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Hepatitis C Antiviral Regimen
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Hepatitis C Antiviral Regimen
, Hepatitis C Treatment with Interferon and Ribavirin
See Also
Hepatitis C
Precautions
Hepatitis C
Antiviral Therapy involves rapidly changing and complex guidelines
U.S. patients typically undergo
Hepatitis C
antiviral therapy under the direction of specialty care
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
Allows for understanding of the adverse effects of treatment regimens
Those prescribing antiviral therapy should use national guideline resources instead
Ensure compliance for least resistance
If an agent needs to be stopped (e.g. for surgery), stop the whole regimen
Emphasize to patients that new regimens may be up to 90% effective with best compliance
Hepatitis B
Reactivation risk
See Adverse Effects below
Screen for
Hepatitis B
before initiating therapy
Drug Interaction
Risk
Exercise
caution when initiating any new medication while patient is on Hepatitis C Antiviral Regimen
Review potential
Drug Interaction
s with gastroenterology or pharmacist
Early treatment is recommended at the time of diagnosis
Early treatment is preferred over waiting to allow for spontaneous clearance
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)
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
Allergy to antiviral agents
Decompensated
Cirrhosis
Pregnancy (
Ribavirin
regimens)
Ongoing
Intravenous Drug Abuse
or
Alcoholism
Relative Contraindications (more specific for
Interferon
and
Ribavirin
protocols)
Leukopenia
Anemia
Thrombocytopenia
Some
Autoimmune Condition
s
Coronary Artery Disease
Uncontrolled mental health condition
Evaluation
Pre-treatment
Complete history and physical for contraindications
Alcohol
and drug use
Medication history (
Drug Interaction
risk,
Hepatotoxin
s)
See Below for antiviral
Drug Interaction
s
Hepatic and Extrahepatic manifestations of
Hepatitis C
Prior
Hepatitis C
Management
Vaccination
status
Immunize against
Hepatitis A
,
Hepatitis B
, Pneumococcal Disease
Evaluate for contraindications to simplified antiviral therapy protocols
Exam to exclude
Hepatic Encephalopathy
Abdominal Ultrasound
in last 6 months
Exclude
Ascites
and
Hepatocellular Carcinoma
Laboratory testing
See
Hepatitis C
See monitoring below for baseline labs for therapy
Positive HCV
Antibody
and HCV RNA
Complete Blood Count
Comprehensive Metabolic Panel (includes
Electrolyte
s and eGFR, AST, ALT,
Bilirubin
,
Alkaline Phosphatase
, Albumin)
INR
Pregnancy Test
Viral Hepatitis
Testing (xHAV,
HBsAg
, HBsAb, HBcAb)
HIV Test
Thyroid Stimulating Hormone
(TSH)
Evaluation
Post-treatment
HCV RNA
HCV RNA Negative at 24 weeks is associated with 99% longterm, sustained viral response
HCV RNA Negative at 12 weeks predicts longterm, sustained viral response
Management
Any
Genotype
Initial therapy (treatment naive patients, without uncompensated
Cirrhosis
): $25,000 per regimen
Mavyret: Glecaprevir and Pibrentasvir three tabs once daily for 8 weeks
Epclusa: Sofosbuvir (Sovaldi) and Velpatasvir one tab daily for 12 weeks
Avoid in
Genotype
3 with protein 5A resistance associated Y93H substitution
Salvage therapy
Mavyret: Glecaprevir and Pibrentasvir three tabs once daily for up to 16 weeks
