ID RC Viral Hep Workbook 2022 FINAL T229150

VIRAL HEPATITIS
David E. Koren, Pharm.D., M.P.H., BCPS, AAHIVP, FIDSA

Clinical Pharmacy Specialist
Temple University Health System
Philadelphia, Pennsylvania
LEARNING OBJECTIVES:
At the end of the presentation and after reviewing the accompanying reading materials, the participant
should be able to:
1. Assess pharmacotherapies for viral hepatitis, including relevant pharmacology and spectrum of
activity.
2. Select the most appropriate pharmacotherapeutic plan and monitoring based on patient- and
disease-specific information, virus and genotype, and best available evidence.
3. Interpret signs, symptoms, and laboratory and other relevant diagnostic test results.
4. Recommend modifications of patient-specific treatment plans based on efficacy, adverse
effects, and drug interactions.
5. Summarize key considerations in effective patient and caregiver education and counseling
techniques.
6. Identify screening guidelines and preventive therapies for viral hepatitis.
©2022 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 1
SELF-ASSESSMENT QUESTIONS
Answer key is provided at the end of this chapter.
1. A homeless individual comes to the Department of Health clinic fearing exposure to hepatitis. Serologies for
hepatitis A, B, and C are drawn and reveal the following:
Anti-HAV IgM: negative
Anti-HAV IgG: positive
Anti-HBs: positive
Anti-HBc: negative
HBsAg: negative
HCV Ab: negative
Which of the following is the most appropriate recommendation?
A. Hepatitis A vaccination is needed.
B. Hepatitis B vaccination is needed.
C. Hepatitis A and B vaccination is needed.
D. No vaccination is needed.
2. Which of the following regimens is most appropriate to initiate in a patient newly diagnosed with HIV and HBV
coinfection?
A. Tenofovir alafenamide/emtricitabine/bictegravir
B. Abacavir/lamivudine/dolutegravir
C. Abacavir/lamivudine + bictegravir
D. Rilpivirine/dolutegravir
3. What hepatitis C treatment regimen is most appropriately matched for treatment-naïve patients?
A. Ledipasvir/sofosbuvir – genotype 2
B. Elbasvir/grazoprevir – genotype 3
C. Glecaprevir/pibrentasvir – genotype 1
D. Sofosbuvir/velpatasvir/voxilaprevir – genotype 4
4. Which of the following hepatitis C therapies is most appropriate to use in a treatment-naïve patient with
genotype 3 decompensated cirrhosis?
A. Ledipasvir/sofosbuvir
B. Elbasvir/grazoprevir
C. Glecaprevir/pibrentasvir
D. Sofosbuvir/velpatasvir
2
5. Which of the following hepatitis C therapies is safe to administer with omeprazole 40 mg orally daily?
A. Ledipasvir/sofosbuvir
B. Elbasvir/grazoprevir
C. Sofosbuvir/velpatasvir
D. Sofosbuvir/velpatasvir/Voxilaprevir
VIRAL HEPATITIS: HEPATITIS A VIRUS (HAV)
SEGMENT 1
I. Just the facts1-3
A. Enveloped RNA virus
B. 24,900 new cases annually in the U.S.
C. Person-to-person transmission
1. Fecal-oral route
2. Contaminated food or water
D. Incubation period: 15-50 days (Average = 28 days)
E. Symptoms usually last less than 2 months (but can last as long as 6 months)
1. Abdominal pain, jaundice, pale stools, dark urine, loss of appetite
2. Considered an acute and not chronic infection
a. Chronic hepatitis is defined as inflammation of the liver lasting >6 months
3. Much more severe in adults vs. children
F. Also can be transmitted through sex or IV drug use
Patient Case #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.
Hepatitis Serologies:
Anti-HAV IgM: negative
Anti-HAV IgG: negative
Anti-HBs: positive
Anti-HBc: negative
HBsAg: negative
HCV Ab: negative
Question 1: Which of the following is the most appropriate recommendation regarding the immunization
requirements for this patient?
A. Immunization is not required; patient is not immune to hepatitis A (due to Anti-HAV IgM and IgG
results being negative).
B. Initiate Twinrix®.
C. Initiate Havrix®.
D. Obtain hepatitis A and B viral loads.
II. Risk factors for hepatitis A virus1-3
A. Travel to or living in an area with poor sanitation or lacking safe water
B. Men who have sex with men
C. Recreational drug use
D. Direct contact with an infected person
1. Living in same home
2. Sexual partner
E. Clotting factor disorders
F. Working with non-human primates
G. Most outbreaks have been due to homelessness and illicit drug use
III. Serologies3
Table 1. Hepatitis A 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
A. Total hepatitis A antibody is not useful for acute infection diagnosis
B. Diagnosis is established by the detection of serum IgM hepatitis A antibodies—indicates whether

there is current, recent, or acute infection
1. This will be detectable at the onset of symptoms and peak during early/convalescent phase of
the disease (remains detectable for 3-6 months)
C. IgG antibodies appear early in convalescent phase of disease and remain detectable for decades,
which reflects lifelong protective immunity (will always remain positive if patient was vaccinated or
previously exposed to it)
IV. Clinical course of hepatitis A virus4
Figure 1: Hepatitis A: Clinical Illness
A. Replicates in liver and excreted in bile
B. ALT level will be elevated when liver is inflamed and usually higher than AST
C. Phase 1: viral replication
D. Phase 2: prodromal phase (anorexia occurs here)
E. Phase 3: icteric phase (dark urine, pale stools, upper GI pain)
F. Phase 4: convalescent phase (symptoms usually resolve, liver enzymes end up returning back to
normal)
V. Management2
A. Self-limiting disease
B. Avoidance of acetaminophen
C. Supportive care
1. Antiemetics
2. Fluids to replete volume loss from vomiting and diarrhea
D. Fluid replacement is the most important thing to address and to avoid anything that can be harmful
to the liver
VI. Prevention2
A. Improved sanitary conditions
B. Safe access to water
C. Ensuring that appropriate food safety procedures are followed
D. Vaccination is going to be the most beneficial prevention technique
1. 2 doses given at least 6 months apart
E. Immune globulin – if exposure has occurred and no vaccination has been given
1. Single dose
Question 2: Hepatitis A vaccination is recommended in all of 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
VII. Who should be immunized against HAV3
A. All children ≥1 year of age
B. Persons with travel to areas with intermediate to high rates of infection
C. Men who have sex with men (MSM)
D. Illegal and injection drug users
E. Homeless
F. Persons with clotting-factor disorders
G. Persons working with HAV-infected primates or with HAV in a research laboratory
H. Persons with chronic liver disease, including HBV- and HCV-infected
I. Persons exposed as result of an outbreak
J. Persons who require post-exposure prophylaxis
VIII. Available vaccines5
Table 2: Vaccines
Product Coverage Dose Based on Age (Years) Number of Doses Timing of Doses
HAVRIX Hepatitis A 1-18: 720 Elisa Units (0.5 mL) 2 0, 6-12 months
≥19: 1440 Elisa Units (1 mL)
VAQTA Hepatitis A 1-18: 25 Units (0.5 mL) 2 0, 6-18 months
≥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)
A. HAVRIX may contain trace amount of neomycin and should be avoided in patients with known allergy
to this compound
IX. Administration considerations5 (protective antibodies usually develop in ~ 95% of adults after first
dose)
A. Inactivated vaccine
B. Hepatitis A vaccines considered interchangeable
C. Safe in pregnancy
D. Intramuscular (IM) injection in deltoid muscle
E. If the second dose is delayed, series does not need to be restarted
X. Pre-exposure prophylaxis6
Table 3: 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
• 0.2 mL/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 • Immune globulin should be added based
immunocompromised/ 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
XI. Post-exposure management6
A. Single dose of separate HAV vaccine or immune globulin (0.1 mL/kg). Twinrix should not be used due
to lower antigenic content
B. Administer as soon as possible and within 2 weeks of exposure
Table 4: Post-Exposure Agents by Age

