Hepatitis C Antiviral Regimen

See Also

Hepatitis C

Precautions

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
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
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
Hepatitis B Reactivation risk
1. See Adverse Effects below
2. Screen for Hepatitis B before initiating therapy
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
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)

Indications
Standard

HCV RNA positive (e.g. >50 copies/ml)
Age over 18 years old
Willing and able to comply with treatment
Increased serum Alanine transaminase (ALT)
1. Some prior guidelines required Serum ALT greater than twice normal
Metavir Scoring System 2 or more

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

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

Contraindications
Older Interferon/Ribavirin Regimens

Absolute Contraindications
1. Allergy to antiviral agents
2. Decompensated Cirrhosis
3. Pregnancy (Ribavirin regimens)
4. Ongoing Intravenous Drug Abuse or Alcoholism
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

Evaluation
Pre-treatment

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
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
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)

Evaluation
Post-treatment

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

Management

Any Genotype
1. Initial therapy (treatment naive patients, without uncompensated Cirrhosis): $25,000 per regimen
  1. Mavyret: Glecaprevir and Pibrentasvir three tabs once daily for 8 weeks
  2. Epclusa: Sofosbuvir (Sovaldi) and Velpatasvir one tab daily for 12 weeks
    1. Avoid in Genotype 3 with protein 5A resistance associated Y93H substitution
2. Salvage therapy
  1. Mavyret: Glecaprevir and Pibrentasvir three tabs once daily for up to 16 weeks
  2. Vosevi: Sofosbuvir (Sovaldi) and Velpatasvir and Voxilaprevir one tab daily for 12 weeks
Genotype 1a
1. Sofosbuvir (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. Sofosbuvir (Sovaldi) and Olysio (with or without Ribavirin) for 12 weeks (24 weeks if Cirrhosis)
Genotype 1b
1. Sofosbuvir (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. Sofosbuvir (Sovaldi) and Olysio (with or without Ribavirin) for 12 weeks (24 weeks if cirrhotic)
Genotype 2
1. Sofosbuvir (Sovaldi) with Ribavirin for 12 weeks (24 weeks if Cirrhosis)
Genotype 3
1. Sofosbuvir (Sovaldi) with Ribavirin for 24 weeks
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
Genotype 5
1. Sofosbuvir (Sovaldi) and pegylated Interferon with Ribavirin for 12 weeks
Genotype 6
1. Sovaldi and Ledipasvir (Harvoni) for 12 weeks

Preparations
Interferon

Replaced in most Hepatitis C protocols by other protocols as of 2014
Interferon alfa-2a (preferred for all Genotypes)
1. Pegylated Interferon alfa-2a (Pegasys)
  1. Adult Dose: 180 mcg SQ per week
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
Adverse Effects
1. See Interferon (numerous potential life-threatening adverse effects)

Preparation
Ribavirin (if not contraindicated)

Genotype 2 or 3 (all weights)
1. Take 400 mg orally twice daily
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
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

Preparation
Protease Inhibitors (NS3/4A Inhibitors)

General
1. Used in combination with oral Ribavirin and injectable Interferon
Telaprevir (Incivek)
1. Discontinued in U.S. in 2014
Boceprevir (Victrelis)
1. Discontinued in U.S. in 2015
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

Preparation
Polymerase Inhibitor (NS5B Inhibitor)

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
Sofosbuvir (Sovaldi)
1. Adverse Effects
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
References
1. (2014) Presc Lett 21(2): 8-9

Protocol
Glecaprevir and Pibrentasvir (Mavyret)

Cost: $26,000 (non-generic) for 8 week course
Indications
1. Initial therapy for any Genotype in patients without Cirrhosis (or with Class A compensated Cirrhosis)
2. Salvage therapy for failed initial protocol for up to 16 weeks
Contraindications
1. Child-Pugh Class B and C Cirrhosis
2. No restriction based on Renal Function
Efficacy
1. Hepatitis C clearance rate of >95% against all Genotypes
Dosing
1. Three tabs once daily

Protocol
Sofosbuvir and Velpatasvir (Epclusa)

Cost: $25,000 generic ($75,000 for non-generic) for 12 week course
Indications
1. Initial therapy for any Genotype
2. Salvage therapy as Vosevi when Sofosbuvir and Velpatasvir are are added to Voxilaprevir
3. May be used in any class of compensated Cirrhosis (Child-Pugh Class A to C Cirrhosis)
  1. Ribavirin is added to regimen in Child-Pugh Class C Cirrhosis
Contraindications
1. Approved for any eGFR and for those on Hemodialysis
2. Genotype 3 with protein 5A resistance associated Y93H substitution
  1. Associated with antiviral resistance
Efficacy
1. Hepatitis C clearance rate of >95% against all Genotypes
Dosing
1. One tab daily for 12 weeks
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
References
1. (2016) Presc Lett 23(9)

Protocol
Sovaldi and Ledipasvir (Harvoni)

Cost: $25,000 generic ($94,500 for non-generic) for 12 week course
Efficacy
1. As effective as combinations that include Ribavirin and Interferon in Genotype I Hepatitis C infections
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
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)

