ID RC Viral Hep 2022 Slides 1up

Viral
Hepatitis
David E. Koren, Pharm.D., M.P.H., BCPS, AAHIVP, FIDSA
Clinical Pharmacy Specialist
Temple University Health System
Philadelphia, Pennsylvania
©2022 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 1
Relevant Financial Relationship Disclosure
The following persons in control of this activity’s content have relevant financial
relationships:
• David Koren: Clinical Advisory Board, Gilead; Independent consulting, Abbvie
• Jason Schafer: Advisory Board and Research support, Merck; Research support,
Gilead
All other persons in control of content do not have any relevant financial relationships
with an ineligible company.
As defined by the Standards of Integrity and Independence in Accredited Education definition of ineligible company. All relevant financial relationships have
been mitigated prior to the CPE activity.
Learning Objectives
• Assess pharmacotherapies for viral hepatitis, including relevant
pharmacology and spectrum of activity.
• Select the most appropriate pharmacotherapeutic plan and monitoring
based on patient‐ and disease‐specific information, virus and genotype,
and best available evidence.
• Interpret signs, symptoms, laboratory and other relevant diagnostic test
results.
• Recommend modifications of patient‐specific treatment plans based on
efficacy, adverse effects, and drug interactions.
• Summarize key considerations in effective patient and caregiver education
and counseling techniques.
• Identify screening guidelines and preventive therapies for viral hepatitis.
Segment 1
Viral Hepatitis:
Hepatitis A Virus (HAV)
Just the Facts
• Estimated 24,900 new infections
• Person‐to‐person transmission
– Fecal‐oral route
– Contaminated food or water
• Incubation period: 15‐50 days
– Average: 28 days
Source: CDC
• Symptoms usually last less than 2 months
– Abdominal pain, jaundice, pale stools, dark urine
Centers for Disease Control and Prevention (CDC). https://www.cdc.gov/hepatitis/hav/havfaq.htm#general. Accessed November 18, 2021.
World Health Organization (WHO). http://www.who.int/mediacentre/factsheets/fs328/en/. Accessed November 18, 2021.
Question 1: A patient with the following serologies is planning a medical mission
trip to a remote area of Western Africa in the next 3 months for a period of 2
weeks.
Anti‐HAV IgM: negative Anti‐HBc: negative
Anti‐HAV IgG: negative HBsAg: negative
Anti‐HBs: positive HCV Ab: negative
What is the most appropriate recommendation regarding the immunization
requirements for this patient?
A. Immunization is not required
B. Initiate Twinrix®
C. Initiate Havrix®
D. Obtain hepatitis A and B viral loads
CDC. https://wwwnc.cdc.gov/travel/yellowbook/2020/travel‐related‐infectious‐diseases/hepatitis‐a. Accessed November 18, 2021.
Risk Factors for Hepatitis A Virus
• Travel to or living in an area with poor sanitation or lacking safe
water
• Homelessness
• Men who have sex with men
• Recreational drug use
• Direct contact with an infected person
– Living in same home
– Sexual partner
• Clotting factor disorders
• Working with non‐human primates
CDC. https://www.cdc.gov/hepatitis/hav/havfaq.htm#general. Accessed November 18, 2021.
WHO. http://www.who.int/mediacentre/factsheets/fs328/en/. Accessed November 18, 2021.
Serologies
Positive
Anti‐HAV • Total antibody (IgG + IgM)
• Present or past infection
• Immunity due to vaccination
Anti‐HAV IgM • Current, recent, or acute infection
Anti‐HAV IgG • Immunity to HAV from past infection or
vaccination
CDC. https://www.cdc.gov/hepatitis/resources/professionals/pdfs/ABCTable.pdf. Accessed November 18, 2021.
Clinical Course of Hepatitis A Virus
CDC. https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5304a1.htm. Accessed November 18, 2021.
Management
• Self‐limiting disease
• Avoidance of acetaminophen
• Supportive care
– Antiemetics
– Fluids to replete volume loss from vomiting and diarrhea
Prevention
• Improved sanitary conditions
• Safe access to water
• Ensuring that appropriate food safety procedures are followed
• Vaccination
– 2 doses given at least 6 months apart
• Immune globulin
– Single dose
Question 2: Hepatitis A vaccination is recommended for all
individuals in the following groups EXCEPT:
A. Men who have sex with men
B. Children < 1 year of age
C. Persons traveling to areas where virus is endemic
D. Injection drug users
Who Should Be Immunized Against HAV
• All children > 1 year of age (and sooner if travel outside the US is planned)
• Persons with travel to areas with intermediate – high rates of infection
• MSM
• Illegal and injection drug users
• Homelessness
• Persons with clotting‐factor disorders
• Persons working with HAV‐infected primates or with HAV in a research
laboratory
• Persons with chronic liver disease, including HBV‐ and HCV‐infected
• Persons living with HIV
• Persons exposed as result of an outbreak
• Persons who require post‐exposure prophylaxis
CDC. https://www.cdc.gov/hepatitis/resources/professionals/pdfs/ABCTable.pdf. Accessed November 18, 2021.
CDC. https://stacks.cdc.gov/view/cdc/59777. Accessed November 18, 2021.
Available Vaccines
Product Coverage Dose Based on Age (Years) Number Timing of Doses
of Doses
HAVRIX Hepatitis A 1‐18: 720 Elisa Units (0.5 mL) 0, 6‐12 months
> 19: 1440 Elisa Units (1 mL) 2
VAQTA Hepatitis A 1‐18: 25 Units 0, 6‐18 months
(0.5 mL) 2
> 19: 50 Units
(1 mL)
Twinrix Hepatitis A + B > 18: Havrix 720 Elisa Units + 3 0, 1, 6 months
Engerix B (20 mcg) (1 mL) 4 0, 7, 21‐30 days,
12 months (booster of
HBV only)
Administration Considerations
• Inactivated vaccine
• Hepatitis A vaccines considered interchangeable
• Safe in pregnancy
• Intramuscular (IM) injection in deltoid muscle
• If the 2nd dose is delayed, series does not need to be restarted
Pre‐Exposure Prophylaxis
Age Preferred Agent Rationale
< 6 months or vaccine Immune globulin 0.1 ‐ 0.2 mL/kg • 0.1 mL/kg for travel up to 1 month
contraindicated • 0.2 mL/kg for travel up to 2 months
• 0.2mL/kg every 2 months for travel of
≥2 months’ duration
6 – 11 months HAV vaccine x 1 dose • This should not count toward the 2‐dose
series which should be initiated at 12
months
12 months – 40 years HAV vaccine x 1 dose • Administer dose as soon as travel is
considered and complete series
according to routine schedule
> 40 years or HAV vaccine x 1 dose +/‐ • Immune globulin should be added based
Immunocompromised/ Immune globulin 0.1 ‐ 0.2 mL/kg on provider's risk assessment
chronic liver disease • Refer to immune globulin dosing for < 6
months or vaccine contraindicated
Nelson NP et al. MMWR Morb Mortal Wkly Rep. 2018; 67:1216.
Post‐Exposure Management
• Single dose of HAV vaccine* or immune globulin (0.1 mL/kg) IM
– Administer as soon as possible and within 2 weeks of exposure
Age Preferred Agent Rationale
< 12 months or Immune globulin
> 12 months + Vaccine allergy
> 12 months – 40 years HAV vaccine • Active immunity
• Greater protection
• Ease of administration and
availability
> 40 years or HAV vaccine x 1 dose +/‐ • Immune globulin should only
> 12 months + Chronic liver Immune globulin be given if a provider's risk
disease or Immunocompromised assessment determines the
need for administration.
* Denotes separate HAV Vaccine. Combined HAV/HBV Vaccine (Twinrix) should not be used due to a lower antigenic content
Nelson NP et al. MMWR Morb Mortal Wkly Rep 2018; 67:1216.
Segment 2
Viral Hepatitis:
Hepatitis B Virus (HBV)
Incidence of Hepatitis B Cases
• Estimated 21,600 new infections in 2018
• Estimated 862,000 people living with chronic HBV infection in
2016
CDC. https://www.cdc.gov/hepatitis/hbv/hbvfaq.htm#overview. Accessed November 18, 2021.
Hepatitis B Lifecycle
Interaction
Entry and
Virion Secretion Uncoating
cccDNA
Formation
Strand Synthesis
Reverse
Transcription
Transcription
Encapsidation
Priming Translation
Viral Protein
Secretion
cccDNA: covalently closed circular double‐stranded DNA Gonzalez SA. http://www.antimicrobe.org/v22.asp#t5. Accessed November 18, 2021.
Hepatitis B Facts
• A member of the Hepadnaviridae family
• Percutaneous/mucosal transmission from infected blood or body fluids
• Mother‐to‐child transmission during childbirth
• Virus survives at least 7 days outside of the body
• Incubation period: 60‐150 days (average: 90 days)
• Common symptoms of acute infection: similar to HAV
• Treatment
– Acute infection: Supportive measures
– Chronic infection: Antiviral therapy
Symptoms of Chronic HBV Infection
• Commonly asymptomatic
• Ascites
• Encephalopathy
• Extrahepatic Manifestations
– Polyarteritis nodosa
– Glomerular disease
• Jaundice
• Peripheral edema
• Splenomegaly
• Transaminitis
Risk Factors for HBV Infection
• Direct contact with an infected person
– Living in same home
– Sexual partner
• Mother‐to‐child transmission during child birth
• MSM
• Occupational exposure to blood or blood‐contaminated body
fluids
• Hemodialysis
Consequences of Untreated Hepatitis
• Cirrhosis
Compensated Decompensated
Stage 1 No Varices/Ascites
Stage 2 Varices/No Ascites
Stage 3 Ascites + Varices
Stage 4 Bleeding + Ascites
• Hepatocellular carcinoma
D’Amico G et al. J Hepatol. 2006; 44:217‐231.
Child‐Turcotte‐Pugh (CTP) Score
Class A Class B Class C
Points allocated1 1 point 2 points 3 points
Ascites None Mild‐to‐Moderate Severe
(diuretic‐responsive) (diuretic‐refractory)
Hepatic None Grade I‐II (or Grade III‐IV (or
encephalopathy suppressed with refractory)
medication)
INR <1.7 1.71‐2.3 >2.3
Serum albumin (g/L) >3.5 2.8‐3.5 <2.8
Total bilirubin (mg/dL) <2 2‐3 >3
Point Total 5‐6 7‐9 10‐15
1 Point is allocated based on the presence or absence of each finding
https://www.mdcalc.com/child‐pugh‐score‐cirrhosis‐mortality. Accessed November 18, 2021.
A Key to Hepatitis B Serologies
Serology Acronym How to use this test
Hepatitis B Surface Antigen HBsAg • Assists in diagnosing
acute/chronic active infection
• Patient is infectious
Hepatitis B Surface Antibody HBsAb or anti‐HBs • Assesses immunity and
recovery from infection
Hepatitis B Core Antibody HBcAb or Total anti‐HBc • Appears at onset of infection
(Total) and remains for life
Hepatitis B Core Antibody (IgM) IgM anti‐HBc • Indicates acute infection
Hepatitis B Envelope Antigen HBeAg • Indicates active viral replication