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 • Immune globulin should only be
≥12 months + chronic liver disease globulin given if a provider’s risk
or immunocompromised assessment determines the
need for administration
VIRAL HEPATITIS: HEPATITIS B (HBV)
SEGMENT 2
I. Incidence of hepatitis B virus infection7
A. There were an estimated 21,600 new HBV infections in 2018 and an estimated 862,000 people living
with chronic HBV infection in 2016 within the U.S.
B. Rate of hepatitis B has been steadily declining due to vaccinations but did have a slight increase in
2014, most likely due to IV drug use
II. Hepatitis B lifecycle8
Figure 2: Hepatitis B Lifecycle
A. cccDNA: covalently closed circular double-stranded DNA
B. Encapsidation = critical step in life cycle that causes assembly of hepatitis B polymerase, pregenomic
RNA, and hepatitis B core protein into the nucleic capsid
C. Most medications are aimed at blocking reverse transcription
III. Hepatitis B facts7,9
A. A member of the Hepadnaviridae family
B. Percutaneous/mucosal transmission from infected blood or body fluids
C. Mother-to-child transmission during childbirth
D. Virus survives at least 7 days outside of the body
E. Incubation period: 60-150 days (average = 90 days)
F. Common symptoms of acute infection: similar to HAV
G. Treatment
1. Acute infection: supportive measures
2. Chronic infection: antiviral therapy
IV. Symptoms of chronic HBV infection7
A. Commonly asymptomatic
B. Ascites
C. Encephalopathy
D. Extrahepatic manifestations
1. Polyarteritis nodosa
2. Glomerular disease
E. Jaundice
F. Peripheral edema
G. Splenomegaly
H. Transaminitis
I. May take years to manifest into compensated or decompensated cirrhosis
V. Risk factors for HBV infection7
A. Direct contact with an infected person
1. Living in same home
2. Sexual partner
B. Mother-to-child transmission during childbirth
C. MSM
D. Occupational exposure to blood or blood-contaminated body fluids
E. Hemodialysis
VI. Consequences of untreated hepatitis (all types of hepatitis) 10
A. Cirrhosis
10
Table 5: Stages of Cirrhosis
Compensated Decompensated
Stage 1 No varices/ascites
Stage 2 Varices/no ascites
Stage 3 Ascites ± varices
Stage 4 Bleeding ± ascites
B. Hepatocellular carcinoma
C. 5-year survival with compensated cirrhosis is around 85%, while for decompensated it is around 14-
35%
VII. Child-Turcotte-Pugh (CTP) score11
A. Used to assess prognosis of liver disease and estimate cirrhosis severity
B. The lower the score = the longer the life expectancy
1. One point is allocated based on the presence or absence of each finding
Table 6: CTP Classifications

Class A Class B Class C
Points allocated1 1 point 2 points 3 points
Ascites None Mild-to-moderate (diuretic-responsive) Severe (diuretic-
refractory)
Hepatic encephalopathy None Grade I-II (or suppressed with medication) Grade III-IV (or refractory)
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
VIII. A key to hepatitis B serologies
Table 7: 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 and remains for life.
(Total)
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.
A. Helpful to tell you if there is active infection going on or if patient is vaccinated

B. Surface antibody can be positive if someone is vaccinated OR if someone started treatment and they
are recovering from the infection
11
C. Envelope antigen being negative represents no active replication is happening
IX. Initial work-up12-14
A. Complete medical/vaccination/family/social history and physical exam
B. Serologies
1. Diagnostic
a. HBsAg, HBV DNA, HCVAb, HDVAb, HIV
2. Therapeutic
a. HBeAb, HBeAg, HBsAg, HBV DNA
C. Biochemical Markers
1. Alpha-fetoprotein (AFP)
a. Alternative screening tool for hepatocellular carcinoma (HCC)
b. Liver ultrasound still preferred based on higher sensitivity, specificity, and diagnostic
accuracy compared to AFP
2. Aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT])
a. Markers of liver inflammation – typically elevated during acute and chronic viral hepatitis
b. Per AASLD guidelines, upper limit of normal (ULN) is 29-33 U/L for males and 19-25 U/L for
females
c. For guiding management of chronic hepatitis B (CHB), an ULN for ALT of 35 U/L for males
and 25 U/L for females is recommended
3. Alkaline phosphatase (ALP)
a. Commonly increased when bile ducts are blocked
4. Complete blood count (CBC)
a. Platelet count typically decreased with increased levels of fibrosis
5. Prothrombin time (PT) / International Normalized Ratio (INR)
a. Commonly elevated in advanced liver disease due to reduced production of coagulation