Protocol
Ombitasvir, Paritaprevir/r and Dasabuvir (Viekira Pak, Technivie) with Ribavirin

Cost: $83,900 for 12 week course
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)
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
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)
References
1. (2015) Presc Lett 12(2): 12
2. FDA Drug Safety
  1. http://www.fda.gov/Drugs/DrugSafety/ucm468634.htm

Protocol
Sovaldi and Olysio

Cost: $150,000 for 12 week course
Efficacy
1. As effective as combinations that include Ribavirin and Interferon in Genotype I Hepatitis C infections
2. Some protocols use with Ribavirin
Course
1. Duration 12 weeks
  1. No Cirrhosis
2. Duration 24 weeks
  1. Cirrhosis
Drug Interactions
1. See Sofosbuvir (Sovaldi) Drug Interactions above (related to potent P-Glycoprotein Inducers)

Protocol
Elbasivir and Grazoprevir (Zepatier)

Cost: $55,000 for 12 weeks
Efficacy
1. As effective as other agents used in Genotype I Hepatitis C infections
Advantages
1. Priced lower than other Genotype I regimens
2. May be used despite GFR <30 ml/min
Drug Interactions
1. Atorvastatin (avoid dose >20 mg daily)
2. Rosuvastatin (avoid dose >10 mg daily)
3. Avoid with strong and moderate CYP3A inducers

Protocol
Interferon and Ribavirin Regimen

Course
1. Overall combined cost: $25,000 for 48 weeks
2. Duration for up to 48 weeks
Check Viral RNA load by PCR
Initiate treatment at doses above
1. Interferon
2. Ribavirin
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
Antiviral Therapy Duration
1. Genotype 1: 48 weeks
2. Genotype 2 and 3: 24 weeks
Check Viral RNA load by PCR at 24 weeks after therapy
1. Virus detected: Relapse
2. Virus not detected: 97% chance of cure

Monitoring
General

Visits
1. Treatment compliance
2. Adverse effects
3. Neuropsychiatric effects
4. Alcohol Abuse
5. Substance Abuse
Labs: Baseline
1. See Hepatitis C
2. Assumes Positive HCV Antibody and HCV RNA
3. Thyroid Stimulating Hormone (due to pegylated Interferon)
4. Complete Blood Count
5. Serum Creatinine (and GFR)
6. Serum Aspartate transaminase (AST)
7. Serum alanine transaminase (ALT)
8. Serum Bilirubin
9. Serum Alkaline Phosphatase
10. INR
11. Urine Pregnancy Test
12. Viral Hepatitis Testing (xHAV, HBsAg, HBsAb, HBcAb)
  1. Hepatitis B may rarely be reactivated during Hepatitis C treatment\
13. HIV Test
Labs: Follow-up at 4 weeks and as needed (at minimum, obtain at 3 months after starting therapy)
1. Not typically required 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
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)

Monitoring
Interferon and Ribavirin Regimen

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
Initial management of adverse blood counts
1. Low Hemoglobin: Epogen 40,000 units SQ weekly
2. Neutropenia: Consider G-CSF
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

Adverse Effects

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

Drug Interactions

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)
Monitor levels closely during therapy
1. INR (for those on Warfarin)
2. Blood Glucose (in Diabetes Mellitus)
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
Statins have various Drug Interactions (increased Statin Myopathy risk)
1. LImit Statin dosing (e.g. Rosuvastatin to 10 mg)
Anticonvulsants reduce antiviral levels
1. Avoid potent CYP3A4 inducers (e.g. Phenytoin, Carbamazepine)
2. Consider Valproic Acid or Lamotrigine (Lamictal) instead
Herbal preparations
1. Stop all herbal and dietary supplements
2. St. Johns Wort lowers antiviral levels
Ethinyl Estradiol containing contraceptives
1. Avoid with Glecaprevir/pibrentasvir (Mavyret)
Amiodarone
1. Avoid with Sofosbuvir/Velpatasvir (Epclusa) due to risk of severe Bradycardia
2. Safe to use with Glecaprevir/pibrentasvir (Mavyret)
References
1. (2019) Presc Lett 26(7):39-40

Efficacy

HCV Genotype 1: 40-50% cure rate at 12 months
HCV Genotype 2-4: 70-80% cure rate at 6 months
Combined therapy is effective (even in relapse)
Efficacy drops significantly with HIV coinfection

Prognosis
Predictors of sustained viral response

HCV Genotypes 2 and 3 (single best predictor of response)
Age <40-45 years old
Absence of advanced fibrosis and Cirrhosis (Metavir Scoring System <3)
Absence of IL28B gene (related to viral resistance)
Normal Insulin sensitivity
Baseline HCV viral load <600k-800k
Non-black patients
Statin use

Resources

IDSA HCV Management Guidelines
1. http://www.hcvguidelines.org
Nurse support lines for protocols (24 hour)
1. Schering-Plough: 888-437-2608
2. Roche Labs: 877-734-2797

References

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