Hepatitis C Antiviral Regimen

Aka: Hepatitis C Antiviral Regimen, Hepatitis C Antiviral Therapy

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II. 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
    2. Screen for Hepatitis B before initiating therapy
  5. Drug Interaction Risk
    1. Exercise caution when initiating any new medication while patient is on Hepatitis C Antiviral Regimen
    2. Review potential Drug Interactions with gastroenterology or pharmacist
  6. Early treatment is recommended at the time of diagnosis
    1. Early treatment is preferred over waiting to allow for spontaneous clearance
    2. Recommended in all patients (except those with Life Expectancy <1 year)

III. 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

IV. Contraindications: New, Simplified Protocols (e.g. Mavyret, Epclusa)

  1. Decompensated Cirrhosis (Child-Pugh Class B or C >7)
  2. Current Pregnancy
  3. Suspected Hepatocellular Carcinoma
  4. Age <18 years old
  5. HIV Infection
  6. Hepatitis B Infection
  7. Prior Liver Transplant
  8. Prior Hepatitis C Treatment
  9. Chronic Kidney Disease Stage 4 or 5 with compensated Cirrhosis

V. Contraindications: Older Interferon/Ribavirin Regimens

  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

VI. Evaluation: Pre-treatment

  1. Complete history and physical for contraindications
    1. Alcohol and drug use
    2. Medication history (Drug Interaction risk, Hepatotoxins)
      1. See Below for antiviral Drug Interactions
    3. Hepatic and Extrahepatic manifestations of Hepatitis C
    4. Prior Hepatitis C Management
    5. Vaccination status
      1. Immunize against Hepatitis A, Hepatitis B, Pneumococcal Disease
  2. Evaluate for contraindications to simplified Antiviral therapy protocols
    1. Exam to exclude Hepatic Encephalopathy
    2. Abdominal Ultrasound in last 6 months
      1. Exclude Ascites and Hepatocellular Carcinoma
  3. Laboratory testing
    1. See Hepatitis C
    2. See monitoring below for baseline labs for therapy
    3. Positive HCV Antibody and HCV RNA
    4. Complete Blood Count
    5. Comprehensive Metabolic Panel (includes Electrolytes and eGFR, AST, ALT, Bilirubin, Alkaline Phosphatase, Albumin)
    6. INR
    7. Pregnancy Test
    8. Viral Hepatitis Testing (xHAV, HBsAg, HBsAb, HBcAb)
    9. HIV Test
    10. Thyroid Stimulating Hormone (TSH)

