Gastroenterology Book

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Hepatitis C Antiviral Regimen

Aka: Hepatitis C Antiviral Regimen, Hepatitis C Treatment with Interferon and Ribavirin
  1. See Also
    1. Hepatitis C
  2. Precautions
    1. Hepatitis C Antiviral Therapy involves rapidly changing and complex guidelines
      1. U.S. patients typically undergo Hepatitis C antiviral therapy under the direction of specialty care
      2. As of 2016, more primary care U.S. providers are prescribing Hepatitis C management
    2. Protocols listed below are intended for review by primary care and emergency providers
      1. Allows for understanding of the adverse effects of treatment regimens
      2. Those prescribing antiviral therapy should use national guideline resources instead
    3. Ensure compliance for least resistance
      1. If an agent needs to be stopped (e.g. for surgery), stop the whole regimen
      2. Emphasize to patients that new regimens may be up to 90% effective with best compliance
    4. Hepatitis B Reactivation risk
      1. See Adverse Effects below
  3. Indications: Standard
    1. HCV RNA positive (e.g. >50 copies/ml)
    2. Age over 18 years old
    3. Willing and able to comply with treatment
    4. Increased serum Alanine transaminase (ALT)
      1. Some prior guidelines required Serum ALT greater than twice normal
    5. Metavir Scoring System 2 or more
  4. Contraindications
    1. Absolute Contraindications
      1. Allergy to antiviral agents
      2. Decompensated Cirrhosis
      3. Pregnancy (Ribavirin regimens)
      4. Ongoing intravenous Drug Abuse or Alcoholism
    2. Relative Contraindications (more specific for interferon and Ribavirin protocols)
      1. Leukopenia
      2. Anemia
      3. Thrombocytopenia
      4. Some Autoimmune Conditions
      5. Coronary Artery Disease
      6. Uncontrolled mental health condition
  5. Evaluation: Pre-treatment
    1. Complete history and physical for contraindications
    2. Laboratory testing as described in Hepatitis C
    3. Baseline labs for therapy - see monitoring below
  6. Evaluation: Post-treatment
    1. HCV RNA
      1. HCV RNA Negative at 24 weeks is associated with 99% longterm, sustained viral response
      2. HCV RNA Negative at 12 weeks predicts longterm, sustained viral response
  7. Management
    1. Any Genotype
      1. Initial therapy
        1. Sofosbuvir and Velpatasvir (Epclusa) one tab daily for 12 weeks
        2. Glecaprevir and Pibrentasvir (Mavyret) three tabs daily for 8 weeks
      2. Salvage therapy
        1. Glecaprevir and Pibrentasvir (Mavyret) three tabs daily for up to 16 weeks
        2. Sofosbuvir and Velpatasvir and Voxilaprevir (Vosevi) one tab daily for 12 weeks
    2. Genotype 1a
      1. Sovaldi and Ledipasvir (Harvoni) for 12 weeks
      2. Elbasivir and Grazoprevir (Zepatier) for 12 weeks
      3. Ombitasvir, Paritaprevir/r and Dasabuvir (Viekira Pak) with Ribavirin for 12 weeks (24 weeks if Cirrhosis)
      4. Sovaldi and Olysio (with or without Ribavirin) for 12 weeks (24 weeks if Cirrhosis)
    3. Genotype 1b
      1. Sovaldi and Ledipasvir (Harvoni) for 12 weeks
      2. Elbasivir and Grazoprevir (Zepatier) for 12 weeks
      3. Ombitasvir, Paritaprevir/r and Dasabuvir (Viekira Pak) for 12 weeks (with Ribavirin for 24 weeks if Cirrhosis)
      4. Sovaldi and Olysio (with or without Ribavirin) for 12 weeks (24 weeks if cirrhotic)