factors
6. Bilirubin
a. Elevation commonly due to red blood cell hemolysis or blocked bile ducts
7. Serum albumin and/or total protein
a. Commonly decreased in severe liver disease or malnutrition
8. Gamma globulins
D. Hepatic ultrasound
E. Fibrosis markers
12
1. Non-invasive
a. Fibroscan (measures stiffness by velocity of vibrations from the skin that bounce off the
liver; unreliable in obese, elderly, presence of ascites, or a metabolic syndrome), Fibrosure
(blood test that uses serum fibrosis markers in order to generate a score), APRI (AST divided
by normal limit of AST, then multiply by 100, then divide by platelet count to generate a
score)
2. Invasive (selected cases)
a. Liver biopsy
Question 3: Which of the following is the earliest serologic marker of hepatitis B infection?
A. HBeAg
B. Anti-HBc
C. HBV DNA
D. HBsAg
X. Hepatitis B serologies: acute infection15
Figure 3: Hepatitis B Serologies: Acute Infection
XI. Hepatitis B serologies: chronic infection15
Figure 4: Hepatitis B Serologies: Chronic Infection
13
XII. Interpreting hepatitis B serologies7,16,17
Table 8: Hepatitis B Serologies

Clinical State HBsAg Total Anti-HBs Total anti-HBc Action
(HBsAb) (HBcAb)
Chronic infection Positive Negative Positive Link to hepatitis B care
Acute infection Positive Negative Positive (IgM Link to hepatitis B care
anti-Hbc)
Resolved infection or immunity Negative Positive Positive Counseling, reassurance
due to exposure
Immune (due to immunization) Negative Positive Negative Reassurance
Susceptible to infection (never Negative Negative Negative Vaccinate
infected and no evidence of
immunization)
*Isolated core antibody Negative Negative Positive Depends on situation
* False positive: repeat testing; Past infection: no action; Occult HBV infection: if patient ever becomes
immunocompromised or receives chemotherapy or treatment for hepatitis C with direct acting antiviral therapy
consider monitoring HBV DNA; Passive transfer to infant born to HBsAg-positive mother: no action
XIII. Phases of chronic hepatitis B (CHB)12,13
Table 9: Phases of Chronic Hepatitis B (CHB)

Phases ALT HBV DNA (IU/mL) HBsAg HBeAg Liver Histology
14
CHB Normal or Undetectable to Positive Either Variable
elevated several billion (>6 months) (positive or necroinflammation
• HBeAg (+) negative) and/or fibrosis
>20,000
• HBeAg (-) 2000-
20,000
Immune- Normal or Elevated Positive Positive Minimal

tolerant CHB elevated (>1 billion) (>6 months) inflammation;
no fibrosis
Immune- Elevated • HBeAg (+) Positive Either Moderate-severe
active CHB (intermittent >20,000 (>6 months) (positive or necroinflammation
or persistent) • HBeAg (-) >2000 negative) + fibrosis
Inactive CHB Normal Low or undetectable Positive Negative Minimal

(>6 months) (HBeAb) necroinflammation
with variable
fibrosis
A. A single ALT and viral load will not properly classify the phase of chronic hepatitis B – seromonitoring
is necessary
Question 4: In an otherwise healthy individual, which of the following patient scenarios 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
XIV. When to initiate HBV treatment: HBeAg (+)12,13
Table 10: HBeAg (+): Initiating Treatment

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 ---
--- --- Cirrhosis
AALSD: American Association for the Study of Liver Diseases; EASL: European Association for the Study of the Liver;
ULN: Upper limit of normal (29-33 units/L for males and 19-25 units/L for females)
XV. When to initiate HBV treatment: HBeAg (-)12,13
Table 11: HBeAg (-): Initiating Treatment

HBV DNA (IU/mL) ALT Extent of Liver Disease
AASLD ≥2,000 ≥2x ULN ---
--- --- Cirrhosis
EASL >2,000 Any ALT elevation and/or moderate inflammation or fibrosis
15
>20,000 >2x ULN ---
--- --- Cirrhosis
XVI. Assessing response to HBV treatment13
Table 12: Assessing Response to HBV Treatment

Virologic Response Nucleos(t)ide Analogues Pegylated interferon-α
Full Undetectable HBV DNA (<10 IU/mL) HBV DNA levels <2,000 IU/mL at
6 months and end of therapy
Non-response <1 log10 decrease in HBV DNA after 3 months
Partial >1 log10 decrease in HBV DNA but detectable HBV
DNA after at least 12 months
Breakthrough >1 log10 increase in HBV DNA compared with
nadir
Resistance Amino acid substitutions conferring reduced
susceptibility
Off therapy HBV DNA <2,000 IU/mL for at least 12 months post-therapy
Serologic Response Goals
HBeAg loss and development of HBeAb (anti-HBe) (Only in HBeAg-positive)
HBsAg loss and development of HBsAb (anti-HBs) (All patients)
Biochemical Response
ALT normalization (followed every 3 months for at least 1 year)
Histologic Response
Decrease in necroinflammatory activity without worsening in fibrosis when compared with pretreatment
findings
A. Want HBV DNA viral load to be undetectable
XVII. Recommended time frames for follow-up with patients with HBV not receiving treatment13
Table 13: Follow-up: No Treatment

Clinical Parameters Follow-up Period
HBeAg (+), <30 years of age, and do not fulfill 3-6 months
treatment criteria
HBeAg (+), HBV DNA 2000 IU/mL to 20,000 May represent seroconversion. Monitor every 1-3 months
IU/mL If persists > 6 months, initiate treatment
HBeAg (-), HBV DNA <2000 IU/mL 6-12 months
HBeAg (-), HBV DNA >2000 IU/mL 3 months for the first year, then every 6 months
XVIII. Timeline for HBV therapy approval
A. 1992: Interferon-α
B. 1998: Lamivudine
C. 2002: Adefovir
D. 2005: Entecavir; pegylated interferon-α
E. 2006: Telbivudine
16
F. 2008: Tenofovir disoproxil fumarate
G. 2016: Tenofovir alafenamide
Patient Case #2:

MO has an extensive treatment history for seizures and was recently initiated on phenytoin. MO’s provider
would like to start Hepatitis B therapy.
Question 5: What agent is most appropriate to initiate?