Vosevi: Sofosbuvir (Sovaldi) and Velpatasvir and Voxilaprevir one tab daily for 12 weeks
Genotype
1a
Sofosbuvir (Sovaldi) and Ledipasvir (Harvoni) for 12 weeks
Elbasivir and Grazoprevir (Zepatier) for 12 weeks
Ombitasvir, Paritaprevir/r and Dasabuvir (Viekira Pak) with
Ribavirin
for 12 weeks (24 weeks if
Cirrhosis
)
Sofosbuvir (Sovaldi) and Olysio (with or without
Ribavirin
) for 12 weeks (24 weeks if
Cirrhosis
)
Genotype
1b
Sofosbuvir (Sovaldi) and Ledipasvir (Harvoni) for 12 weeks
Elbasivir and Grazoprevir (Zepatier) for 12 weeks
Ombitasvir, Paritaprevir/r and Dasabuvir (Viekira Pak) for 12 weeks (with
Ribavirin
for 24 weeks if
Cirrhosis
)
Sofosbuvir (Sovaldi) and Olysio (with or without
Ribavirin
) for 12 weeks (24 weeks if cirrhotic)
Genotype
2
Sofosbuvir (Sovaldi) with
Ribavirin
for 12 weeks (24 weeks if
Cirrhosis
)
Genotype
3
Sofosbuvir (Sovaldi) with
Ribavirin
for 24 weeks
Genotype
4
Sovaldi and Ledipasvir (Harvoni) for 12 weeks
Ombitasvir, Paritaprevir/r and Dasabuvir (Viekira Pak) with
Ribavirin
for 12 weeks
Sofosbuvir (Sovaldi) with
Ribavirin
for 24 weeks
Genotype
5
Sofosbuvir (Sovaldi) and pegylated
Interferon
with
Ribavirin
for 12 weeks
Genotype
6
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
Genotype
s)
Pegylated
Interferon alfa
-2a (Pegasys)
Adult Dose: 180 mcg SQ per week
Interferon alfa
-2b
Interferon alfa
-2a is preferred instead (see above)
Pegylated
Interferon alfa
-2b (PEG-Intron)
Adult Dose: 1.5 mcg/kg per week
Interferon alfa
-2b (Intron A)
Dose: 3 Million Units SQ three times per week
Administer with
Ribavirin
if not contraindicated
Cost: $8000 per 24 week course
Rebetron combines
Ribavirin
and
Interferon alfa
-2b
Adverse Effects
See
Interferon
(numerous potential life-threatening adverse effects)
Preparation
Ribavirin
(if not contraindicated)
Genotype
2 or 3 (all weights)
Take 400 mg orally twice daily
Genotype
1a, 1b and 4
Weight >75 kg (165 lb): 600 mg orally twice daily
Weight <75 kg (165 lb): 400 mg qAM, 600 mg qPM
Adverse effects
Hemolytic Anemia
Exacerbation of
Coronary Artery Disease
Highly
Teratogen
ic
Requires high efficacy, dual
Contraception
in women of child bearing age
Includes women who are sexual partners of men on
Ribavirin
Contraception
should be continued throughout therapy and for 6 months after
Preparation
Protease Inhibitor
s (NS3/4A Inhibitors)
Gene
ral
Used in combination with oral
Ribavirin
and injectable
Interferon
Telaprevir (Incivek)
Discontinued in U.S. in 2014
Boceprevir (Victrelis)
Discontinued in U.S. in 2015
Simeprevir (Olysio)
Effective for HCV
Genotype
s 1, 4, 5 and 6
Advantages over other
Protease Inhibitor
s in
Hepatitis C
Dosed only once daily
May be better tolerated than other
Protease Inhibitor
s with fewer
Drug Interaction
s
Contraindications
Sulfonamide Allergy
Hepatitis C
types more responsive to Incivek or Victrelis (35% of cases)
Adverse Effects
Anemia
Fatigue
Flu-like symptoms
Pruritus
Headache
Nausea
References
(2014) Presc Lett 21(2): 8-9
Preparation
Polymerase Inhibitor (NS5B Inhibitor)
Indications
Used in place of
Protease Inhibitor
s as adjunct to
Ribavirin
(and
Interferon
in some
Genotype
s)
Shorter course than
Protease Inhibitor
s (12-24 weeks instead of 24-48 weeks)
Hepatitis
Genotype
s 2 and 3