    4. Genotype 2
      1. Sofosbuvir (Sovaldi) with Ribavirin for 12 weeks (24 weeks if Cirrhosis)
    5. Genotype 3
      1. Sofosbuvir (Sovaldi) with Ribavirin for 24 weeks
    6. Genotype 4
      1. Sovaldi and Ledipasvir (Harvoni) for 12 weeks
      2. Ombitasvir, Paritaprevir/r and Dasabuvir (Viekira Pak) with Ribavirin for 12 weeks
      3. Sofosbuvir (Sovaldi) with Ribavirin for 24 weeks
    7. Genotype 5
      1. Sofosbuvir (Sovaldi) and pegylated interferon with Ribavirin for 12 weeks
    8. Genotype 6
      1. Sovaldi and Ledipasvir (Harvoni) for 12 weeks
  8. Preparations: Interferon
    1. Replaced in most Hepatitis C protocols by other protocols as of 2014
    2. Interferon alfa-2a (preferred for all Genotypes)
      1. Pegylated Interferon alfa-2a (Pegasys)
        1. Adult Dose: 180 mcg SQ per week
    3. Interferon alfa-2b
      1. Interferon alfa-2a is preferred instead (see above)
      2. Pegylated Interferon alfa-2b (PEG-Intron)
        1. Adult Dose: 1.5 mcg/kg per week
      3. Interferon alfa-2b (Intron A)
        1. Dose: 3 Million Units SQ three times per week
        2. Administer with Ribavirin if not contraindicated
        3. Cost: $8000 per 24 week course
        4. Rebetron combines Ribavirin and Interferon alfa-2b
    4. Adverse Effects
      1. See Interferon (numerous potential life-threatening adverse effects)
  9. Preparation: Ribavirin (if not contraindicated)
    1. Genotype 2 or 3 (all weights)
      1. Take 400 mg orally twice daily
    2. Genotype 1a, 1b and 4
      1. Weight >75 kg (165 lb): 600 mg orally twice daily
      2. Weight <75 kg (165 lb): 400 mg qAM, 600 mg qPM
    3. Adverse effects
      1. Hemolytic Anemia
      2. Exacerbation of Coronary Artery Disease
      3. Highly Teratogenic
        1. Requires high efficacy, dual Contraception in women of child bearing age
        2. Includes women who are sexual partners of men on Ribavirin
        3. Contraception should be continued throughout therapy and for 6 months after
  10. Preparation: Protease Inhibitors (NS3/4A Inhibitors)
    1. General
      1. Used in combination with oral Ribavirin and injectable interferon
    2. Telaprevir (Incivek)
      1. Discontinued in U.S. in 2014
    3. Boceprevir (Victrelis)
      1. Discontinued in U.S. in 2015
    4. Simeprevir (Olysio)
      1. Effective for HCV Genotypes 1, 4, 5 and 6
      2. Advantages over other Protease Inhibitors in Hepatitis C
        1. Dosed only once daily
        2. May be better tolerated than other Protease Inhibitors with fewer Drug Interactions
      3. Contraindications
        1. Sulfonamide Allergy
        2. Hepatitis C types more responsive to Incivek or Victrelis (35% of cases)
      4. Adverse Effects
        1. Anemia
        2. Fatigue
        3. Flu-like symptoms
        4. Pruritus
        5. Headache
        6. Nausea
      5. References
        1. (2014) Presc Lett 21(2): 8-9
  11. Preparation: Polymerase Inhibitor (NS5B Inhibitor)
    1. Indications
      1. Used in place of Protease Inhibitors as adjunct to Ribavirin (and interferon in some Genotypes)
        1. Shorter course than Protease Inhibitors (12-24 weeks instead of 24-48 weeks)
      2. Hepatitis Genotypes 2 and 3
        1. Used in combination with oral Ribavirin only (no injectable interferon)
      3. Hepatitis Genotypes 1 and 4
        1. Used in combination with oral Ribavirin and injectable interferon