A. Adefovir
B. Lamivudine
C. Tenofovir alafenamide
D. Tenofovir disoproxil fumarate
XIX. Preferred for HBV treatment initiation: nucleos(t)ide analogues (NAs) 12,13
Table 14: HBV Treatment: NAs

Generic (Brand) Name Oral Dosing Dosing in Renal/Hepatic Impairment
Entecavir (Baraclude) Nucleoside treatment- CrCl 30-49: 0.25 mg daily or 0.5 mg every 48 hours
naïve: 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 CrCl <10, HD* or CAPD: 0.1 mg daily or 1 mg every 7 days
disease: 1 mg daily
Tenofovir 25 mg daily CrCl <15 : Use not recommended unless receiving chronic
alafenamide** hemodialysis
(Vemlidy) (TAF)
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
* Administer post-HD
** TAF has been shown to be associated with less bone and kidney adverse drug effects compared to TDF
CAPD: Continuous ambulatory peritoneal dialysis; CrCl: Creatinine clearance (mL/min); HD: Hemodialysis
XX. Guideline-recommended HBV treatment initiation12,13
Table 15: HBV Treatment Initiation

Generic (Brand) Normal Dosing Dosing in Renal/Hepatic Dosing in the Presence of Toxicity
Name Impairment
Pegylated interferon- 180 mcg CrCl <30 or HD*: 135 mcg ANC 500 to <750/mm3: 135 mcg
α, peginterferon subcutaneously once weekly once weekly
(Pegasys)** once weekly for Contraindicated in ANC <500/mm3: Hold until ANC >
48 weeks autoimmune hepatitis and 1000/mm3, resume at 90 mcg once
hepatic decompensation weekly
ALT >5x ULN: 135 mcg once Platelets 25,000 to <50,000/mm3: 90
weekly or temporarily mcg once weekly
discontinue Platelets <25,000/mm3: Discontinue
17
ALT >10 x ULN: DiscontinueMild 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
*Reduce dose to 90 mcg once weekly in HD patients with severe side effects or lab abnormalities
**Not usually used due to high level of adverse events and administration concerns
XXI. Alternative agents for HBV treatment12,13
Table 16: HBV Treatment Alternatives

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
*Many practitioners use full dose lamivudine in the setting of renal impairment since the risk of toxicity is very low
XXII. Mechanisms of action13
A. Nucleos(t)ide analogues
1. Intracellularly phosphorylated  inhibits hepatitis B viral polymerase  blocks reverse

transcriptase  reduces viral DNA synthesis
B. Pegylated interferon-α
1. Exact mechanism unknown
2. Believed to interfere with virus entry, virion uncoating, transcription of viral RNA into proteins,
and assembly of nucleocapsids
3. May augment cell-mediated immunity
4. Produces higher rates of HBeAg and HBsAg loss along with a durable response
XXIII. Nucleos(t)ide analogue therapy Vs. PegIFN13
A. Nucleos(t)ide analogue therapy
1. Advantages
a. High barrier to resistance with entecavir and both tenofovir formulations
b. Long-term efficacy
c. Safety profile
18
d. Only treatment option
1) Decompensated liver disease
2) Liver transplants
3) Extrahepatic manifestations
4) Acute or severe chronic exacerbation
5) Prevention of reactivation in patients receiving immunosuppression or transmission in

those with high viremia
B. PegIFN
1. Advantages
a. No concerns for resistance
b. Finite duration of treatment (48 weeks)
c. Long-term immunologic control
2. Disadvantages
a. Variability of response
b. Numerous adverse effects
XXIV. Research comparing TAF vs. TDF in chronic HBV infection18,19
A. TAF non-inferior to TDF at weeks 48 and 96 in CHB based on HBV DNA
B. No resistance in either TAF or TDF
C. Significantly higher rate of ALT normalization with TAF
D. For HBeAg-positive: higher rate of seroconversion at week 96 compared to 48 with both TAF and TDF
E. For HBeAg-negative: minimal decline from baseline in HBsAg with either TDF or TAF
F. Tenofovir alafenamide (TAF)
1. Lower dosage requirements
2. Lower systemic exposure
3. Fewer renal and bone effects
4. No dosage reduction needed until CrCl <15 mL/min
G. Tenofovir disoproxil fumarate (TDF)
1. Fewer drug-drug interactions (such as with the patient in previous question that was being
started on RIPE therapy)
Patient Case #2, continued:
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.
19
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.
XXV. HBV treatment adverse effects
Table 17: Adverse Effects of Treatment

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 serum creatinine,
fumarate* 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
XXVI. HBV treatment drug interactions
Table 18: HBV Treatment Drug Interactions

Treatment Contraindication 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- Ledipasvir, velpatasvir, NSAIDs
fumarate formulated tenofovir
products
Pegylated interferon-α Tizanidine
Adefovir Tenofovir
Lamivudine Emtricitabine Sorbitol
XXVII. Current FDA-approved product prescribing information20-25
Table 19: Product Prescribing Information

Treatment HBV Pretreatment Monitoring HBV On-Treatment Monitoring Parameters
Entecavir --- Lactic acid (if concern for lactic acidosis)
Tenofovir Creatinine clearance, serum Creatinine clearance, serum phosphate, urine
Alafenamide phosphate, urine glucose and protein glucose and protein (annually or as indicated)
Tenofovir Creatinine clearance, serum Creatinine clearance, serum phosphate, urine
Disoproxil phosphate, urine glucose and protein, glucose and protein (annually or as indicated)
Fumarate bone density (fracture history or risk Bone density (as clinically indicated)
for osteopenia) Lactic acid (if concern for lactic acidosis)
20
Pegylated --- CBC (every 1-3 months)
interferon-α 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)
XXVIII. Discontinuation of HBV therapy13
A. Nucleos(t)ide analogues
1. Confirmed HBsAg loss ± HBsAb seroconversion
2. Non-cirrhotic HBeAg-positive patients with chronic HBV and stable HBeAg seroconversion +
undetectable HBV DNA + completed at least 12 months of therapy
3. Selected non-cirrhotic HBeAg-negative patients with long-term virologic suppression (≥3 years)
as long as close monitoring is maintained
4. Higher rates of relapse occur with discontinuation of therapy
B. PegIFN
1. After 48 weeks
XXIX. Causes of hepatitis B virus reactivation (HBVr)
A. Receipt of chemotherapy, solid organ or bone marrow transplantation
B. Receipt of immunosuppressive therapy
1. Rituximab
2. High-dose steroids
3. Anti-tumor necrosis factor (TNF) agents
C. Discontinuation of HBV agents, especially if co-infected with HIV
D. Co-infection with HCV
1. Treatment with direct-acting antivirals (DAAs)  BOXED WARNING
E. Spontaneous
F. Reactivation could result in development of secondary symptoms related to the liver and could lead
to death
G. Risk of HBV reactivation7
Table 20: Risk of HBV reactivation

