paritaprevir, ritonavir, and dasabuvir are inhibitors of BCRP.10
  • Paritaprevir and ritonavir are metabolized mainly by CYP3A4.10
  • Dasabuvir is metabolized mainly by CYP2C8.10
  • Ombitasvir, paritaprevir, dasabuvir, and ritonavir are substrates of P-glycoprotein.10
  • Ombitasvir, paritaprevir, and dasabuvir are substrates of BCRP.10
  • Paritaprevir is a substrate of OATP1B1 and OATP1B3.10

Contraindicated Drugs:7,10,11,15,18,b alfuzosin, atorvastatin, bosentan (Canada), carbamazepine, cisapride, colchicine (U.S.; Canada: in renal or liver impairment), dronedarone (U.S.), ergots, efavirenz, ethinyl estradiol, etravirine (Canada), everolimus (U.S.), gemfibrozil (not Technivie), lovastatin, lurasidone (U.S.), midazolam (oral), modafinil (Canada), nevirapine (Canada), phenytoin, phenobarbital, pimozide, ranolazine (U.S.), rifampin, salmeterol (Canada; U.S.: not recommended), sildenafil (for pulmonary hypertension), simvastatin, sirolimus (U.S.), St. John’s wort, tacrolimus (U.S.), triazolam

Not recommended with voriconazole, quetiapine (Canada; U.S: reduce quetiapine dose to 1/6 of current dose), rilpivirine, salmeterol (U.S.; Canada: contraindicated). 7,10,11,15,18

Reduce amlodipine dose by at least 50%. Also reduce dose of other calcium channel blockers.7,10,15

Reduce digoxin dose by 30% to 50% (Technivie).15

See labeling for interactions with HIV antivirals.


≥5% of patients (without ribavirin): nausea, itching, insomnia, skin reactions.10

Technivie (with ribavirin): >10% of patients: weakness, fatigue, nausea, insomnia.15

Contraindicated in moderate or severe hepatic impairment (Child-Pugh B and C) due to risk of hepatic decompensation.7,10,15,19


See “All regimens,” above.

In patients with compensated cirrhosis, check liver function tests and monitor for clinical signs of decompensated cirrhosis at week two and week four, and as clinically indicated. Discontinue immediately in the event of ascites, encephalopathy, or a significant increase in direct bilirubin or transaminases.1

Simeprevir (Olysio [U.S.], Galexos [Canada])

CYP3A4 substrate and weak intestinal CYP3A4 inhibitor.12

Weak CYP1A2 inhibitor.12

Inhibits P-gp, BCRP, and OATP1B1/3.12

Dose statins conservatively, and monitor for myopathy.12

Use with moderate or strong CYP3A4 inhibitors or inducers is not recommended.12

With sofosbuvir (Sovaldi): >20% of patients have fatigue, headache, or nausea.12


See “All regimens,” above.

Sofosbuvir (Sovaldi)

Generally, has fewest drug interactions.

Use with amiodarone and another direct-acting antiviral may result in serious bradycardia; avoid.2,3

No CYP450-mediated interactions.

Substrate of P-gp and BCRP.4

Does not interact with statins.

P-gp inducers may reduce levels.4


With ledipasvir (in Harvoni): ≥10% of patients: headache, weakness, fatigue;8 ≥5% of patients may have nausea or insomnia with 12 weeks of treatment.8

With simeprevir (Olysio): >20% of patients: fatigue, headache, nausea.12

See “All regimens,” above.