• Patient is infectious
Hepatitis B Envelope Antibody HBeAb or anti‐HBe • No replication occurring
Hepatitis B Virus DNA HBV DNA • How rapidly the virus is

reproducing in the liver
Initial Work‐Up
• Complete medical/vaccination/family/social history and physical exam
• Serologies
– Diagnostic
— HBsAg, HBV DNA, HCVAb, HDVAb, HIV
– Therapeutic
— HBeAb, HBeAg, HBsAg, HBV DNA
• Biochemical Markers
– AFP; AST/ALT; ALP; CBC; GGT; PT/INR; bilirubin; serum albumin and gamma globulins
• Hepatic Ultrasound
• Fibrosis Markers
– Non‐Invasive
— Fibroscan, Fibrosure, APRI
– Invasive (Selected cases)
— Liver biopsy
AFP: Alpha‐fetoprotein
ALP: Alkaline phosphatase
APRI: Aspartate aminotransferase to platelet ratio index Terrault NA et al. Hepatology. 2018; 67:1560‐1599.
CBC: Complete Blood Count European Association for the Study of the Liver (EASL). J Hepatol. 2017; 67:370‐398.
GGT: Gamma‐glutamyl transpeptidase EASL. J Hepatol. 2015; 63:237‐264.
Question 3: What is the earliest serologic marker of
Hepatitis B infection?
A. HBeAg
B. Anti‐HBc
C. HBV DNA
D. HBsAg
Hepatitis B Serologies: Acute Infection
CDC. https://www.cdc.gov/hepatitis/resources/professionals/training/serology/training.htm. Accessed November 18, 2021.
Hepatitis B Serologies: Chronic Infection
Interpreting Hepatitis B Serologies
Phases of Chronic Hepatitis B (CHB)
Phases ALT HBV DNA (IU/mL) HBsAg HBeAg Liver Histology
CHB Normal or elevated Undetectable ‐ Positive Either (positive or Variable

several billion (> 6 months) negative) necroinflammation
• HBeAg (+) and/or fibrosis
> 20,000
• HBeAg (‐)
2000‐20,000
Immune‐tolerant Normal or minimal Elevated Positive Positive Minimal
CHB elevation ( >1,000,000,000) (> 6 months) inflammation;
no fibrosis
Immune‐active CHB Elevated • HBeAg (+) Positive Either (positive or Moderate‐severe
(intermittent or > 20,000 (> 6 months) negative) necroinflammation +
persistent) • HBeAg (‐) fibrosis
>2000
Inactive CHB Normal Low or undetectable Positive Negative (HBeAb Minimal
(> 6 months) positive) necroinflammation
with variable fibrosis
Terrault NA et al. Hepatology. 2018; 67:1560‐1599.
Question 4: In an otherwise healthy individual, what
patient scenario meets the criteria for treatment
initiation?
A. HBeAg (+) with HBV DNA 32,875 IU/mL and an ALT 152 U/L
B. HBeAg (+) with HBV DNA 72,743 IU/mL, ALT 37 U/L, and a fibrosis
score of F0
C. HBeAg (‐) with HBV DNA 1,743 IU/mL and ALT 207 U/L
D. HBeAg (‐) with HBV DNA 7,456 IU/mL, ALT 24 U/L, and a fibrosis score
of F0
When to Initiate HBV Treatment: HBeAg (+)
HBV DNA (IU/mL) ALT Extent of Liver
Disease
AASLD > 20,000 > 2x ULN ‐‐‐
‐‐‐ ‐‐‐ Cirrhosis
EASL > 2,000 Any ALT elevation and/or moderate
inflammation or fibrosis
> 20,000 > 2x ULN ‐‐‐
AALSD: American Association for the Study of Liver Diseases Terrault NA et al. Hepatology. 2018; 67:1560‐1599.

ULN: Upper limit of normal (29 to 33 Units/L for males and 19 to 25 Units/L for females) EASL. J Hepatol. 2017; 67:370‐398.
When to Initiate HBV Treatment: HBeAg (‐)
HBV DNA (IU/mL) ALT Extent of Liver
Disease
AASLD > 2,000 > 2x ULN ‐‐‐
EASL > 2,000 Any ALT elevation and/or
moderate inflammation or fibrosis
> 20,000 > 2x ULN ‐‐‐
AALSD: American Association for the Study of Liver Diseases Terrault NA et al. Hepatology. 2018; 67:1560‐1599.

ULN: Upper limit of normal (29 to 33 Units/L for males and 19 to 25 Units/L for females) EASL. J Hepatol. 2017; 67:370‐398.
Assessing Response to HBV Treatment
EASL. J Hepatol. 2017; 67:370‐398.
Efficacy of First‐Line Treatments – HBeAg (+)
Tenofovir Tenofovir Entecavir Pegylated‐
alafenamide disoproxil interferon
fumarate
HBV‐DNA 73% 76% 61% 30‐42%
suppression
HBeAg loss 22% ‐‐‐ 22‐25% 32‐36%
HBsAg loss 1% 8% 4‐5% 2‐7%
ALT ‐‐‐ 68% 68‐81% 34‐52%
normalized
Efficacy of First‐Line Treatments – HBeAg (‐)
Tenofovir Tenofovir Entecavir Pegylated‐
alafenamide disoproxil interferon
fumarate
HBV‐DNA 90% 93% 90‐91% 43%
suppression
HBsAg loss <1% 0% 0‐1% 4%
ALT 81 76% 78‐88% 59%
normalized
Recommended Follow‐Up for Patients without Treatment
Clinical Parameters Follow‐up Period
HBeAg (+), <30 years of age, and do 3‐6 months
not fulfill treatment criteria
HBeAg (+), HBV DNA May represent seroconversion