Used in combination with oral
Ribavirin
only (no injectable
Interferon
)
Hepatitis
Genotype
s 1 and 4
Used in combination with oral
Ribavirin
and injectable
Interferon
Sofosbuvir (Sovaldi)
Adverse Effects
Headache
Anemia
Fatigue
Nausea
Significant
Drug Interaction
s
Reacts with potent
P-Glycoprotein Inducer
s such as
Rifampin
,
Phenytoin
and St. Johns Wort
Lower Sofosbuvir drug levels
Amiodarone
Causes severe
Bradycardia
resulting in
Cardiac Arrest
and pacer placement
See
Amiodarone
References
(2014) Presc Lett 21(2): 8-9
Protocol
Glecaprevir and Pibrentasvir (Mavyret)
Cost: $26,000 (non-generic) for 8 week course
Indications
Initial therapy for any
Genotype
in patients without
Cirrhosis
(or with Class A compensated
Cirrhosis
)
Salvage therapy for failed initial protocol for up to 16 weeks
Contraindications
Child-Pugh Class
B and C
Cirrhosis
No restriction based on
Renal Function
Efficacy
Hepatitis C
clearance rate of >95% against all
Genotype
s
Dosing
Three tabs once daily
Protocol
Sofosbuvir and Velpatasvir (Epclusa)
Cost: $25,000 generic ($75,000 for non-generic) for 12 week course
Indications
Initial therapy for any
Genotype
Salvage therapy as Vosevi when Sofosbuvir and Velpatasvir are are added to Voxilaprevir
May be used in any class of compensated
Cirrhosis
(
Child-Pugh Class
A to C
Cirrhosis
)
Ribavirin
is added to regimen in
Child-Pugh Class
C
Cirrhosis
Contraindications
Approved for any eGFR and for those on
Hemodialysis
Genotype
3 with protein 5A resistance associated Y93H substitution
Associated with antiviral resistance
Efficacy
Hepatitis C
clearance rate of >95% against all
Genotype
s
Dosing
One tab daily for 12 weeks
Drug Interaction
s
Rosuvastatin
(
Crestor
) - limit to 10 mg daily
Antacid
s reduce Epclusa absorption
Avoid
Antacid
s within 4 hours of taking
H2 Blocker
s may be taken at same time as Epclusa (and again in 12 hours)
Omeprazole
20 mg daily (is best option if
Proton Pump Inhibitor
is needed)
Take with food 4 hours prior to Epclusa
References
(2016) Presc Lett 23(9)
Protocol
Sovaldi and Ledipasvir (Harvoni)
Cost: $25,000 generic ($94,500 for non-generic) for 12 week course
Efficacy
As effective as combinations that include
Ribavirin
and
Interferon
in
Genotype
I
Hepatitis C
infections
Course
Duration 8 weeks (consider)
Low viral load, no
Cirrhosis
and no treatment failure
Duration 12 weeks
Standard duration for most patients
Duration 24 weeks
Cirrhosis
and prior treatment failure
Drug Interaction
s
See Sofosbuvir (Sovaldi)
Drug Interaction
s above (related to potent
P-Glycoprotein Inducer
s)
Avoid
Antacid
s if possible and do not take within 4 hours of Harvoni dose (
Antacid
s reduce absorption)
Protocol
Ombitasvir, Paritaprevir/r and Dasabuvir (Viekira Pak, Technivie) with
Ribavirin
Cost: $83,900 for 12 week course
Components
Ombitasvir (NS5A Inhibitor)
Paritaprevir with
Ritonavir
(
Protease Inhibitor
)
Dasabuvir (Polymerase Inhibitor, not included in Technivie)
Ribavirin
(used in conjunction with above 3 components in the Viekira Pak)
Drug Interaction
s
Do not use with
Simvastatin
,
Salmeterol
Do not use with
Ethinyl Estradiol
(risk of liver injury)
Avoid concurrent
Rosuvastatin
doses >10 mg daily
Precautions
Do not use
Ribavirin
in pregnancy and use high quality
Contraception
(see above)