VII. 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

VIII. Management

  1. Any Genotype
    1. Initial therapy (treatment naive patients, without uncompensated Cirrhosis): $25,000 per regimen
      1. Mavyret (Glecaprevir/Pibrentasvir) three tabs once daily for 8 weeks
      2. Epclusa (Velpatasvir/Sofosbuvir): one tab daily for 12 weeks
        1. Avoid in Genotype 3 with Protein 5A resistance associated Y93H substitution
    2. Salvage therapy
      1. Mavyret (Glecaprevir/Pibrentasvir) three tabs once daily for up to 16 weeks
      2. Vosevi (Velpatasvir/Voxilaprevir/Sofosbuvir) one tab daily for 12 weeks
  2. Genotype 1a (or unknown subtype, without Cirrhosis or with compensated Cirrhosis Child Pugh Class A)
    1. Epclusa (Velpatasvir/Sofosbuvir) once daily for 12 weeks
    2. Harvoni (Ledipasvir/Sofosbuvir) once daily for 12 weeks
      1. May use 8 weeks if not HIV positive and HCV RNA <6 million IU/ml and no Cirrhosis
    3. Mavyret (Glecaprevir/Pibrentasvir) three tabs once daily for 8 weeks
    4. Zepatier (Elbasivir/Grazoprevir) once daily for 12 weeks
      1. Alternative to other agents
      2. Contraindicated if baseline NS5A resistance
  3. Genotype 1b (without Cirrhosis or with compensated Cirrhosis Child Pugh Class A)
    1. Epclusa (Velpatasvir/Sofosbuvir) once daily for 12 weeks
    2. Harvoni (Ledipasvir/Sofosbuvir) once daily for 12 weeks
      1. May use 8 weeks if not HIV positive and HCV RNA <6 million IU/ml and no Cirrhosis
    3. Mavyret (Glecaprevir/Pibrentasvir) three tabs once daily for 8 weeks
    4. Zepatier (Elbasivir/Grazoprevir) once daily for 12 weeks
  4. Genotype 2
    1. Epclusa (Velpatasvir/Sofosbuvir) once daily for 12 weeks
    2. Mavyret (Glecaprevir/Pibrentasvir) three tabs once daily for 8 weeks
  5. Genotype 3
    1. Epclusa (Velpatasvir/Sofosbuvir) once daily for 12 weeks
    2. Mavyret (Glecaprevir/Pibrentasvir) three tabs once daily for 8 weeks
    3. Alternatives if Baseline NS5A resistance substitution Y93H (including in compensated Cirrhosis, Child Pugh Class A)
      1. Eplcusa AND weight based Ribavirin
      2. Vosevi (Velpatasvir/Voxilaprevir/Sofosbuvir) one tab daily for 12 weeks
  6. Genotype 4
    1. Epclusa (Velpatasvir/Sofosbuvir) once daily for 12 weeks
    2. Mavyret (Glecaprevir/Pibrentasvir) three tabs once daily for 8 weeks
    3. Harvoni (Ledipasvir/Sofosbuvir) once daily for 12 weeks
      1. May use 8 weeks if not HIV positive, HCV RNA <6 million IU/ml, not type 4r and no Cirrhosis
    4. Zepatier (Elbasivir/Grazoprevir) once daily for 12 weeks
  7. Genotype 5 or 6
    1. Epclusa (Velpatasvir/Sofosbuvir) once daily for 12 weeks
    2. Mavyret (Glecaprevir/Pibrentasvir) three tabs once daily for 8 weeks
    3. Harvoni (Ledipasvir/Sofosbuvir) once daily for 12 weeks

IX. Medications

  1. NS5B Polymerase Inhibitors (...buvirs)
    1. Sofosbuvir (alone in Sovaldi, combined in Epclusa, Harvoni, Vosevi)
    2. Dasabuvir (Viekira Pak)
  2. NS3/4A Protease Inhibitors (...previrs)
    1. Glecaprevir (Mavyret)
    2. Grazoprevir (Zepatier)
    3. Paritaprevir (Viekira Pak)
    4. Voxilaprevir (Vosevi)
  3. NS5A Protein Inhibitors (...asvirs)
    1. Elbasvir (Zepatier)
    2. Leipasvir (Harvoni)
    3. Ombitasvir (Viekira Pak)
    4. Pibrentasvir (Mavyret)
    5. Velpatasvir (Epclusa, Vosevi)
  4. Older agents (discontinued or replaced)
    1. See Ribavirin and Interferon Protocol for Hepatitis C
    2. Multiple NS3/4A Protease Inhibitors have been discontinued (Simeprevir, Telaprevir, Boceprevir)

X. Monitoring: General

  1. Visits
    1. Treatment compliance
    2. Adverse effects
    3. Neuropsychiatric effects
    4. Alcohol Abuse
    5. Substance Abuse
  2. Labs: Baseline
    1. See Hepatitis C
    2. Assumes Positive HCV Antibody and HCV RNA (and identified Genotype)
    3. HIV Test
    4. Viral Hepatitis Testing (xHAV, HBsAg, HBsAb, HBcAb)
      1. Hepatitis B may rarely be reactivated during Hepatitis C treatment
    5. Hepatic Fibrosis staging
    6. Thyroid Stimulating Hormone (due to pegylated Interferon)
    7. Complete Blood Count
    8. Serum Creatinine (and GFR)
    9. Serum Aspartate transaminase (AST)
    10. Serum Alanine transaminase (ALT)
    11. Serum Bilirubin
    12. Serum Alkaline Phosphatase
    13. INR
    14. Urine Pregnancy Test
  3. Labs: Follow-up at 4 weeks and as needed (at minimum, obtain at 3 months after starting therapy)
    1. Monitoring
      1. Stop treatment if ALT increases >10 fold over baseline
      2. Stop treatment for any symptomatic increase in LFTs
      3. Less frequent testing may be allowed for treatment-naive patients without Cirrhosis
    2. Complete Blood Count
    3. Serum Creatinine with eGFR
    4. Serum Aspartate transaminase (AST)
    5. Serum Alanine transaminase (ALT)
    6. Serum Bilirubin
    7. Serum Albumin
  4. Labs: Viral Response
    1. Quantitative HCV Viral Load (HIV RNA PCR) at 4 weeks of treatment (optional, typically checked after treatment)
    2. Quantitative HCV Viral Load (HIV RNA PCR) at 12 weeks and 24 weeks AFTER treatment
      1. Undetectable HCV RNA at 12 weeks suggests virologic cure (correlates with 5 year follow-up)