2000 IU/mL to 20,000 IU/mL Monitor every 1‐3 months
If persists > 6 months, initiate treatment
HBeAg (‐), HBV DNA 6‐12 months
<2000 IU/mL
HBeAg (‐), HBV DNA 3 months for the 1st year, then every 6 months
>2000 IU/mL
EASL. J Hepatol. 2017; 67:370‐398.
Timeline for HBV Therapy Approval
2005 2008
2016
1992 1998 2002 Entecavir 2006 Tenofovir
Tenofovir
Interferon‐α Lamivudine Adefovir Pegylated Telbivudine disoproxil
alafenamide
interferon‐α fumarate
Question 5: MO has an extensive treatment history for seizures
and was recently initiated on phenytoin. MO’s provider would
like to start Hepatitis B therapy. What agent is most appropriate
to initiate?
A. Adefovir
B. Lamivudine
C. Tenofovir alafenamide
D. Tenofovir disoproxil fumarate
Preferred for HBV Treatment Initiation: Nucleos(t)ide Analogues
Generic (Brand) Name Oral Dosing (NAs) Dosing in Renal/Hepatic Impairment
Entecavir (Baraclude) Nucleoside treatment‐naïve: • CrCl 30‐49: 0.25 mg daily or 0.5 mg every 48 hours
0.5 mg daily • CrCl 10‐29: 0.15 mg daily or 0.5 mg every 72 hours
• CrCl < 10, HD* or CAPD: 0.05 mg daily or 0.5 mg every 7 days
Lamivudine‐refractory, • CrCl 30‐49: 0.5 mg daily or 1 mg every 48 hours

resistant viremia, or • CrCl 10‐29: 0.3 mg daily or 1 mg every 72 hours
decompensated liver disease: • CrCl < 10, HD* or CAPD: 0.1 mg daily or 1 mg every 7 days
1 mg daily
Tenofovir alafenamide 25 mg daily • CrCl < 15 : Use not recommended unless undergoing
(Vemlidy) (TAF) hemodialysis
Tenofovir disoproxil 300 mg daily • CrCl 30‐49: 300 mg every 48 hours
fumarate (Viread) • CrCl 10‐29: 300 mg every 72‐96 hours
(TDF) • HD: 300 mg post‐HD every 7 days
CAPD: Continuous ambulatory peritoneal dialysis
CrCl: Creatinine clearance (mL/min),
HD: Hemodialysis
*Administer post‐HD EASL. J Hepatol. 2017; 67:370‐398.
Guideline Recommended HBV Treatment Initiation
Generic (Brand) Normal Dosing Dosing in Renal/Hepatic Dosing in the Presence of Toxicity
Name Impairment
Pegylated 180 mcg • CrCl <30 or HD*: 135 mcg • ANC 500 to <750/mm3: 135 mcg once weekly
interferon‐α, subcutaneously once weekly
peginterferon once weekly for • Contraindicated in • ANC <500/mm3: Hold until ANC > 1000/mm3,
(Pegasys) 48 weeks autoimmune hepatitis and resume at 90 mcg once weekly
hepatic decompensation
• ALT > 5x ULN: 135 mcg once • Platelets 25,000 to <50,000/mm3: 90 mcg once
weekly or temporarily weekly
discontinue • Platelets <25,000/mm3: Discontinue
• ALT > 10 x ULN: Discontinue • Mild Depression: No dosage adjustment;
Evaluate once weekly
• Moderate Depression: Reduce dose to 90 or
135 mcg weekly; Evaluate
• Severe Depression: Discontinue
ANC: Absolute neutrophil count, CrCl: Creatinine clearance (mL/min), HD: Hemodialysis Terrault NA et al. Hepatology. 2018; 67:1560‐1599.
*Reduce dose to 90 mcg once weekly in HD patients with severe side effects or lab abnormalities EASL. J Hepatol. 2017; 67:370‐398.
Alternative Agents for HBV Treatment
Generic (Brand) Name Oral Dosing Dosing in Renal Impairment
Adefovir (Hepsera) 10 mg daily • CrCl 30‐49: 10 mg every 48 hours
• CrCl 10‐29: 10 mg every 72 hours
• HD: 10 mg post‐HD every 7 days
Lamivudine (Epivir HBV)* 100 mg daily • CrCl 30‐49: 100 mg 1st dose, then
50 mg once daily
• CrCl 15‐29: 100 mg 1st dose, then
25 mg once daily
• CrCl 5‐14: 35 mg 1st dose, then 15
mg once daily
• CrCl < 5, HD, or CAPD: 35 mg 1st
dose, then 10 mg once daily
Telbivudine (Tyzeka) No longer available for use in the United States
CAPD: Continuous ambulatory peritoneal dialysis
CrCl: Creatinine clearance (mL/min),
HD: Hemodialysis
Terrault NA et al. Hepatology. 2018;67:1560‐1599.
*Many practitioners use full dose lamivudine in the setting of renal impairment since the risk of toxicity is very low
EASL. J Hepatol. 2017;67:370‐398.
Mechanisms of Action
• Nucleos(t)ide Analogues • Pegylated interferon‐α
– Intracellularly phosphorylated  – Exact mechanism unknown
inhibits hepatitis B viral – Believed to interfere with virus
polymerase  blocks reverse entry, virion uncoating,
transcriptase  reduces viral DNA transcription of viral RNA into
synthesis proteins, and assembly of
nucleocapsids
– May augment cell‐mediated
immunity
– Produces higher rates of HBeAg
and HBsAg loss along with a
durable response
EASL. J Hepatol. 2017; 67:370‐398.
Nucleos(t)ide Analogue Therapy vs. PegIFN
• Nucleos(t)ide Analogue Therapy • PegIFN
– Advantages – Advantages
— High barrier to resistance with entecavir — No concerns for resistance
and both tenofovir formulations
— Finite duration of treatment (48
— Long‐term efficacy
weeks)
— Safe
— Long‐term immunologic control
— Only treatment option
– Decompensated liver disease – Disadvantages
– Liver transplants — Variability of response
– Extrahepatic manifestations — Numerous adverse effects
– Acute or severe chronic exacerbation
– Prevention of reactivation in patients
receiving immunosuppression or
transmission in those with high
viremia EASL. J Hepatol. 2017; 67:370‐398.
Research comparing TAF vs. TDF in Chronic HBV Infection
• TAF non‐inferior to TDF at weeks 48 and 96 in CHB based on HBV DNA
• No resistance in either TAF or TDF
• Significantly higher rate of ALT normalization with TAF
• For HBeAg‐positive: higher rate of seroconversion at week 96 compared to 48 with
both TAF and TDF
• For HBeAg‐negative: minimal decline from baseline in HBsAg with either TDF or TAF
• Tenofovir Alafenamide (TAF)
– Lower dosage requirements • Tenofovir Disoproxil Fumarate (TDF)
– Lower systemic exposure − Fewer drug‐drug interactions
– Fewer renal and bone effects
– No dosage reduction in ESRD if receiving HD
Brunetto M et al. EASL 2017. Abstract PS‐042.
Agarwal K et al. EASL 2017. Abstract FRI‐153.
Kaneko S et al. J Gastroenterol Hepatol. 2019 Apr 24.
Question 6: What education should you provide to [MO in
question #5] when starting HBV therapy?
A. Frequent lab monitoring is required because of the risk of bone
marrow suppression.
B. Do not stop taking this medication because it could result in worsening
of hepatitis B infection.
C. This medication can worsen depression, so report any mood changes
to your health provider.
D. Take this medication at least 2 hours before or after meals because
food delays absorption of the drug.
HBV Treatment Adverse Effects
Entecavir* Dizziness, Fatigue, Headache, Nausea
Tenofovir Alafenamide* Abdominal or Back Pain, Cough, Fatigue, Headache, Nausea
Tenofovir Disoproxil Decreased Bone Mineral Density, Fanconi Syndrome, Increased
Fumarate* Serum Creatinine, Nausea
Pegylated interferon‐α Numerous; Bone Marrow Suppression, Fatigue, Flu‐like Symptoms,
Mood Changes
Adefovir* Acute Renal Failure, Fanconi Syndrome, Nephrogenic Diabetes
Insipidus
Lamivudine* Minimal
* Boxed warnings include: Acute hepatitis exacerbation upon discontinuation along with lactic acidosis/severe hepatomegaly with steatosis
Current FDA‐approved product prescribing information.
HBV Treatment Drug Interactions
Contraindicated Use with Caution
Entecavir Food delays absorption; Give 2
hours before or after a meal
Tenofovir Alafenamide Adefovir; Carbamazepine;
Fosphenytoin/Phenytoin;
Oxcarbazepine; Phenobarbital;
Primidone; Rifabutin; Rifampin;
Rifapentine; St. John’s Wort;
Tipranavir; Other co‐formulated
tenofovir products; NSAIDs
Tenofovir Disoproxil Adefovir; Other co‐formulated tenofovir Ledipasvir, Velpatasvir, NSAIDs
Fumarate products
Pegylated interferon‐α Tizanidine
Adefovir Tenofovir
Lamivudine Emtricitabine Sorbitol
HBV Pretreatment Monitoring HBV On‐Treatment Monitoring Parameters
Entecavir ‐‐‐ • Lactic acid (if concern for lactic acidosis)
Tenofovir Alafenamide • Creatinine Clearance, serum phosphate, • Creatinine Clearance, serum phosphate, urine glucose