    2. Sofosbuvir (Sovaldi)
      1. Adverse Effects
        1. Headache
        2. Anemia
        3. Fatigue
        4. Nausea
      2. Significant Drug Interactions
        1. Reacts with potent P-Glycoprotein Inducers such as Rifampin, Phenytoin and St. Johns Wort
          1. Lower Sofosbuvir drug levels
        2. Amiodarone
          1. Causes severe Bradycardia resulting in Cardiac Arrest and pacer placement
          2. See Amiodarone
    3. References
      1. (2014) Presc Lett 21(2): 8-9
  12. Protocol: Glecaprevir and Pibrentasvir (Mavyret)
    1. Cost: $26,000 for 8 week course
    2. Indications
      1. Initial therapy for any Genotype in patients without Cirrhosis
      2. Salvage therapy for failed initial protocol for up to 16 weeks
    3. Efficacy
      1. Hepatitis C clearance rate of >95% against all Genotypes
    4. Dosing
      1. Three tabs once daily
  13. Protocol: Sofosbuvir and Velpatasvir (Epclusa)
    1. Cost: $75,000 for 12 week course
    2. Indications
      1. Initial therapy for any Genotype
      2. Salvage therapy as Vosevi when Sofosbuvir and Velpatasvir are are added to Voxilaprevir
    3. Efficacy
      1. Hepatitis C clearance rate of >95% against all Genotypes
    4. Dosing
      1. One tab daily for 12 weeks
    5. Drug Interactions
      1. Rosuvastatin (Crestor) - limit to 10 mg daily
      2. Antacids reduce Epclusa absorption
        1. Avoid Antacids within 4 hours of taking
        2. H2 Blockers may be taken at same time as Epclusa (and again in 12 hours)
        3. Omeprazole 20 mg daily (is best option if Proton Pump Inhibitor is needed)
          1. Take with food 4 hours prior to Epclusa
    6. References
      1. (2016) Presc Lett 23(9)
  14. Protocol: Sovaldi and Ledipasvir (Harvoni)
    1. Cost: $94,500 for 12 week course
    2. Efficacy
      1. As effective as combinations that include Ribavirin and Interferon in Genotype I Hepatitis C infections
    3. Course
      1. Duration 8 weeks (consider)
        1. Low viral load, no Cirrhosis and no treatment failure
      2. Duration 12 weeks
        1. Standard duration for most patients
      3. Duration 24 weeks
        1. Cirrhosis and prior treatment failure
    4. Drug Interactions
      1. See Sofosbuvir (Sovaldi) Drug Interactions above (related to potent P-Glycoprotein Inducers)
      2. Avoid Antacids if possible and do not take within 4 hours of Harvoni dose (Antacids reduce absorption)
  15. Protocol: Ombitasvir, Paritaprevir/r and Dasabuvir (Viekira Pak, Technivie) with Ribavirin
    1. Cost: $83,900 for 12 week course
    2. Components
      1. Ombitasvir (NS5A Inhibitor)
      2. Paritaprevir with Ritonavir (Protease Inhibitor)
      3. Dasabuvir (Polymerase Inhibitor, not included in Technivie)
      4. Ribavirin (used in conjunction with above 3 components in the Viekira Pak)
    3. Drug Interactions
      1. Do not use with Simvastatin, Salmeterol
      2. Do not use with Ethinyl Estradiol (risk of liver injury)
      3. Avoid concurrent Rosuvastatin doses >10 mg daily
    4. Precautions
      1. Do not use Ribavirin in pregnancy and use high quality Contraception (see above)
      2. Risk of fulminant liver failure (especially in pre-existing Cirrhosis) typically in first 1-4 weeks of treatment
        1. Repeat Liver Function Tests at 4 weeks after starting regimen (or earlier if needed)