Variable High Risk Moderate Risk Low Risk
21
Definition Anticipated incidence Anticipated incidence of Anticipated incidence of
of HBVr >10% HBVr 1-10% HBVr <1%
Causative drugs • B cell–depleting • Tumor necrosis factor α • Traditional
agents inhibitors immunosuppression
• Anthracycline • Cytokine or integrin • Intra-articular
derivatives inhibitors corticosteroids
• High-dose • Tyrosine kinase • Systemic corticosteroids for
corticosteroids (≥20 inhibitors <1 wk
mg prednisone for ≥4 • High-dose
wk) corticosteroids (≥20 mg
prednisone for ≥4 wk)
Screening for HBsAg and anti-HBc, HBsAg and anti-HBc, • Routine screening not
serological markers followed by HBV DNA, if followed by HBV DNA, if recommended by AGA
positive positive • All individuals requiring
immunosuppressive
therapy should be
screened for HBsAg,
according to the CDC
Prophylaxis needed Yes Yes No
Monitoring Yes, for 6-12 months Yes, for 6-12 months Yes, every 1-3 months
after discontinuing after discontinuing
prophylaxis; then prophylaxis; then
occasionally long term occasionally long term
XXX. Antiviral resistance26
A. Risk factors
1. High baseline HBV DNA
2. Slow decline in HBV DNA
3. Prior suboptimal treatment with nucleos(t)ide analogue
B. Perform genotypic resistance testing in multidrug resistance
C. Entecavir, TAF, and TDF have high genetic barriers to resistance
D. Resistance spectrum
1. Lamivudine > Adefovir > Entecavir > TAF/TDF
XXXI. Managing antiviral resistance in HBV12,13
Table 21: 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
22
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
4
Drug no longer available in the US
XXXII. HIV and HBV co-infection27
A. Accelerated progression to cirrhosis, end-stage liver disease, and hepatocellular carcinoma (HCC)
B. Initiate antiretroviral therapy regardless of CD4 count
C. Treatment should be for both HIV and HBV
1. A fully active antiretroviral (ARV) regimen should be used
D. Agents with activity against both HIV and HBV
1. Tenofovir (both disoproxil fumarate and alafenamide)
2. Lamivudine (cross-resistance to emtricitabine)
3. Emtricitabine (cross-resistance to lamivudine)
E. Single-tablet regimens
1. Atripla
a. Efavirenz/tenofovir disoproxil fumarate/emtricitabine
2. Biktarvy
a. Bictegravir/tenofovir alafenamide/emtricitabine
3. Complera
a. Rilpivirine/tenofovir disoproxil fumarate/emtricitabine
4. Delstrigo
a. Doravirine/tenofovir disoproxil fumarate/emtricitabine
5. Genvoya
a. Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine
6. Odefsey
a. Rilpivirine/tenofovir alafenamide/emtricitabine
7. Stribild
a. Elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine
F. Medications that should be combined with additional ARVs
1. Descovy
a. Tenofovir alafenamide/emtricitabine
2. Truvada
23
a. Tenofovir disoproxil fumarate/emtricitabine
G. If patient is living with HIV, must add in a third agent with the TAF/TDF and emtricitabine to make
sure there is a full antiretroviral regimen
XXXIII. Choosing between HBV therapies12,13
A. No comorbidities, decompensated cirrhosis, HBV/HCV co-infection, nucleoside-naïve
1. Entecavir
2. TAF
3. TDF
B. Elderly patients, risk of preexisting bone or renal disease
1. Entecavir
a. Preferred in CrCl <15 mL/min; less expensive generic available
2. TAF
a. Preferred in HIV/HBV coinfection; prior nucleoside exposure
b. Use not recommended if CrCl <15 mL/min unless patient is receiving chronic hemodialysis
(HD)
1) TAF should be administered after HD for those receiving chronic HD
XXXIV. Antiviral therapy choice with comorbidities12,13
Table 22: Antiviral Therapy Choices For Patients With Comorbidities

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
XXXV. Who should be immunized against HBV—EVERYONE28
A. Per CDC Advisory Committee on Immunization Practice meeting on November 3rd 2021, all adults
between 19-59 should be immunized against the Hepatitis B Virus
24
B. Adults over 60 should continue to follow risk-based assessments
1) Persons at risk for infection by sexual exposure
2) Persons at risk for infection by percutaneous or mucosal exposure to blood
3) Other
a) International travelers to areas of high endemicity
b) Persons with Hepatitis C infection
c) Persons with Chronic Liver Disease
d) Persons with HIV infection
e) Incarcerated persons
f) All other persons seeking protection against HBV
XXXVI. Single-antigen HBV vaccines29
Table 23: 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
XXXVII. Combination vaccines29
Table 24: Combination HBV Vaccines

Product Coverage Dose Based on Age Number of Doses Timing of Doses
TWINRIX Hepatitis A + B ≥18 years: 20 mcg 3 0, 1, 6 months
(1 mL) 4 0, 7, 21-30 days,
12 months (booster
of HBV only)
Pediarix DTaP, Hepatitis B, 6 weeks-6 years: 10 3 2, 4, 6 months
inactivated polio mcg (0.5 mL)
Dtap: diphtheria, tetanus, and acellular pertussis
XXXVIII. Administration considerations29
A. Intramuscular administration
B. Postvaccination serologic testing recommended

25
1. Patients receiving hemodialysis
2. Immunocompromised patients including HIV
3. Sex partners of HBsAg-positive persons
4. Infants born to HBsAg-positive women
C. Booster doses may be required and administered if anti-HBs levels fall below 10 mIU/mL
1. Patients receiving hemodialysis
2. Immunocompromised patients
XXXIX. HBV vaccine non-responders
A. Risk factors for non-response
1. Vaccine factors (dose, schedule, vaccination site)
2. Age ≥40 years
3. Male gender
4. Obesity
5. Smoking
6. Chronic illness
B. Management
1. Repeat a second series of 3 doses
2. Given doses on a schedule of 0, 1, and 6 months
3. Retest 1-2 months after repeat HBV vaccination
4. If still no response, check HBsAg
XL. HBV postexposure prophylaxis30
A. Administer within 12-24 hours after exposure
Table 25: HBV Postexposure Prophylaxis