urine glucose and protein and protein (Annually or as indicated)
Tenofovir Disoproxil • Creatinine Clearance, serum phosphate, • Creatinine Clearance, serum phosphate, urine glucose
urine glucose and protein and protein (Annually or as indicated)
Fumarate
• Bone Density (Fracture history or risk for • Bone Density (as clinically indicated)
osteopenia) • Lactic acid (if concern for lactic acidosis)
Pegylated interferon‐α ‐‐‐ • CBC (every 1‐3 months)
• TSH (every 3 months)
• Autoimmune/ischemic/neuropsychiatric/ infectious
complications (as clinically indicated)
Adefovir • Creatinine Clearance • Creatinine Clearance, serum phosphate, urine glucose
and protein (Annually)
• Bone Density (as clinically indicated)
• Lactic acid (if concern for lactic acidosis)
Lamivudine ‐‐‐ • Amylase (if concern for pancreatitis)
• Lactic acid (if concern for lactic acidosis)
Discontinuation of HBV Therapy
• Nucleos(t)ide Analogues
– Confirmed HBsAg loss + HBsAb seroconversion
– Non‐cirrhotic HBeAg‐positive patients with chronic HBV and stable
HBeAg seroconversion + undetectable HBV DNA + completed at least
12 months of therapy
– Selected non‐cirrhotic HBeAg‐negative patients with long‐term
virologic suppression (> 3 years) as long as close monitoring
maintained
• PegIFN
– After 48 weeks
EASL. J Hepatol. 2017; 67:370‐398.
Causes of Hepatitis B Reactivation
• Receipt of chemotherapy, solid organ or bone marrow
transplantation
• Receipt of immunosuppressive therapy
– Rituximab
– High‐dose steroids
– Anti‐Tumor Necrosis Factor (TNF) agents
• Discontinuation of HBV agents, especially if co‐infected with HIV
• Co‐infection with HCV
– Treatment with direct‐acting antivirals (DAAs)  BOXED WARNING
• Spontaneous
CDC. https://www.cdc.gov/hepatitis/hbv/hbvfaq.htm. Accessed November 18, 2021.
Antiviral Resistance
• Risk factors
– High baseline HBV DNA
– Slow decline in HBV DNA
– Prior suboptimal treatment with nucleos(t)ide analogue
• Perform genotypic resistance testing in multidrug resistance
• Entecavir, TAF, and TDF have high genetic barriers to resistance
• Resistance Spectrum
– Lamivudine > Adefovir > Entecavir > TAF/TDF
Ghany MG, Doo EC. Hepatology. 2009; 49(suppl):S174‐84.
Managing Antiviral Resistance in HBV
Resistance Switch1 Add2
Adefovir Lamivudine‐naïve: Entecavir Entecavir
Lamivudine‐resistance: TAF/TDF
Entecavir TAF or TDF Tenofovir
(or tenofovir/emtricitabine)3
Lamivudine TAF or TDF Tenofovir
(or tenofovir/emtricitabine)3
Telbivudine4 TAF or TDF Tenofovir
TAF or TDF Lamivudine‐naïve: Entecavir Lamivudine‐resistance: Entecavir
Multidrug TAF or TDF Tenofovir + entecavir
TAF: Tenofovir alafenamide; TDF: Tenofovir disoproxil fumarate
1 May switch to another monotherapy option
2 May add another agent to existing treatment
3 Emtricitabine also provides HBV activity and exhibits cross‐resistance with lamivudine Terrault NA et al. Hepatology. 2018; 67:1560‐1599.
4 Drug no longer available in the US EASL. J Hepatol. 2017; 67:370‐398.
HIV and HBV Co‐Infection
• Accelerated progression to cirrhosis, end‐stage liver disease,
and hepatocellular carcinoma (HCC)
• Initiate antiretroviral therapy regardless of CD4 count
• Treatment should be for both HIV and HBV
– A fully active antiretroviral (ARV) regimen should be used
• Agents with activity against both HIV and HBV
– Tenofovir (both disoproxil fumarate and alafenamide)
– Lamivudine (cross‐resistance to emtricitabine)
– Emtricitabine (cross‐resistance to lamivudine)
AIDSinfo. https://clinicalinfo.hiv.gov/en/guidelines/adult‐and‐adolescent‐arv/hepatitis‐b‐virushiv‐coinfection?view=full. Accessed November 18, 2021.
HIV and HBV Co‐Infection
• Single‐tablet regimens that manage both infections
– Atripla
— Efavirenz/tenofovir disoproxil fumarate/emtricitabine
– Biktarvy
— Bictegravir/tenofovir alafenamide/emtricitabine
– Complera
— Rilpivirine/tenofovir disoproxil fumarate/emtricitabine
– Delstrigo
— Doravirine/tenofovir disoproxil fumarate/lamivudine
– Genvoya
— Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine
– Odefsey
— Rilpivirine/tenofovir alafenamide/emtricitabine
– Stribild
— Elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine
– Symtuza
— Darunavir/cobicistat/tenofovir alafenamide/emtricitabine
Choosing Between HBV Therapies
No Comorbidities, Decompensated
Elderly Patients, risk of preexisting bone
Cirrhosis, HBV/HCV Co‐infection,
or renal disease
Nucleoside‐Naïve
Entecavir TAF
Entecavir TAF TDF Preferred in CrCl Preferred in
<15 mL/min (if not HIV/HBV
on dialysis); Less coinfection; Prior
expensive generic nucleoside
available exposure
EASL. J Hepatol. 2017; 67:370‐398.
Antiviral Therapy
Clinical Scenario Preferred Management
Decompensated Cirrhosis Entecavir, TAF, or TDF
Bone Disease Entecavir or TAF
Elderly (Age > 60 years) Entecavir or TAF
HBV/HCV Co‐infection Entecavir, TAF, or TDF
HBV/HDV Co‐infection PegIFNα for at least 48 weeks
HIV/HBV Co‐infection TAF* or TDF‐ based antiretroviral therapy
NA‐naïve patients Entecavir, TAF, or TDF
Post Liver Transplant Prevention of Recurrent HBV Hepatitis B Immunoglobulin + Entecavir, TAF, or TDF
Pregnancy TDF
Previous lamivudine resistance TAF or TDF
Renal Disease Entecavir or TAF
Renal Transplant or Dialysis Entecavir or TAF
*TAF preferred in HIV therapy EASL. J Hepatol. 2017; 67:370‐398.
Who Should Be Immunized Against HBV
• Per ACIP meeting November 3, 2021
– All adults under age 19‐59
– Adults over 60 should continue to follow previous risk‐based assessments
—Persons at risk for infection by sexual exposure
—Persons at risk for infection by percutaneous or mucosal exposure to blood
—Other
– International travelers to areas of high endemicity
– Persons with Hepatitis C infection
– Persons with Chronic Liver Disease
– Persons with HIV infection
– Incarcerated persons
– All other persons seeking protection against HBV
CDC. https://www.cdc.gov/vaccines/acip/meetings/slides‐2021‐11‐2‐3.html. Accessed November 17, 2021.
CDC. https://www.cdc.gov/hepatitis /hbv/vaccadults.htm#guidelines. Accessed February 8, 2022
Single‐Antigen HBV Vaccines
Product Coverage Dose Based on Age (Years) Number of Doses Timing of Doses
Engerix‐B Hepatitis B 0‐19: 10 mcg (0.5 mL)

3 0, 1, 6 months
> 20: 20 mcg (1 mL)
> 20 on HD: 40 mcg (2 mL) 4 0, 1, 2, 6 months
Recombivax HB Hepatitis B 0‐10: 5 mcg (0.5 mL) 3 0, 1, 6 months
11‐15: 10 mcg (1 mL) 2 0, 4‐6 months
11‐19: 5 mcg (0.5 mL) 3 0, 1, 6 months
> 20: 10 mcg (1 mL) 3 0, 1, 6 months
> 20 on HD*: 40 mcg (1 mL) 3 0, 1, 6 months
Heplisav‐B Hepatitis B > 18: 20 mcg (0.5 mL) 2 0, 1 month
*Dialysis formulation CDC. https://www.cdc.gov/vaccines/pubs/pinkbook/hepb.html. Accessed November 18, 2021.
Combination Vaccines
Product Coverage Dose Based on Age Number of Timing of Doses
Doses
Twinrix Hepatitis A + > 18 years: 20 mcg 3 0, 1, 6 months
B (1 mL) 4 0, 7, 21‐30 days,
12 months (booster
of HBV only)
Pediarix DTaP, 6 weeks – 6 years: 10 3 2, 4, 6 months