Risk of fulminant liver failure (especially in pre-existing
Cirrhosis
) typically in first 1-4 weeks of treatment
Repeat
Liver Function Test
s at 4 weeks after starting regimen (or earlier if needed)
Consider stopping regimen if ALT >10 times normal (esp. if increased
Bilirubin
or INR)
References
(2015) Presc Lett 12(2): 12
FDA Drug Safety
http://www.fda.gov/Drugs/DrugSafety/ucm468634.htm
Protocol
Sovaldi and Olysio
Cost: $150,000 for 12 week course
Efficacy
As effective as combinations that include
Ribavirin
and
Interferon
in
Genotype
I
Hepatitis C
infections
Some protocols use with
Ribavirin
Course
Duration 12 weeks
No
Cirrhosis
Duration 24 weeks
Cirrhosis
Drug Interaction
s
See Sofosbuvir (Sovaldi)
Drug Interaction
s above (related to potent
P-Glycoprotein Inducer
s)
Protocol
Elbasivir and Grazoprevir (Zepatier)
Cost: $55,000 for 12 weeks
Efficacy
As effective as other agents used in
Genotype
I
Hepatitis C
infections
Advantages
Priced lower than other
Genotype
I regimens
May be used despite GFR <30 ml/min
Drug Interaction
s
Atorvastatin
(avoid dose >20 mg daily)
Rosuvastatin
(avoid dose >10 mg daily)
Avoid with strong and moderate CYP3A inducers
Protocol
Interferon
and
Ribavirin
Regimen
Course
Overall combined cost: $25,000 for 48 weeks
Duration for up to 48 weeks
Check Viral RNA load by PCR
Initiate treatment at doses above
Interferon
Ribavirin
Check Viral RNA load by PCR at 12 weeks
Viral load High (<100 fold decrease)
Stop treatment as unlikely to respond
Viral load markedly lowered (>100 fold decrease)
Continue antiviral course
Antiviral Therapy Duration
Genotype
1: 48 weeks
Genotype
2 and 3: 24 weeks
Check Viral RNA load by PCR at 24 weeks after therapy
Virus
detected: Relapse
Virus
not detected: 97% chance of cure
Monitoring
Gene
ral
Visits
Treatment compliance
Adverse effects
Neuropsychiatric effects
Alcohol Abuse
Substance Abuse
Labs: Baseline
See
Hepatitis C
Assumes Positive HCV
Antibody
and HCV RNA
Thyroid Stimulating Hormone
(due to pegylated
Interferon
)
Complete Blood Count
Serum Creatinine
(and GFR)
Serum
Aspart
ate transaminase (AST)
Serum alanine transaminase (ALT)
Serum Bilirubin
Serum
Alkaline Phosphatase
INR
Urine Pregnancy Test
Viral Hepatitis
Testing (xHAV,
HBsAg
, HBsAb, HBcAb)
Hepatitis B
may rarely be reactivated during
Hepatitis C
treatment\
HIV Test
Labs: Follow-up at 4 weeks and as needed (at minimum, obtain at 3 months after starting therapy)
Not typically required for treatment-naive patients without
Cirrhosis
Complete Blood Count
Serum Creatinine
with eGFR
Serum
Aspart
ate transaminase (AST)
Serum alanine transaminase (ALT)
Serum Bilirubin
Serum Albumin
Labs: Viral Response
Quantitative HCV Viral Load (
HIV RNA
PCR) at 4 weeks of treatment (optional, typically checked after treatment)
Quantitative HCV Viral Load (
HIV RNA
PCR) at 12 weeks and 24 weeks AFTER treatment
Undetectable HCV RNA at 12 weeks suggests virologic cure (correlates with 5 year follow-up)
Monitoring
Interferon
and
Ribavirin
Regimen
Protocol
Baseline labs
Complete Blood Count
(CBC) with
Platelet
s
Urine Pregnancy Test
Thyroid Stimulating Hormone
(TSH)
Liver Function Test
s (AST, ALT,
Bilirubin
)
Repeat labs at 2 weeks, 4 weeks and then monthly
Complete Blood Count
(CBC) with
Platelet
s
Urine Pregnancy Test