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
26
VIRAL HEPATITIS: HEPATITIS C VIRUS (HCV)
SEGMENT 3
I. Global prevalence of hepatitis C virus31,32
Figure 4: Global Prevalence of Hepatitis C Virus
A. Dark areas = higher rates of infection
B. 2011-2015 had increase due to opioid epidemic
II. Worldwide distribution of HCV based on genotype33
Figure 5: HCV Distribution Based on Genotype
27
III. Hepatitis C lifecycle34
A. Viral entry
B. Uncoating and translation
C. Viral replication
D. Viral assembly and release
IV. Hepatitis C facts35
A. Single-stranded RNA virus in the Flaviviridae family
B. 2.4 million people in the U.S. have chronic HCV
C. 15-25% of those with HCV clear the virus without treatment
D. Percutaneous transmission
1. Injection drug use
2. Received donated blood, blood products, or organs prior to 1992
3. Needlestick injuries
4. Born to HCV-infected mother
5. Sex with an HCV-infected person
6. Sharing personal items with infected blood
Question 7: For which of the following individuals should HCV screening be performed?
A. An individual who is actively injecting substances
B. Individuals who were born between 1945 and 1965
C. An individual who required a blood transfusion in 1996
D. An individual with hemophilia who received clotting factors in 1992
V. Recommended testing for HCV35
A. One time screening for all adults greater than 18 years of age
B. Pregnant women during each pregnancy
C. People who have ongoing risk factors (e.g. persons who inject drugs, share needles or other
preparatory equipment, or who have selected medical conditions including receiving maintenance
hemodialysis) should be tested routinely
VI. Symptoms of HCV35
A. Acute
1. Commonly asymptomatic but may experience mild symptoms (fatigue, abdominal pain, poor
appetite, jaundice)
B. Chronic
28
1. Commonly asymptomatic
2. Typically insidious over several decades but can progress to cirrhosis and HCC
3. HBV and HIV co-infection can accelerate the progression of liver injury and are often associated
with poor outcomes
VII. HCV testing and diagnosis – relies largely on antibody testing and viral loads36
Table 26: HCV Testing and Diagnosis

Test Outcome Interpretation Further Actions
HCV antibody nonreactive No HCV antibody Sample can be reported as nonreactive for HCV antibody.
detected No further action required. If recent exposure in person
tested is suspected, test for HCV RNA*.
HCV antibody reactive Presumptive HCV A repeatedly reactive result is consistent with current HCV
infection infection, or past HCV infection that has resolved, or
biologic false positivity for HCV antibody. Test for HCV RNA
to identify current infection.
HCV antibody reactive, Current HCV Provide person tested with appropriate counseling and link
HCV RNA detected infection person tested to care and treatment†.
HCV antibody reactive, No current HCV No further action required in most cases. If distinction
HCV RNA not detected infection between true positivity and biologic false positivity for HCV
antibody is desired, and if sample is repeatedly reactive in
the initial test, test with another HCV antibody assay. In
certain situations§, follow up with HCV RNA testing and
appropriate counseling.
* If HCV RNA testing is not feasible and person tested is not immunocompromised, do follow-up testing for HCV
antibody to demonstrate seroconversion. If the person tested is immunocompromised, consider testing for HCV
RNA.
† It is recommended before initiating antiviral therapy to retest for HCV RNA in a subsequent blood sample to
confirm HCV RNA positivity.
§ If the person tested is suspected of having HCV exposure within the past 6 months, or has clinical evidence of
HCV disease, or if there is concern regarding the handling or storage of the test specimen.
VIII. Chronic HCV infection15
Figure 6: Chronic HCV Infection
29
A. Fluctuating ALT levels indicate varying times when there is liver inflammation that occurs
B. Typically takes 10-11 weeks to detect hepatitis C antibodies, and usually remains positive for life
C. Hepatitis C RNA can be detectable 1-2 weeks after exposure
IX. Goals of therapy for HCV37
A. Reduce all-cause mortality and liver-related adverse health outcomes (including end-stage liver
disease and HCC)
B. Achieve Sustained Virologic Response (SVR)
1. Marker of cured infection
2. Undetectable viral load (HCV RNA) at least 12 weeks after completing treatment
3. Undetectable viral load considered ≤25 IU/mL or lower
Question 8. Which of the following patients does NOT meet the 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
X. Treatment recommendations37
A. ALL PATIENTS with chronic HCV infection due to mortality benefit
30
B. Exceptions include those with a short life expectancy that cannot be lengthened with HCV therapy,
liver transplantation, or other therapy
XI. Monitoring parameters for those who do not meet criteria for simplified treatment37
Table 27: Treatment Monitoring Parameters

Treatment Phase Parameters
Pretreatment (within 6 • Complete blood count (CBC)
months prior to treatment • International normalized ratio (INR)
initiation) • Hepatic function panel (i.e., albumin, total and direct bilirubin, ALT, AST,
alkaline phosphatase levels)
• Serum creatinine and calculated glomerular filtration rate
Pretreatment (any time • Quantitative HCV viral load
prior to treatment • Staging of hepatic fibrosis
initiation) • Drug-drug interactions
• Genotype and subtype (if non-pan-genotypic, DAA will be prescribed)
• Assess for HBV (HBsAg, HBcAb, HBsAb) and HIV co-infection
• Child-Turcotte-Pugh (CTP) Scoring
Resistance Testing (prior to Elbasvir/grazoprevir • NS5A RAS testing recommended for treatment-naïve
treatment) 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
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)a-c
• 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
Post-treatment • Monitor for hypoglycemia if on diabetes medications
• Quantitative HCV viral load (>12 weeks post completion) to assess for
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
a
Check panel at 8 weeks if receiving elbasvir/grazoprevir and again at 12 weeks if receiving therapy for 16 weeks
31
b
Discontinue 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)
c
Monitor at 2-week intervals if <10-fold increase in ALT and asymptomatic, consider discontinuing DAA therapy if
persistently elevated
XII. Determining severity of liver disease37-40
A. Features of liver fibrosis
1. Fibrosis is a common sign of chronic hepatitis
2. Chronic inflammation causes the production and accumulation of collagen and extracellular
matrix proteins
3. Fibrosis is a precursor for cirrhosis
B. Noninvasive/minimally invasive methods
1. Physical exam of liver
2. Blood tests (CBC with platelet count, liver panel, bilirubin, INR)
a. AST to Platelet Ratio Index (APRI)
3. Serum fibrosis marker panels (e.g., FibroSURE)
4. Liver imaging (ultrasound, CT scan)
a. Ultrasound useful for HCC screening every 6-12 months
5. Transient elastography (e.g., Fibroscan)
a. Measures liver stiffness to determine level of fibrosis
b. Results can be confounded by factors such as obesity, alcohol consumption, ascites
C. Invasive methods
1. Liver biopsy
a. Determines amount and pattern of scar tissue (collagen) in the liver along with severity of
inflammation, hepatic steatosis, or HCC
b. Metavir and Ishak fibrosis scores derived from biopsy
c. Considered gold standard for diagnosis but is limited by its invasive nature
D. Metavir Fibrosis Scoring
Table 28: 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
E. APRI
32
1. [(Patient’s AST / ULN AST1) x 100] / Platelets (109/L)]
2. <0.5: Rule out significant fibrosis (Metavir F0-F1)
3. >1.5: Rules in significant fibrosis (Metavir F2-F4)
4. >2.0: Probable cirrhosis (Metavir F4)
a. Commonly accepted value for this equation: 40 U/L
XIII. Accelerated fibrosis progression
A. Host factors
Table 29: Host Factors in Fibrosis Progression