Hepatitis B, mcg (0.5 mL)
inactivated
polio
CDC. https://www.cdc.gov/vaccines/pubs/pinkbook/hepb.html. Accessed November 18, 2021.
Dtap: diphtheria, tetanus, and acellular pertussis Pediarix [Package Insert]. GlaxoSmithKline. Research Triangle Park, NC. November, 2019.
Administration Considerations
• Intramuscular administration
• Postvaccination serologic testing recommended
– Patients receiving hemodialysis
– Immunocompromised patients including HIV
– Sex partners of HBsAg‐positive persons
– Infants born to HBsAg‐positive women
• Booster doses may be required and administered if anti‐HBs levels
fall below 10 mIU/mL
– Patients receiving hemodialysis
– Immunocompromised patients
HBV Vaccine Non‐Responders
• Risk factors for non‐response • Management
– Vaccine factors (dose, schedule, – Repeat a second series of 3 doses
vaccination site) – Give doses on schedule of 0, 1, and
– Age > 40 years 6 months
– Male gender – Retest 1‐2 months after repeat
– Obesity HBV vaccination
– Smoking – If still no response, check HBsAg
– Chronic illness
HBV Post‐Exposure Prophylaxis
• Administer within 12 – 24 hours after exposure
Vaccination Status Source HBsAg‐positive or Status Unknown HBsAg‐negative Source
Unvaccinated or Non‐immune • Hepatitis B immune globulin x 1 dose • Start HBV vaccine series
• Start HBV vaccine series
HBV Vaccine Responder • No Treatment • No Treatment
HBV Vaccine Non‐Responder • Hepatitis B immune globulin x 1 dose • No Treatment
• Start HBV vaccine series
• Hepatitis B immune globulin x 2 doses
HBsAb Response Unknown • HBV vaccine booster dose x 1 • No Treatment
Undergoing HBV Vaccination • Hepatitis B immune globulin x 1 dose • Complete HBV vaccine series
• Complete HBV vaccine series
CDC. https://www.cdc.gov/mmwr/preview/mmwrhtml/rr6210a1.htm. Accessed November 18, 2021.
Segment 3
Viral Hepatitis:
Hepatitis C Virus (HCV)
Global Prevalence of Hepatitis C Virus
CDC. https://wwwnc.cdc.gov/travel/yellowbook/2020/travel‐related‐infectious‐diseases/hepatitis‐c. Accessed November 18, 2021.
Worldwide Distribution of HCV Based on Genotype
Messina JP et al. Hepatology. 2015; 61:77‐87.
Hepatitis C Lifecycle
Viral Entry
Viral Assembly Uncoating and
and Release Translation
Viral
Replication
Sklan EJ et al. Nat Rev Gastroenterol Hepatol. 2009; 6:217‐227.
Hepatitis C Facts
• Single‐stranded RNA virus in the Flaviviridae family
• 2.4 million people in the U.S. have chronic HCV
• 15‐25% of those with HCV clear the virus without treatment
• Percutaneous transmission
– Injection drug use
– Received donated blood, blood products, or organs prior to 1992
– Needlestick injuries
– Born to HCV‐infected mother
– Sex with an HCV‐infected person
– Sharing personal items with infected blood
CDC. https://www.cdc.gov/hepatitis/hcv/hcvfaq.htm#b1. Accessed November 18, 2021.
Recommended Testing for HCV
• One time for all adults greater than or equal to 18 years of age
• Pregnant women during each pregnancy
• People whom have ongoing risk factors (e.g. persons who
inject drugs, share needles or other preparatory equipment)
should be tested routinely
CDC. https://www.cdc.gov/mmwr/volumes/69/rr/rr6902a1.htm#B1_down. Accessed February 8, 2022
CDC. https://www.cdc.gov/hepatitis/hcv/hcvfaq.htm#section3. Accessed November 18, 2021.
Question 7: In what scenario should HCV screening
be routinely performed?
A. An individual actively injecting substances
B. Individuals born between 1945‐1965
C. An individual requiring a blood transfusion in 1996
D. An individual with hemophilia who received clotting factors in
1992
Symptoms of HCV
• Acute
– Commonly asymptomatic but may experience mild symptoms (fatigue,
abdominal pain, poor appetite, jaundice)
• Chronic
– Commonly asymptomatic
– Typically insidious over several decades but can progress to cirrhosis and
HCC
– HBV and HIV co‐infection can accelerate the progression of liver injury and
are often associated with poor outcomes
CDC. https://www.cdc.gov/hepatitis/hcv/hcvfaq.htm#section1. Accessed November 18, 2021.
HCV Testing and Diagnosis
CDC. https://www.cdc.gov/hepatitis/hcv/pdfs/hcv_graph.pdf. Accessed November 18, 2021.
Goals of Therapy for HCV
• Reduce all‐cause mortality and liver‐related adverse health
outcomes (including end‐stage liver disease and HCC)
• Achieve Sustained Virologic Response (SVR)
– Marker of cured infection
– Undetectable viral load (HCV RNA) at least 12 weeks after completing
treatment
– Undetectable viral load considered < 25 IU/mL or lower
AASLD/IDSA. https://www.hcvguidelines.org/evaluate/when‐whom. Accessed November 18, 2021.
Question 8: What patient does NOT meet criteria
for initiation of HCV therapy?
A. A patient with HCV and prior non‐response to PegIFN and ribavirin
B. A patient co‐infected with HCV, HIV, and HBV
C. A patient with HCV genotype 1a and fibrosis score F0
D. A patient with HCV and metastatic HCC
Treatment Recommendations
• ALL PATIENTS with chronic HCV infection
• Exceptions include those with a short life expectancy that
cannot be lengthened with HCV therapy, liver transplantation,
or other therapy
AASLD/IDSA. https://www.hcvguidelines.org/evaluate/when‐whom. Accessed November 18, 2021.
Monitoring Parameters – Prior to Treatment Initiation*
Pretreatment • Complete blood count (CBC)
(within 6 • International normalized ratio (INR)
months prior • Hepatic function panel (i.e. albumin, total and direct bilirubin, ALT, AST,
to treatment alkaline phosphatase levels)
initiation)1 • Serum creatinine and calculated glomerular filtration rate
Pretreatment • Quantitative HCV viral load
(any time • Staging of hepatic fibrosis
prior to • Drug‐drug interactions
treatment • Genotype and subtype (if non‐pan‐genotypic DAA will be prescribed)
initiation)1 • Assess for HBV (HBsAg, HBcAb, HBsAb) and HIV co‐infection
• Child‐Turcotte‐Pugh (CTP) Scoring
ALT: Alanine aminotransferase *For simplified therapy, refer to treatment section for specific monitoring and treatment algorithms.
AST: Aspartate aminotransferase
DAA: Direct‐Acting Antiviral
1May be based on insurance requirements
AASLD/IDSA. https://www.hcvguidelines.org/evaluate/monitoring. Accessed November 18, 2021.
Resistance Testing – Prior to Treatment
DAA‐Regimen Recommendation
Elbasvir/grazoprevir • NS5A RAS testing recommended for treatment‐naïve and
experienced patients with genotype 1A infection being
considered for this therapy
• If present, use a different regimen
Ledipasvir/sofosbuvir • NS5A RAS testing may be considered for treatment‐
experienced patients with genotype 1A infection being
considered for this therapy
• If >100‐fold shift in ledipasvir, use a different regimen
Sofosbuvir/velpatasvir • NS5A RAS testing recommended for genotype
3, treatment‐naïve patients with cirrhosis and treatment‐
experienced patients without cirrhosis being considered
for 12 weeks of therapy with these agents
• If Y93H is present, use another regimen or add weight‐
based ribavirin
AASLD/IDSA. https://www.hcvguidelines.org/evaluate/resistance. November 18, 2021.
Monitoring Parameters – On‐Treatment*
On‐Treatment • Clinic visits or telephone contact to ensure medication adherence, evaluate
drug interactions, and monitor adverse events
• CBC, SCr, CrCl, Hepatic Function Panel (4 weeks post treatment
initiation and as needed)1,2,3
• Quantitative HCV viral load (4 weeks post treatment initiation – if
detectable check after treatment week 6)
• Monthly Pregnancy Test (if RBV is used)
• Monitor for hypoglycemia if on diabetes medications
• Monitor INR closely if on warfarin
1Check panel at 8 weeks if receiving Elbasvir/Grazoprevir and again at 12 weeks if receiving therapy for 16 weeks
2Discontinue therapy if there is a 10‐fold increase in ALT or <10‐fold increase and symptomatic (weakness, vomiting,
jaundice, significantly increased bilirubin, ALP, or INR)
3Monitor at 2 week intervals if <10‐fold increase in ALT and asymptomatic, consider discontinuing DAA therapy if
persistently elevated
*For simplified therapy, refer to treatment section for specific monitoring and treatment algorithms.
Monitoring Parameters – Post Treatment*
• AASLD/IDSA. https://www.hcvguidelines.org/evaluate/monitor
Post‐ • Monitor for hypoglycemia if on diabetes medications
ing. Accessed
Treatment December 2, 2019.12 weeks post completion) to assess for
• Quantitative HCV Viral Load (>
sustained virologic response (SVR)
• Hepatic function panel
• Hepatocellular carcinoma surveillance twice yearly in F3‐F4
• Monthly pregnancy test (if RBV is used) for 6 months following treatment
*For simplified therapy, refer to treatment section for specific monitoring and treatment algorithms.
Determining Severity of Liver Disease
• Noninvasive Methods • Invasive Methods
– Physical exam of liver – Liver biopsy
– Blood tests (CBC with platelet —Determines amount and pattern
count, liver panel, bilirubin, INR) of scar tissue (collagen) in the liver
—AST to Platelet Ratio Index (APRI) along with severity of
– Serum fibrosis marker panels (e.g. inflammation, hepatic steatosis, or
FibroSURE) HCC
– Liver imaging (ultrasound, CT scan) —Metavir and Ishak fibrosis scores
– Transient elastography (e.g. derived from biopsy
Fibroscan) —Not routinely recommended
—Measures liver stiffness to
determine level of fibrosis
AASLD‐IDSA. https://www.hcvguidelines.org/evaluate/monitoring. Accessed November 18, 2021.
Metavir Fibrosis Scoring
Fibrosis (F) Extent of Fibrosis Interpretation
F0 No Fibrosis Absent Fibrosis
F1 Portal fibrosis without septa Mild Fibrosis
F2 Portal fibrosis with rare septa Significant Fibrosis
F3 Numerous septa, not cirrhosis Severe Fibrosis
F4 Cirrhosis
Bedossa P, Poynard T. Hepatology. 1996; 24:289‐293.
AST to Platelet Ratio Index (APRI)
• [(Patient’s AST / ULN AST1) x 100] / Platelets (109/L)
• <0.5: Rule out significant fibrosis (Metavir F0‐F1)
• >1.5: Rules in significant fibrosis (Metavir F2‐F4)
• >2.0: Probable cirrhosis (Metavir F4)
Loaeza‐del‐Castillo A et al. Ann Hepatology. 2008; 7:350‐357.
1 Commonly accepted value: 40 U/L
Wai CT et al. Hepatology. 2003; 38:518‐526.
Accelerated Fibrosis Progression
Host Factors
Non‐Modifiable Modifiable
Fibrosis stage Alcohol use
Inflammation grade Insulin resistance
Male gender Nonalcoholic fatty liver disease
Older age at time of infection Obesity
Organ transplantation
Viral Factors
Co‐infection with HBV and/or HIV
HCV genotype 3 infection
AASLD‐IDSA. http://www.hcvguidelines.org. Accessed November 18, 2021.
Determining Cirrhosis
• FIB‐4 score >3.25
– FIB‐4 = Age (years) x AST (U/L)
Platelet (109/L) x √ALT (U/L)
• Transient elastography indicating cirrhosis
– FibroScan > 12.5kPa
• Noninvasive serologic tests indicating cirrhosis
– FibroSure, Enhanced Liver Fibrosis Test, etc.
• Clinical evidence of cirrhosis
– Liver nodularity and/or splenomegaly on imaging, platelet count <150,000/mm3,
etc.
• Prior biopsy indicating cirrhosis
AASLD & IDSA. https://www.hcvguidelines.org/treatment‐naive/simplified‐treatment‐compensated‐cirrhosis. Accessed November 18, 2021.
Sterling RK. Hepatology 2006; 43:1317‐1325.
Segment 4
Viral Hepatitis:
HCV Treatment
A Guide to Oral HCV Medications
Generic Name + Standard Available Dose Brand Name Acronym
Elbasvir 50 mg/grazoprevir 100 mg Zepatier EBR/GZR