Liver Function Test
s (AST, ALT,
Bilirubin
)
Repeat TSH every 3 months
Initial management of adverse blood counts
Low
Hemoglobin
:
Epogen
40,000 units SQ weekly
Neutropenia
: Consider G-CSF
Response to labs refractory to
Erythropoietin
Indications to lower
Ribavirin
dose 200-400 mg/day
Hemoglobin
decreased <10 g/dl
Hemoglobin
drops >2 g/dl in one month if CAD
Indications to lower PEG-Intron dose by 25-50%
Hemoglobin
drops >2 g/dl in one month if CAD
WBC Count
<1.5 x10^3/ul
Neutrophil Count
<0.75 x10^3/ul
Platelet Count
<50,000 to 80,000
Indications to stop therapy
Hemoglobin
<8.5 g/dl
Hemoglobin
<12 g/dl after month on low dose if CAD
WBC Count
<1.0 x10^3/ul
Neutrophil Count
<0.5 x10^3/ul
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
Eat small, frequent meals
Headache
Acetaminophen
is safe up to 2000 mg per day
Major Depression
Screen at baseline and every 3 months
See
Major Depression
for treatment options
Fatigue
Regular low level
Exercise
Insomnia
See
Insomnia
for non-pharmacologic management
Myalgia
Analgesic
s,
Local Cold Therapy
Cough
Usually self-limited; observe for pneumonitis
Pruritus
See
Pruritus Management
Liver
Injury
Drugs appear safe with small association, but not causation for liver injury
Based on case reports, as of 2016, Viekira Pak and Technivie include warnings of liver injury risk
https://www.fda.gov/Drugs/DrugSafety/ucm468634.htm
Hepatitis B
Reactivation
Screen for
Hepatitis B
before starting
Hepatitis C
treatment and concurrently treat active
Hepatitis B
Observe for reactivation of prior
Hepatitis B
https://www.fda.gov/Drugs/DrugSafety/ucm522932.htm
Drug Interactions
Multiple
Drug Interaction
s
Especially agents with
Ritonavir
(e.g. Technivie, Viekira, Olysio)
Acetaminophen
is safe (limit total daily dose to <2000 mg)
No significant interactions with Epclusa or Mavyret and
Opioid Addiction
therapy (
Methadone
,
Buprenorphine
)
Monitor levels closely during therapy
INR (for those on
Warfarin
)
Blood Glucose
(in
Diabetes Mellitus
)
Proton Pump Inhibitor
s (acid suppression)
Avoid
Proton Pump Inhibitor
s with Harvoni, Sofosbuvir/Velpatasvir (Epclusa)
Proton Pump Inhibitor
s are safe to use with Glecaprevir/pibrentasvir (Mavyret)
If acid suppression needed, limit to
H2 Blocker
(and space doses 4-12 hours apart)
Famotidine
40 mg orally twice daily
Statin
s have various
Drug Interaction
s (increased
Statin Myopathy
risk)
LImit
Statin
dosing (e.g.
Rosuvastatin
to 10 mg)
Anticonvulsants reduce antiviral levels
Avoid potent
CYP3A4
inducers (e.g.
Phenytoin
,
Carbamazepine
)
Consider
Valproic Acid
or
Lamotrigine
(
Lamictal
) instead
Herbal preparations
Stop all herbal and dietary supplements
St. Johns Wort lowers antiviral levels
Ethinyl Estradiol
containing contraceptives
Avoid with Glecaprevir/pibrentasvir (Mavyret)
Amiodarone
Avoid with Sofosbuvir/Velpatasvir (Epclusa) due to risk of severe
Bradycardia
Safe to use with Glecaprevir/pibrentasvir (Mavyret)
References
(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
Genotype
s 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
http://www.hcvguidelines.org
Nurse support lines for protocols (24 hour)
Schering-Plough: 888-437-2608
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]
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