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
B. Viral Factors
1. Co-infection with HBV and/or HIV
2. HCV genotype 3 infection
C. Determining Cirrhosis
1. FIB-4 score >3.25
a. FIB-4 = Age (years) x AST (U/L)
Platelet (109/L) x √ALT (U/L)
2. Transient elastography indicating cirrhosis
a. FibroScan >12.5kPa
3. Noninvasive serologic tests indicating cirrhosis
a. FibroSure, Enhanced Liver Fibrosis Test, etc.
4. Clinical evidence of cirrhosis
a. Liver nodularity and/or splenomegaly on imaging, platelet count <150,000/mm3, etc.
5. Prior biopsy indicating cirrhosis
33
VIRAL HEPATITIS: HCV TREATMENT
I. A guide to oral HCV medications
Table 30: 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/voxilaprevir 100 mg Vosevi SOF/VEL/VOX
II. Direct-Acting Antivirals (DAAs)
Table 31: Direct-Acting Antiviral Medications

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
• Barrier to resistance dependent on the generation Voxilaprevir
NS5A inhibitors • Interferes with viral replication and assembly of the HCV Elbasvir
virus Ledipasvir
• High potency Pibrentasvir
• Intermediate barrier to resistance Velpatasvir
NS5B nucleotide • Inhibits viral replication through the inhibition of HCV Sofosbuvir
polymerase NS5B RNA polymerase
inhibitor (NPI) • Intermediate potency
• High barrier to resistance
DAAs = Molecules that work to target specific proteins of the virus and disrupt replication
34
VIRAL HEPATITIS: SINGLE AGENTS FOR HCV
I. Sofosbuvir41
A. Drug class
1. NS5B nucleotide polymerase inhibitor
B. Available formulations
1. 400-mg tablets
2. Co-formulated products: Epclusa, Harvoni, Vosevi
C. Standard dosing
1. 400 mg PO daily
D. Dosing in renal/hepatic impairment
1. No dosage recommendations available in patients with CrCl <30 mL/min, ESRD, or HD
E. Administration considerations
1. Give with or without food
2. Contraindicated in pregnancy and male partners of pregnant women when used with RBV
F. Side effects (reported in combination with other antiviral agents)
1. Fatigue, headache, insomnia, pruritus, rash, hematologic (in combination with RBV)
G. Drug interactions
1. Contraindicated: Amiodarone (symptomatic bradycardia), carbamazepine, modafinil,

oxcarbazepine, phenobarbital, primidone, rifabutin, rifampin, rifapentine, tipranavir
II. Ribavirin42,43
A. Drug class
1. Nucleoside analog
B. Mechanism of action
1. Inhibits viral replication through viral protein synthesis inhibition
C. Available formulations (various brand and generic formulations)
1. 200-mg tablets or capsules (brand and generic); 400- and 600-mg tablets (brand); 40 mg/mL oral
solution (brand)
D. Standard dosing
1. Weight-based: ≥75 kg: 1200 mg daily (divided doses); <75 kg: 1000 mg daily (divided doses)
2. Post-liver transplantation, certain instances in decompensated cirrhosis: Start at 600 mg daily

and increase as tolerated
E. Dosing in renal/hepatic impairment (based on formulation)
1. CrCl 30-50 mL/min: alternate 200 mg and 400 mg every other day (Copegus)
35
2. CrCl <30 mL/min and ESRD requiring HD: 200 mg once daily (Copegus)
3. CrCl <50 mL/min: contraindicated (Rebetol)
F. Administration considerations
1. Give with food
2. Contraindicated: pregnancy and male partners of pregnant women; hemoglobinopathies
G. Side effects (numerous)
1. Hemolytic anemia, teratogenic (2 forms of birth control must be used during therapy and 6
months after its completion)
2. Anorexia, fatigue, headache, insomnia, nausea, hematologic, pulmonary dysfunction
H. Drug interactions
1. Azathioprine (increased myelosuppression, monitor closely)
III. Managing ribavirin toxicity43
Table 32: 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: Which of the following regimens is most appropriate to use in a treatment-naïve patient that is
non-cirrhotic with HCV genotype 1b (HCV viral load 10,256,986 IU/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
36
VIRAL HEPATITIS: FIXED DOSE COMBINATIONS FOR HCV
I. Elbasvir/grazoprevir (Zepatier)44
A. Drug Class
1. NS3/4A inhibitor, NS5A inhibitor
B. Available formulation
1. Elbasvir 50 mg/grazoprevir 100 mg tablet
C. Standard dosing
1. 1 tablet PO once daily
2. Used for genotype 1 or 4 infection
3. Treatment usually lasts around 12 weeks, unless there is resistance – may need to extend
treatment to 16 weeks and weight-based RBV should be added
1. Contraindicated: Child-Turcotte-Pugh Class B or C
2. In genotype 1a patients, test for NS5A resistance-associated polymorphisms prior to treatment
F. Side effects (reported in combination with SOF)
1. Fatigue, headache, nausea, ALT elevations
G. Drug interactions (numerous, refer to package insert)
1. Contraindicated: moderate and strong CYP3A4 inhibitors and inducers, Child-Turcotte-Pugh class
A or B
II. Glecaprevir/pibrentasvir (Mavyret)45
A. Drug class
1. NS3/4A inhibitor, NS5A inhibitor
1. Glecaprevir 100 mg/pibrentasvir 40 mg tablet
C. Standard dosing
1. 3 tablets PO once daily
1. Contraindicated: Child-Turcotte-Pugh Class C
2. Use not recommended: Child-Turcotte-Pugh Class B