Glecaprevir 100 mg/pibrentasvir 40 mg Mavyret GLE/PIB
Ledipasvir 90 mg/sofosbuvir 400 mg Harvoni LDV/SOF
Ribavirin 200 mg CoPegus RBV
Sofosbuvir 400 mg Sovaldi SOF
Sofosbuvir 400 mg/velpatasvir 100 mg Epclusa SOF/VEL
Sofosbuvir 400 mg/velpatasvir 100 mg/ Vosevi SOF/VEL/VOX
Voxilaprevir 100 mg
Direct‐Acting Antivirals (DAAs)
Mechanism of Action Medications
NS3/4A Protease • Inhibits NS3/4A serine protease which disrupts HCV by Glecaprevir
Inhibitors blocking the NS3 catalytic site or the NS3/4A interaction
Grazoprevir
• High potency
• Low barrier to resistance Voxilaprevir
NS5A Inhibitors • Interferes with viral replication and assembly of the HCV virus Elbasvir
• High potency
Ledipasvir
• Intermediate barrier to resistance
Pibrentasvir
Velpatasvir
NS5B Nucleotide • Inhibits viral replication through the inhibition of HCV NS5B Sofosbuvir
polymerase inhibitor RNA polymerase
(NPI) • Intermediate potency
• High barrier to resistance
Viral Hepatitis:
Single Agents for HCV
Sofosbuvir
• Drug Class
– NS5B Nucleotide polymerase inhibitor
• Available Formulations
– 400 mg tablets
– Co‐formulated products: Epclusa, Harvoni, Vosevi
• Standard Dosing
– 400 mg PO daily
• Dosing in Renal/Hepatic Impairment
– No dosage recommendations available in patients with CrCl <30 mL/min, ESRD, or HD
• Administration Considerations
– Give with or without food
– Contraindicated in pregnancy and male partners of pregnant women when used with RBV
• Side Effects (reported in combination with other antiviral agents)
– Fatigue, headache, insomnia, pruritus, rash, hematologic (in combination with RBV)
• Drug Interactions
– Contraindicated: Amiodarone (symptomatic bradycardia), carbamazepine, modafinil, oxcarbazepine, phenobarbital,
primidone, rifabutin, rifampin, rifapentine, tipranavir
Sovaldi [package insert]. Foster City, CA: Gilead Sciences, Inc.; March 2020.
Ribavirin
• Drug Class
– Nucleoside analog
• Mechanism of Action
– Inhibits viral replication through viral protein synthesis inhibition
• Available Formulations (Various brand and generic formulations)
– 200 mg tablets or capsules (brand and generic); 400 and 600 mg tablets (brand); 40 mg/mL oral solution
(brand)
• Standard Dosing
– Weight‐based: >75 kg: 1200 mg daily (divided doses); <75 kg: 1000 mg daily (divided doses)
– Post‐liver transplantation, certain instances in decompensated cirrhosis: Start at 600 mg daily and increase
as tolerated
• Dosing in Renal/Hepatic Impairment (Based on formulation)
– CrCl 30‐50 mL/min: Alternate 200 mg and 400 mg every other day (Copegus)
– CrCl < 30 mL/min and ESRD requiring HD: 200 mg once daily (Copegus)
– CrCl < 50 mL/min: contraindicated (Rebetol)
Rebetol (ribavirin capsules) prescribing information. Whitehouse Station, NJ: Merck & Co., Inc.; January 2020.
Copegus (ribavirin capsules) [package insert]. South San Francisco, CA: Genentech USA, Inc.; August 2011.
Ribavirin
• Administration Considerations
– Give with food
– Contraindicated: Pregnancy and male partners of pregnant women;
hemoglobinopathies
• Side Effects (Numerous)
– Hemolytic anemia, teratogenic (2 forms of birth control must be used
during therapy and 6 months after its completion)
– Anorexia, fatigue, headache, insomnia, nausea, hematologic, pulmonary
dysfunction
• Drug Interactions
– Azathioprine (increased myelosuppression, monitor closely)
Managing Ribavirin Toxicity
No Cardiac History Cardiac History
Hemoglobin
↓ > 2 g/dL in 4‐weeks ‐‐‐ • Oral capsules, soln: ↓ dose by 200 mg daily
• Oral tablets: ↓ to 600 mg daily (200 mg in the
AM, 400 mg in the evening)
• Hgb <12 g/dL after 4 weeks of dose reduction,
permanently discontinue
8.5 to <10 g/dL ↓ to 600 mg daily (200 mg in the AM,
400 mg in the evening)
<8.5 g/dL Permanently discontinue Any time after dose reduction, permanently
discontinue
Platelets
<25,000/mm3 Permanently discontinue
White Blood Cells
WBC <1000/mm3, Permanently discontinue
neutrophils <500/mm3
Question 9: What regimen is most appropriate to use in a
treatment‐naïve patient without cirrhosis with HCV genotype 1b
(HCV viral load 10,256,986 International Units/mL) on
hemodialysis?
A. Ribavirin plus sofosbuvir for 12 weeks
B. Elbasvir/grazoprevir for 8 weeks
C. Glecaprevir/pibrentasvir for 8 weeks
D. Ledipasvir/sofosbuvir for 8 weeks
Viral Hepatitis:
Fixed‐Dose Combinations for HCV
Elbasvir/Grazoprevir (Zepatier)
Drug Class NS3/4A Inhibitor, NS5A Inhibitor
Available Formulation Elbasvir 50 mg/ Grazoprevir 100 mg tablet
Standard Dosing 1 tablet PO once daily
Dosing in Renal/Hepatic Impairment Contraindicated: Child‐Turcotte‐Pugh Class B or C
Administration Considerations • Give with or without food
• Genotype 1a: test for NS5A resistance‐
associated polymorphisms prior to treatment
Side Effects (reported in combination with SOF) Fatigue, headache, nausea, ALT elevations
Drug Interactions (numerous, refer to package insert) Contraindicated: Moderate and Strong CYP3A4
inhibitors and inducers
Zepatier [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; December 2019.
Glecaprevir/Pibrentasvir (Mavyret)
Drug Class NS3/4A Inhibitor, NS5A Inhibitor
Available Formulation Glecaprevir 100 mg/ Pibrentasvir 40 mg tablet
Standard Dosing 3 tablets PO once daily
Dosing in Renal/Hepatic Impairment Contraindicated: Child‐Turcotte‐Pugh Class C
Use not recommended: Child‐Turcotte‐Pugh Class
B
Administration Considerations Give with food
Side Effects Fatigue, headache, nausea
Drug Interactions (numerous, refer to package insert) Atazanavir, rifampin, and various other agents
Mavyret [package insert]. North Chicago, IL: AbbVie Inc.; May 2020.
Ledipasvir/Sofosbuvir (Harvoni)
Drug Class NS5B RNA Polymerase Inhibitor, NS5A Inhibitor
Available Formulation Ledipasvir 90 mg/ Sofosbuvir 400 mg tablet
Dosing in Renal/Hepatic Impairment No dosage recommendations available in patients with CrCl < 30 mL/min, ESRD, or
HD
Administration Considerations • Give with or without food
• Contraindicated in pregnancy and male partners of pregnant women when
used with RBV
Side Effects (reported in combination Fatigue, headache, weakness
with SOF)
Drug Interactions (numerous, refer to • Contraindicated: Amiodarone (symptomatic bradycardia), carbamazepine,
package insert) modafinil, oxcarbazepine, phenobarbital, primidone, rifabutin, rifampin,
rifapentine, tipranavir
• Separate: Antacids, H2‐blockers, and proton pump inhibitors
Harvoni [package insert]. Foster City, CA: Gilead Sciences, Inc.; March 2020.
Sofosbuvir/Velpatasvir (Epclusa)
Drug Class NS5B RNA Polymerase Inhibitor, NS5A Inhibitor
Available Formulation Sofosbuvir 400 mg/ Velpatasvir 100 mg tablet
Dosing in Renal/Hepatic Impairment No dosage recommendations available in patients
with CrCl < 30 mL/min, ESRD, or HD
Administration Considerations Give with or without food
Side Effects (reported in combination with other Fatigue, headache, nausea
antiviral agents)
Drug Interactions (numerous, refer to package insert) • Contraindicated: Amiodarone (symptomatic
bradycardia), CYP2B6 and CYP3A4 inducers,
and PPIs, refer to ledipasvir/sofosbuvir slide
• Separate: antacids and H2‐blockers
Epclusa [package insert]. Foster City, CA: Gilead Sciences, Inc.; July 2020.
Sofosbuvir/Velpatasvir/Voxilaprevir (Vosevi)
Drug Class NS3/4A Inhibitor, NS5B RNA Polymerase Inhibitor, NS5A
Inhibitor
Available Formulation Sofosbuvir 400 mg/ Velpatasvir 100 mg/ Voxilaprevir 100 mg
tablet
Dosing in Renal/Hepatic Impairment Use not recommended in Child‐Turcotte‐Pugh Class B and C
Administration Considerations Give with food
Side Effects (reported in combination Diarrhea, fa gue, headache, ↑ bilirubin
with other antiviral agents)
Drug Interactions (numerous, refer to • Contraindicated: Amiodarone (symptomatic bradycardia),
package insert) CYP2B6 and CYP3A4 inducers,
and PPIs, refer to ledipasvir/sofosbuvir slide
• Separate: antacids and H2‐blockers
Vosevi [package insert]. Foster City, CA: Gilead Sciences, Inc.; November 2019.
Question 10: What regimen is most appropriate to use in a
treatment‐naïve patient with compensated cirrhosis and HCV
genotype 3 (HCV viral load 8,145,724 International Units/mL and
no resistance)?
A. Ribavirin plus sofosbuvir for 24 weeks
B. Sofosbuvir/velpatasvir for 12 weeks
C. Glecaprevir/pibrentasvir for 16 weeks
D. Ledipasvir/sofosbuvir for 8 weeks
Viral Hepatitis:
HCV Treatment‐Naïve Options
Candidates for Simplified HCV Treatment in
Treatment‐Naïve Without Cirrhosis
• Who is Eligible • Who is NOT Eligible
– Prior HCV treatment
– Chronic HCV (any genotype) – Cirrhosis or likely cirrhosis
– No cirrhosis — FIBROSIS (FIB)‐4 >3.25
— APRI >2.0
– No previous treatment for HCV — Platelet Count <150,000/mm3
— Fibroscan stiffness >12.5 kPa
– Prior liver transplant recipient
– HIV diagnosis
– HBsAg positive
– Pregnancy
– Known or suspected hepatocellular
carcinoma
AASLD/IDSA. https://www.hcvguidelines.org/treatment‐naive/simplified‐treatment. Accessed November 18, 2021.
Treatment Options for Simplified HCV Treatment in
Treatment‐Naïve Without Cirrhosis
Treatment Options
Glecaprevir (300 mg)/Pibrentasvir (120 mg) for 8 weeks
OR
Sofosbuvir (400 mg)/Velpatasvir (100 mg) for 12 weeks
Pretreatment Assessment
• Calculate FIB‐4 score
• Ensure cirrhosis is not present
• Medication reconciliation