        2. Consider stopping regimen if ALT >10 times normal (esp. if increased Bilirubin or INR)
    5. References
      1. (2015) Presc Lett 12(2): 12
      2. FDA Drug Safety
        1. http://www.fda.gov/Drugs/DrugSafety/ucm468634.htm
  16. Protocol: Sovaldi and Olysio
    1. Cost: $150,000 for 12 week course
    2. Efficacy
      1. As effective as combinations that include Ribavirin and Interferon in Genotype I Hepatitis C infections
      2. Some protocols use with Ribavirin
    3. Course
      1. Duration 12 weeks
        1. No Cirrhosis
      2. Duration 24 weeks
        1. Cirrhosis
    4. Drug Interactions
      1. See Sofosbuvir (Sovaldi) Drug Interactions above (related to potent P-Glycoprotein Inducers)
  17. Protocol: Elbasivir and Grazoprevir (Zepatier)
    1. Cost: $55,000 for 12 weeks
    2. Efficacy
      1. As effective as other agents used in Genotype I Hepatitis C infections
    3. Advantages
      1. Priced lower than other Genotype I regimens
      2. May be used despite GFR <30 ml/min
    4. Drug Interactions
      1. Atorvastatin (avoid dose >20 mg daily)
      2. Rosuvastatin (avoid dose >10 mg daily)
      3. Avoid with strong and moderate CYP3A inducers
  18. Protocol: Interferon and Ribavirin Regimen
    1. Course
      1. Overall combined cost: $25,000 for 48 weeks
      2. Duration for up to 48 weeks
    2. Check Viral RNA load by PCR
    3. Initiate treatment at doses above
      1. Interferon
      2. Ribavirin
    4. Check Viral RNA load by PCR at 12 weeks
      1. Viral load High (<100 fold decrease)
        1. Stop treatment as unlikely to respond
      2. Viral load markedly lowered (>100 fold decrease)
        1. Continue antiviral course
    5. Antiviral Therapy Duration
      1. Genotype 1: 48 weeks
      2. Genotype 2 and 3: 24 weeks
    6. Check Viral RNA load by PCR at 24 weeks after therapy
      1. Virus detected: Relapse
      2. Virus not detected: 97% chance of cure
  19. Monitoring: General
    1. Visits
      1. Treatment compliance
      2. Adverse effects
      3. Neuropsychiatric effects
      4. Alcohol Abuse
      5. Substance Abuse
    2. Labs: Baseline
      1. Thyroid Stimulating Hormone (pegylated interferon)
      2. Complete Blood Count
      3. Serum Creatinine (and GFR)
      4. Serum Aspartate transaminase (AST)
      5. Serum alanine transaminase (ALT)
      6. Serum alkaline phsophatase
      7. Urine Pregnancy Test
    3. Labs: Follow-up at 4 weeks and as needed
      1. Complete Blood Count
      2. Serum Creatinine
      3. Serum Aspartate transaminase (AST)
      4. Serum alanine transaminase (ALT)
    4. Labs: Viral Response
      1. Quantitative HCV Viral Load at 4 weeks of treatment
      2. Quantitative HCV Viral Load at 12 weeks and 24 weeks AFTER treatment
  20. Monitoring: Interferon and Ribavirin Regimen
    1. Protocol
      1. Baseline labs
        1. Complete Blood Count (CBC) with platelets
        2. Urine Pregnancy Test
        3. Thyroid Stimulating Hormone (TSH)
        4. Liver Function Tests (AST, ALT, Bilirubin)
      2. Repeat labs at 2 weeks, 4 weeks and then monthly
        1. Complete Blood Count (CBC) with platelets
        2. Urine Pregnancy Test
        3. Liver Function Tests (AST, ALT, Bilirubin)
      3. Repeat TSH every 3 months
    2. Initial management of adverse blood counts
      1. Low Hemoglobin: Epogen 40,000 units SQ weekly
      2. Neutropenia: Consider G-CSF
    3. Response to labs refractory to Erythropoietin