Sofosbuvir/Velpatasvir (Epclusa)

Velpatasvir and sofosbuvir are P-gp and BCRP substates.22

Velpatasvir is metabolized by CYP2B6, CYP2C8, and CYP3A4.22

Velpatasvir inhibits P-gp, BCRP, OATP1B1, OATP1B3, and OATP2B1.22

Use with inducers of P-gp and/or moderate or potent inducers of CYP2B6, CYP2C8, or CYP3A4 is not recommended.22

Separate from antacids by four hours. Give H2-blockers with or 12 hours apart from Epclusa at a dose not greater than famotidine 40 mg twice daily, or equivalent. Use with proton pump inhibitors not recommended per U.S. labeling. If use is necessary, give Epclusa with food four hours before omeprazole 20 mg (Canada: omeprazole 20 mg or equivalent can be taken with Epclusa, with food23).22

Use with amiodarone may result in serious bradycardia; avoid.22

Max daily rosuvastatin dose is 10 mg.22

Monitor digoxin levels.22


≥10% of patients: headache, fatigue.22

With ribavirin, ≥10% of patients with decompensated cirrhosis: fatigue, anemia, nausea, headache, insomnia, diarrhea.22

See “All regimens,” above.

Sofosbuvir/Velpatasvir/Voxilaprevir (Vosevi): only for salvage/retreatment for all genotypes (once daily)

Velpatasvir, sofosbuvir, and voxilaprevir are P-gp and BCRP substates.17 Voxilaprevir is a substrate of OATP1B1 and OATP1B3.17

Velpatasvir is metabolized by CYP2B6, CYP2C8, and CYP3A4.17 Voxilaprevir is metabolized by CYP1A2, CYP2C8, and mainly CYP3A4.17

Velpatasvir and voxilaprevir are inhibitors of P-gp, BCRP, OATP1B1, and OATP1B3. Velpatasvir is also an inhibitor of OATP2B1.17

Contraindicated with rifampin, dabigatran (Canada), phenobarbital (Canada), phenytoin (Canada), St. John’s wort (Canada), rosuvastatin (Canada).17,20

Not recommended with inducers of P-gp and/or moderate or potent inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., carbamazepine, phenytoin [Canada: contraindicated], phenobarbital [Canada: contraindicated], oxcarbazepine, rifabutin, rifapentine, St. John’s wort [Canada: contraindicated]); OATP inhibitors such as cyclosporine; or BCRP substrates such as methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, sulfasalazine or topotecan. Use with atazanavir, lopinavir, tipranavir/ritonavir, or efavirenz is not recommended.17 Use with amiodarone may result in serious bradycardia; avoid.17

Statins: not recommended with rosuvastatin (Canada: contraindicated), or

pitavastatin limit pravastatin to 40 mg/day; limit atorvastatin to 10 mg/day (Canada). Use lowest effective dose of other statins.17,20

Separate from antacids by four hours. Limit H2-blocker dose to famotidine 40 mg twice daily, or equivalent. Omeprazole 20 mg can be given with Vosevi.17

Canada: consider monitoring ALT if used with ethinyl estradiol.20

Monitor digoxin levels.17

See dabigatran labeling for dosing with P-gp inhibitors (U.S.; Canada: contraindicated with Vosevi).17,20


≥10% of patients: headache, fatigue, diarrhea, nausea.17

See “All regimens,” above.

Ribavirin (Copegus [U.S.], Rebetol capsule and solution, [U.S.], Ibavyr [Canada])

Ribavirin does not inhibit CYP2C9, CYP2C19, CYP2D6, or CYP3A4.5

Contraindicated with didanosine.5,13


With Sovaldi: >20% of patients, fatigue, headache.4

With Technivie: >10% of patients, weakness, fatigue, nausea, insomnia.15

With Harvoni: >10% of patients, weakness, headache.8

With Viekira Pak, Viekira XR, Holkira Pak: >10% of patients, fatigue, nausea, dermatologic reactions, insomnia, weakness.10


Pregnancy test at baseline, then monthly during treatment and for six months after discontinuation.5,13

Patients with cardiac disease should have a baseline electrocardiogram (due to cardiac risk conferred by anemia).5,13

CBC at baseline, weeks two and four, and periodically.5,13 Biochemical tests (e.g., liver function, uric acid) at baseline, week four, and periodically.5

Dose reduction or discontinuation may be indicated in the event of hemoglobin reduction.5,13

Also see “All regimens,” above.