• Assess for potential drug‐drug interactions
• Educate the patient of proper administration, adherence, and prevention of reinfection
Within 6 months of treatment initiation
• CBC
• Hepatic function panel (albumin, total and direct bilirubin, ALT, AST)
• Calculated eGFR
Anytime prior to treatment initiation
• Quantitative HCV RNA (HCV viral load)
• HIV antigen/antibody test
• Hepatitis B surface antigen
Before Treatment Initiation
• Pregnancy test and counseling about risks of pregnancy while on HCV treatment for women of childbearing age
Monitoring
On‐treatment
• Monitor for hypoglycemia in patients taking diabetes medications
• Monitor INR in patients taking warfarin (potential for subtherapeutic concentrations)
• No laboratory monitoring is required for other patients
• Consider in‐person or telehealth visit, if needed (patient support, assess for side effects/new medications)
Post‐treatment
• Assess quantitative HCV RNA and hepatic function panel > 12 weeks following completion of HCV treatment to
confirm HCV RNA is undetectable (virologic cure) and transaminase normalizes
Follow‐up after SVR
• No liver‐related follow‐up recommended in patients who are noncirrhotic and achieve SVR
• Patients with ongoing risks should receive risk reduction counseling and tested for HCV RNA annually and
whenever elevations in AST, ALT, or bilirubin is present
• Advise patients to avoid excess alcohol use
Follow‐up for patients who do not achieve SVR
• Refer for retreatment
• Assess disease progression every 6‐12 months until retreatment occurs (CBC, hepatic function panel, and INR)
Candidates for Simplified HCV Treatment in
Treatment‐Naïve With Compensated Cirrhosis
• Who is Eligible • Who is NOT Eligible
– Chronic HCV (any genotype) – Current or previous decompensated
cirrhosis (Child‐Turcotte‐Pugh score
– Compensated cirrhosis (Child‐Pugh >7)
A) – Prior HCV treatment
– No previous treatment for HCV – ESRD (eGFR < 30mL/min/m2)
– HIV
– HBsAg positive
– Pregnancy
– Known or suspected hepatocellular
*Note: Patients with genotype 3 baseline NS5A resistance‐associated substitution must
be performed. Those without Y93H can be treated with 12 weeks of carcinoma
– Prior liver transplantation
sofosbuvir/velpatasvir
AASLD & IDSA. https://www.hcvguidelines.org/treatment‐naive/simplified‐treatment‐compensated‐cirrhosis. Accessed November 18, 2021.
Treatment Options for Simplified HCV Treatment in
Treatment‐Naïve With Compensated Cirrhosis
Treatment Options
Glecaprevir (300 mg)/Pibrentasvir (120 mg) for 8 weeks (GENOTYPES 1 – 6)
OR
Sofosbuvir (400 mg)/Velpatasvir (100 mg) for 12 weeks (All genotypes EXCEPT genotype 3*)
Pretreatment Assessment
• Calculate FIB‐4 score
• Calculate CTP score (decompensated cirrhosis with score > 7 and does not qualify for simplified treatment)
• Medication reconciliation
• Assess for potential drug‐drug interactions
• Educate the patient of proper administration, adherence, and prevention of reinfection
• Liver ultrasound to exclude HCC and subclinical ascites
• CBC, INR, hepatic function panel (albumin, total and direct bilirubin, ALT, AST)
• Calculated eGFR
Anytime prior to treatment initiation
• Quantitative HCV RNA (HCV viral load)
• HIV antigen/antibody test
• Hepatitis B surface antigen
• HCV genotype (if treating with sofosbuvir/velpatasvir)
Before Treatment Initiation
• Pregnancy test and counseling about risks of pregnancy while on HCV treatment for women of childbearing age
Monitoring
On‐treatment
• Blood test to monitor for liver injury since hepatic decompensation can occur (rarely) in patients with cirrhosis
• Refer to specialist if worsening bilirubin, AST, ALT, jaundice, ascites, encephalopathy, or new liver‐related symptoms
• Monitor for hypoglycemia in patients taking diabetes medications
• Monitor INR in patients taking warfarin (potential for subtherapeutic concentrations)
• Consider in‐person or telehealth visit, if needed (patient support, assess for side effects/new medications)
Post‐treatment
• Assess quantitative HCV RNA and hepatic function panel > 12 weeks following completion of HCV treatment to confirm HCV RNA is
undetectable (virologic cure) and transaminase normalizes
Follow‐up after SVR
• Liver US to assess for HCC (with or without alpha‐fetoprotein testing) every 6 months
• Upper endoscopic surveillance for esophageal varices
• Patients with ongoing risks should receive risk reduction counseling and tested for HCV RNA annually and whenever elevations in AST,
ALT, or bilirubin are present
• Advise patients to abstain from alcohol to avoid liver disease progression
Follow‐up for patients who do not achieve SVR
• Refer for retreatment
• Assess disease progression every 6‐12 months until retreatment occurs (CBC, hepatic function panel, and INR)
Question 11: A patient receiving once daily bictegravir/tenofovir
alafenamide/emtricitabine would like to start treatment for the
management of HCV. The patient is to start
glecaprevir/pibrentasvir. What is the most appropriate recommendation?
A. Bictegravir should be changed to dolutegravir in order to avoid drug‐drug interactions.
B. Bictegravir/tenofovir alafenamide/emtricitabine should be held until HCV therapy is
completed.
C. The patient may continue taking bictegravir/tenofovir alafenamide/emtricitabine while
on glecaprevir/pibrentasvir therapy.
D. Bictegravir/tenofovir alafenamide/emtricitabine should be changed to abacavir/lamivudine and
darunavir/cobicistat.
Genotype 1a Genotype 1b Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6
ELB/GZR
No Cirrhosis 12 weeks (no 12 weeks ‐‐‐ ‐‐‐ 12 weeks ‐‐‐ ‐‐‐
NS5A RASs)
Compensated Cirrhosis ‐‐‐ ‐‐‐ ‐‐‐ ‐‐‐ ‐‐‐
GLE/PIB
No Cirrhosis 8 weeks 8 weeks 8 weeks 8 weeks 8 weeks 8 weeks1 8 weeks1
Compensated Cirrhosis 8 weeks1 8 weeks1 8 weeks1 8 weeks1 8 weeks1
LDV/SOF
No Cirrhosis 12 weeks2 12 weeks2 ‐‐‐ ‐‐‐ 12 weeks5 12 weeks 12 weeks
Compensated Cirrhosis 12 weeks 12 weeks ‐‐‐ ‐‐‐ 12 weeks
SOF/VEL
No Cirrhosis 12 weeks 12 weeks 12 weeks 12 weeks 12 weeks 12 weeks 12 weeks6
Compensated Cirrhosis 12 weeks3,4
SOF/VEL/VOX
No Cirrhosis ‐‐‐ ‐‐‐ ‐‐‐ ‐‐‐ ‐‐‐ ‐‐‐ ‐‐‐
Compensated Cirrhosis ‐‐‐ ‐‐‐ ‐‐‐ 12 weeks ‐‐‐ ‐‐‐ ‐‐‐
1 For patients with HIV, 12 weeks is recommended
2 8‐weeks of therapy may be considered in HIV‐uninfected and whose HCV RNA <6 million IU/mL Green = Preferred Treatment; Yellow = Alternative Treatment
3 For patients without baseline NS5A RAS Y93H for velpatasvir
4 As an alternative regimen, add weight‐based RBV in patients with Y93H and compensated cirrhosis RASs: Resistance‐associated substitutions
5 8‐weeks of therapy may be considered in patients without cirrhosis, HCV RNA <6 million IU/mL, and absence of genotype 4r)
6 Not recommended in genotype 6e (if subtype is known)
AASLD/IDSA. https://www.hcvguidelines.org/treatment‐naive. Accessed November 18, 2021.
Mixed Genotypes
• Rare
• Data sparse with DAAs
• Use pangenotypic regimen
Question 12: A patient with decompensated cirrhosis and
HCV genotype 1a is treatment‐naïve. What is the most
appropriate therapy to initiate?
A. Ledipasvir/sofosbuvir with low initial dose of ribavirin x 24 weeks
B. Ribavirin plus sofosbuvir x 12 weeks
C. Sofosbuvir/velpatasvir with weight‐based ribavirin x 12 weeks
D. Elbasvir/grazoprevir x 24 weeks
Viral Hepatitis:
HCV Therapy for Decompensated Cirrhosis
Genotype 1 Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6
LDV/SOF
RBV‐Eligible 12 weeks1 ‐‐‐ ‐‐‐ 12 weeks1 12 weeks1 12 weeks1
RBV‐Ineligible 24 weeks ‐‐‐ ‐‐‐ 24 weeks 24 weeks 24 weeks
SOF/VEL
RBV‐Eligible 12 weeks2 12 weeks 12 weeks 12 weeks2 12 weeks2 12 weeks2
RBV‐Ineligible 24 weeks 24 weeks 24 weeks 24 weeks 24 weeks 24 weeks
1 Start with low dose RBV (600 mg) and increase as tolerated
2 Start with low dose RBV (600 mg) and increase as tolerated for Child‐Turcotte‐Pugh class C
AASLD & IDSA. https://www.hcvguidelines.org/unique‐populations/decompensated‐cirrhosis. Accessed November 18, 2021.
Viral Hepatitis:
HIV/HCV Co‐infection
Antiviral Drug Interactions
AVOID CAUTION
Elbasvir/Grazoprevir Cobicistat, efavirenz, etravirine, nevirapine, or HIV protease ‐‐‐
inhibitors
Glecaprevir/ Atazanavir, ritonavir‐containing regimens, efavirenz, etravirine
Pibrentasvir
Ledipasvir/Sofosbuvir ‐‐‐ ↑ renal monitoring with TDF
use
Ribavirin Didanosine, stavudine, zidovudine
Sofosbuvir Tipranavir
Sofosbuvir/Velpatasvir Efavirenz, etravirine, or nevirapine ↑ monitoring with TDF use
Sofosbuvir/Velpatasvir/ • Ritonavir‐boosted atazanavir, efavirenz, etravirine, or ↑ monitoring with TDF use
Voxilaprevir nevirapine
• Caution with darunavir/ritonavir and elvitegravir/cobicistat (no
data)
TDF = tenofovir disoproxil fumarate Current FDA‐approved product prescribing information.
Conclusions
• Drug therapy for viral hepatitis depends on various factors such as
the type of virus, antiviral resistance, presence of co‐infection, lab
test results, prior antiviral treatment, symptoms, disease severity,
renal and hepatic function, potential for drug interactions,
insurance coverage, and convenience
• Immunization is among the preventive strategies for viral hepatitis
caused by HAV and HBV
• Infectious diseases pharmacists play an important role in managing
drug therapy for patients with or at risk for viral hepatitis
Viral Hepatitis