      1. Indications to lower Ribavirin dose 200-400 mg/day
        1. Hemoglobin decreased <10 g/dl
        2. Hemoglobin drops >2 g/dl in one month if CAD
      2. Indications to lower PEG-Intron dose by 25-50%
        1. Hemoglobin drops >2 g/dl in one month if CAD
        2. WBC Count <1.5 x10^3/ul
        3. Neutrophil Count <0.75 x10^3/ul
        4. Platelet Count <50,000 to 80,000
      3. Indications to stop therapy
        1. Hemoglobin <8.5 g/dl
        2. Hemoglobin <12 g/dl after month on low dose if CAD
        3. WBC Count <1.0 x10^3/ul
        4. Neutrophil Count <0.5 x10^3/ul
        5. Platelet Count <25,000 to 50,000
  21. Adverse Effects
    1. Anorexia or Nausea
      1. Eat small, frequent meals
    2. Headache
      1. Acetaminophen is safe up to 2000 mg per day
    3. Major Depression
      1. Screen at baseline and every 3 months
      2. See Major Depression for treatment options
    4. Fatigue
      1. Regular low level Exercise
    5. Myalgia
      1. Analgesics, Local Cold Therapy
    6. Cough
      1. Usually self-limited; observe for pneumonitis
    7. Pruritus
      1. See Pruritus Management
    8. Liver Injury
      1. Drugs appear safe with small association, but not causation for liver injury
      2. Based on case reports, as of 2016, Viekira Pak and Technivie include warnings of liver injury risk
        1. https://www.fda.gov/Drugs/DrugSafety/ucm468634.htm
    9. Hepatitis B Reactivation
      1. Screen for Hepatitis B before starting Hepatitis C treatment and concurrently treat active Hepatitis B
      2. Observe for reactivation of prior Hepatitis B
      3. https://www.fda.gov/Drugs/DrugSafety/ucm522932.htm
  22. Drug Interactions
    1. Avoid acid suppression with Harvoni
      1. If acid suppression needed, limit to Omeprazole 20 mg daily or Famotidine 40 mg bid
      2. Avoid Harvoni within 4 hours of Antacid dose
    2. Multiple Drug Interactions
      1. Especially agents with Ritonavir (e.g. Technivie, Viekira, Olysio)
      2. Statins have various Drug Interactions
  23. Efficacy
    1. HCV Genotype 1: 40-50% cure rate at 12 months
    2. HCV Genotype 2-4: 70-80% cure rate at 6 months
    3. Combined therapy is effective (even in relapse)
    4. Efficacy drops significantly with HIV coinfection
  24. Prognosis: Predictors of sustained viral response
    1. HCV Genotypes 2 and 3 (single best predictor of response)
    2. Age <40-45 years old
    3. Absence of advanced fibrosis and Cirrhosis (Metavir Scoring System <3)
    4. IL28B gene is related to viral resistance
    5. Normal Insulin sensitivity
    6. Baseline HCV viral load <600k-800k
    7. Non-black patients
    8. Statin use
  25. Resources
    1. IDSA HCV Management Guidelines
      1. http://www.hcvguidelines.org
    2. Nurse support lines for protocols (24 hour)
      1. Schering-Plough: 888-437-2608
      2. Roche Labs: 877-734-2797
  26. References
    1. (2017) Presc Lett 24(10): 60
    2. (2016) Presc Lett 23(1):3
    3. (2014) Presc Lett 21(12): 70
    4. Fried (2002) N Engl J Med 347:975-82 [PubMed]
    5. Kjaergard (2001) BMJ 323:1151-5 [PubMed]
    6. Patel (2006) BMJ 332(7548): 1013-7 [PubMed]
    7. Ward (2005) Am Fam Physician 72:655-62 [PubMed]
    8. Wilkins (2010) Am Fam Physician 81(11): 1351-7 [PubMed]
    9. Wilkins (2015) Am Fam Physician 91(12): 835-42 [PubMed]

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