XI. Adverse Effects

  1. Newer agents are tolerated well enough that only 1-2% of patients discontinue therapy for adverse effects
  2. Anorexia or Nausea
    1. Eat small, frequent meals
  3. Headache
    1. Acetaminophen is safe up to 2000 mg per day
  4. Major Depression
    1. Screen at baseline and every 3 months
    2. See Major Depression for treatment options
  5. Fatigue
    1. Regular low level Exercise
  6. Insomnia
    1. See Insomnia for non-pharmacologic management
  7. Myalgia
    1. Analgesics, Local Cold Therapy
  8. Cough
    1. Usually self-limited; observe for pneumonitis
  9. Pruritus
    1. See Pruritus Management
  10. 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
  11. 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

XII. Drug Interactions

  1. Multiple Drug Interactions
    1. Especially agents with Ritonavir (e.g. Technivie, Viekira, Olysio)
    2. Acetaminophen is safe (limit total daily dose to <2000 mg)
    3. No significant interactions with Epclusa or Mavyret and Opioid Addiction therapy (Methadone, Buprenorphine)
  2. Monitor levels closely during therapy
    1. INR (for those on Warfarin)
    2. Blood Glucose (in Diabetes Mellitus)
  3. Proton Pump Inhibitors (acid suppression)
    1. Avoid Proton Pump Inhibitors with Harvoni, Sofosbuvir/Velpatasvir (Epclusa)
    2. Proton Pump Inhibitors are safe to use with Glecaprevir/Pibrentasvir (Mavyret)
    3. If acid suppression needed, limit to H2 Blocker (and space doses 4-12 hours apart)
      1. Famotidine 40 mg orally twice daily
  4. Statins have various Drug Interactions (increased Statin Myopathy risk)
    1. All except Sofosbuvir reduce Statin metabolism
    2. Consider stopping Statin or limiting Statin dosing (e.g. Rosuvastatin to 10 mg)
  5. Anticonvulsants reduce Antiviral levels
    1. Avoid potent CYP3A4 inducers (e.g. Phenytoin, Carbamazepine)
    2. Consider Valproic Acid or Lamotrigine (Lamictal) instead
  6. Herbal preparations
    1. Stop all herbal and dietary supplements
    2. St. Johns Wort lowers Antiviral levels
  7. Ethinyl Estradiol containing contraceptives
    1. Avoid with Glecaprevir/Pibrentasvir (Mavyret)
  8. Amiodarone
    1. Avoid with Sofosbuvir/Velpatasvir (Epclusa) due to risk of severe Bradycardia
    2. Safe to use with Glecaprevir/Pibrentasvir (Mavyret)
  9. References
    1. (2019) Presc Lett 26(7):39-40

XIII. 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

XIV. 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. Absence of IL28B gene (related to viral resistance)
  5. Normal Insulin sensitivity
  6. Baseline HCV viral load <600k-800k
  7. Non-black patients
  8. Statin use

XV. 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

XVI. References

  1. (2023) Presc Lett, Hepatitis C Treatment Overview, Resource #390902
  2. (2020) Presc Lett 27(2): 9
  3. (2017) Presc Lett 24(10): 60
  4. (2016) Presc Lett 23(1):3
  5. (2014) Presc Lett 21(12): 70
  6. Fried (2002) N Engl J Med 347:975-82 [PubMed]
  7. Kjaergard (2001) BMJ 323:1151-5 [PubMed]
  8. Maness (2021) Am Fam Physician 104(6): 626-35 [PubMed]
  9. Patel (2006) BMJ 332(7548): 1013-7 [PubMed]
  10. Ward (2005) Am Fam Physician 72:655-62 [PubMed]
  11. Wilkins (2010) Am Fam Physician 81(11): 1351-7 [PubMed]
  12. Wilkins (2015) Am Fam Physician 91(12): 835-42 [PubMed]

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