  1. Not a complete list of drug interactions. For additional drug interactions, see http://www.hep-druginteractions.org/, U.S. MedGuide, and product labeling.
  2. Contraindicated with drugs highly dependent on CYP3A4 for metabolism and for which increased levels may cause serious events.7,10 Contraindicated with moderate or strong CYP3A4 inducers.7,10 Also contraindicated with strong CYP2C8 inhibitors or inducers due to dasabuvir component (does not apply to Technivie15).7,10

Project Leader in preparation of this clinical resource (331010): Melanie Cupp, Pharm.D., BCPS

References

  1. American Association for the Study of Liver Diseases and Infectious Diseases Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C. http://hcvguidelines.org/full-report-view. (Accessed September 2, 2017).
  2. U.S. Food & Drug Administration. FDA drug safety communication: FDA warns of serious slowing of the heart when antiarrhythmic drug amiodarone is used with hepatitis C treatments containing sofosbuvir (Harvoni) or Sovaldi in combination with another direct acting antiviral drug. March 24, 2015. http://www.fda.gov/Drugs/DrugSafety/ucm439484.htm. (Accessed September 5, 2017).
  3. Health Canada. Amiodarone-slow heart rate in patients taking amiodarone together with Harvoni or Sovaldi and a direct acting antiviral. April 2, 2015. http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2015/52801a-eng.php?_ga=1.6879089.259317099.1448392445. (Accessed September 5, 2017).
  4. Product information for Sovaldi. Gilead Sciences, Inc. Foster City, CA 94404. April 2017.
  5. Product information for Copegus. Genentech, Inc. South San Francisco, CA 94080. August 2015.
  6. Product information for Daklinza. Bristol-Myers Squibb Company. Princeton, NJ 08543. February 2017.
  7. Product information for Viekira XR. AbbVie, Inc. North Chicago, IL 60064. March 2017.
  8. Product information for Harvoni. Gilead Sciences, Inc. Foster City, CA 94404. April 2017.
  9. FDA. FDA drug safety communication: FDA warns about the risk of hepatitis B reactivating in some patients treated with direct-acting antivirals for hepatitis C. October 4, 2016. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM523499.pdf. (Accessed September 5, 2017).
  10. Product information for Viekira Pak. AbbVie, Inc. North Chicago, IL 60064. March 2017.
  11. Product monograph for Holkira Pak. AbbVie Corporation. Saint Laurent, QC H4S 1Z1. August 2017.
  12. Product information for Olysio. Janssen Products LP. Janssen Therapeutics. Titusville, NJ 08560. May 2017.
  13. Product information for Rebetol. Merck & Co., Inc. Whitehouse Station, NJ 08889. January 2016.
  14. Product information for Mavyret. AbbVie, Inc. North Chicago, IL 60064. August 2017.
  15. Product information for Technivie. AbbVie, Inc. North Chicago, IL 60064. June 2016.
  16. Product monograph for Maviret. AbbVie Corporation. St. Laurent. QC H4S 1Z1 August 2017.
  17. Product information for Vosevi. Gilead Sciences, Inc. Foster City, CA 94404. July 2017.
  18. Product monograph for Technivie. AbbVie Corporation. Saint-Laurent, QC H4S 1Z1. August 2017.
  19. Health Canada. Information update-risk of serious liver injury associated with hepatitis C treatments: Holkira Pak and Technivie. November 10, 2015. http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2015/55800a-eng.php. (Accessed September 5, 2017).
  20. Product monograph for Vosevi. Gilead Sciences Canada, Inc. Mississauga, ON L5N 2W3. August 2017.
  21. Product information for Zepatier. Merck & Co., Inc. Whitehouse Station, NJ 08889. February 2017.
  22. Product information for Epclusa. Gilead Sciences, Inc. Foster City, CA 94404. August 2017.
  23. Product monograph for Epclusa. Gilead Sciences, Inc. Foster City, CA 94404. May 2017.
  24. Product monograph for Zepatier. Merck Canada, Inc. Kirkland, QC H9H 4M7. June 2017.

Cite this document as follows: Clinical Resource, Hepatitis C Treatment Overview. Pharmacist’s Letter/Prescriber’s Letter. October 2017.

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