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Viral

cccDNA: covalently closed circular double‐stranded DNA Gonzalez SA. http://www.antimicrobe.org/v22.asp#t5. Accessed November 18, 2021.

Hepatitis B Envelope Antigen HBeAg • Indicates active viral replication

Hepatitis B Virus DNA HBV DNA • How rapidly the virus is

CHB Normal or elevated Undetectable ‐ Positive Either (positive or Variable

AALSD: American Association for the Study of Liver Diseases Terrault NA et al. Hepatology. 2018; 67:1560‐1599.

AALSD: American Association for the Study of Liver Diseases Terrault NA et al. Hepatology. 2018; 67:1560‐1599.

HBeAg (+), HBV DNA May represent seroconversion

Lamivudine‐refractory, • CrCl 30‐49: 0.5 mg daily or 1 mg every 48 hours

Tenofovir Alafenamide • Creatinine Clearance, serum phosphate, • Creatinine Clearance, serum phosphate, urine glucose

Engerix‐B Hepatitis B 0‐19: 10 mcg (0.5 mL)

*Dialysis formulation CDC. https://www.cdc.gov/vaccines/pubs/pinkbook/hepb.html. Accessed November 18, 2021.

Pediarix DTaP, 6 weeks – 6 years: 10 3 2, 4, 6 months

AASLD/IDSA. https://www.hcvguidelines.org/evaluate/monitoring. Accessed November 18, 2021.

AASLD/IDSA. https://www.hcvguidelines.org/evaluate/monitoring. Accessed November 18, 2021.

Elbasvir 50 mg/grazoprevir 100 mg Zepatier EBR/GZR

RBV‐Eligible 12 weeks1 ‐‐‐ ‐‐‐ 12 weeks1 12 weeks1 12 weeks1

RBV‐Ineligible 24 weeks ‐‐‐ ‐‐‐ 24 weeks 24 weeks 24 weeks

RBV‐Eligible 12 weeks2 12 weeks 12 weeks 12 weeks2 12 weeks2 12 weeks2

RBV‐Ineligible 24 weeks 24 weeks 24 weeks 24 weeks 24 weeks 24 weeks

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