37
1. Give with food
2. Can be used for any genotype (1-6) – why it is a preferred option to use
1. Fatigue, headache, nausea
G. Drug interactions (numerous)
1. Contraindicated: atazanavir, rifampin, and various other agents, refer to package insert
III. Ledipasvir/sofosbuvir (Harvoni)46
A. Drug class
1. NS5B RNA polymerase inhibitor, NS5A inhibitor
1. Ledipasvir 90 mg/sofosbuvir 400 mg tablet
C. Standard dosing
1. 1 tablet PO once daily ± RBV (adding RBV can be considered because it has been shown to
maximize SVR rates and reducing post-treatment viral relapse)
2. Preferred in genotypes 1, 4, 5, and 6 without or with compensated cirrhosis
3. Treatment duration = 12 weeks
a. 8 weeks can be considered in patients with genotype 1 virus without evidence of cirrhosis,
non-black, HIV negative, and viral load <6 million
1. Fatigue, headache, weakness
1. Contraindicated: amiodarone (symptomatic bradycardia), refer to sofosbuvir interactions
2. Antacids, H2-blockers, and proton pump inhibitors
a. Dose of <40 mg of famotidine or dose equivalents of other H2 blockers can be given

simultaneously or separated by 12 hours
b. Antacids should be separated by at least 4 hours
c. Dose equivalents of 20-mg omeprazole or lower may be given under fasting conditions
IV. Sofosbuvir/velpatasvir (Epclusa)47

38
A. Drug class
1. NS5B RNA polymerase inhibitor, NS5A Inhibitor
1. Sofosbuvir 400 mg /velpatasvir 100 mg tablet
C. Standard dosing
1. Sofosbuvir 400 mg /velpatasvir 100 mg tablet 1 tablet PO once daily + RBV
1. Give with or without food for 12 weeks
2. Pan-genotypic
F. Side effects (reported in combination with other antiviral agents)
1. Fatigue, headache, nausea
1. Contraindicated: amiodarone (symptomatic bradycardia), CYP2B6 inducers, CYP3A4 inducers,

proton-pump inhibitors, refer to sofosbuvir interactions
V. Sofosbuvir/velpatasvir/voxilaprevir (Vosevi)48
A. Drug class
1. NS3/4A inhibitor, NS5B RNA polymerase inhibitor, NS5A inhibitor
B. Indication
1. Treatment-experienced, pangenotypic
2. Not recommended for initial use. Reserve for patients who have failed treatment with preferred
option.
C. Available formulation
1. Sofosbuvir 400 mg /velpatasvir 100 mg/voxilaprevir 100 mg tablet
D. Standard dosing
1. 1 tablet PO once daily for 12 weeks
E. Dosing in renal/hepatic impairment
1. Use not recommended in Child-Turcotte-Pugh Class B and C
F. Administration considerations
1. Give with food
39
G. Side effects (reported in combination with other antiviral agents)
1. Diarrhea, fatigue, headache, ↑ bilirubin
H. Drug interactions (numerous)
1. Contraindicated: amiodarone (symptomatic bradycardia), CYP2B6 Inducers, CYP3A4 inducers,

proton-pump inhibitors, refer to sofosbuvir interactions
Question 10: Which of the following regimens is most appropriate to use in a treatment-naïve patient with
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
40
VIRAL HEPATITIS: HCV TREATMENT-NAÏVE OPTIONS
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. Which of the following is
the most appropriate recommendation?
A. Bictegravir/tenofovir alafenamide/emtrictiabine 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.
I. Options for treatment-naïve patients37
Figure 7: Treatment Options for Treatment-Naïve Patients
A. Simplified HCV treatment in treatment-naïve patients (all genotypes) without cirrhosis
Table 33: Simplified HCV Treatment: Without Cirrhosis

Who is Eligible Who is NOT Eligible
– Chronic HCV – Prior HCV treatment
– No cirrhosis – Cirrhosis or likely cirrhosis
– No previous treatment for HCV — Fibrosis (FIB)-4 >3.25*
— APRI >2.0**
— Platelet Count <150,000/mm3
— Fibroscan stiffness >12.5 kPa
41
– Prior liver transplant recipient
– HIV diagnosis
– HBsAg positive
– ESRD
– Pregnancy
* Fibrosis-4 calculator available at https://www.hepatitisc.uw.edu/page/clinical-calculators/fib-4
** AST to platelet ratio index (APRI) calculator available at https://www.hepatitisc.uw.edu/page/clinical-
calculators/apri.
1. Treatment options for non-cirrhotic patients
a. Glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks
b. Sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks
Figure 8: Pretreatment Assessment
Figure 9: On-treatment and Post-treatment Monitoring
42
Table 34: Simplified HCV Treatment: Compensated Cirrhosis
Who is Eligible Who is NOT Eligible
– Chronic HCV (any genotype) – Current or previous decompensated cirrhosis
– Compensated cirrhosis (Child-Pugh A) (Child-Turcotte-Pugh score >7)
– No previous treatment for HCV – Prior HCV treatment
– ESRD (eGFR <30mL/min/m2)
– HIV
– HBsAg positive
– Pregnancy
– Known or suspected hepatocellular carcinoma
– Prior liver transplantation
2. Treatment options for compensated cirrhotic patients
a. Glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks (genotypes 1-6)
b. Sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks (all genotypes EXCEPT genotype 3)
1) Patients with genotype 3: baseline NS5A resistance-associated substitution must be

performed. Those without Y93H can be treated with 12 weeks of sofosbuvir/velpatasvir
Figure 10: Pretreatment Assessment
Figure 11: On-treatment and Post-treatment Monitoring
43
II. Mixed genotypes
A. Rare
B. Data sparse with DAAs
C. Use pangenotypic regimen
44
VIRAL HEPATITIS: TREATMENT-EXPERIENCED HCV THERAPY
I. Sofosbuvir-based and elbasvir/grazoprevir treatment failures with or without compensated cirrhosis37
A. Sofosbuvir/velpatasvir/voxilaprevir for 12 weeks
B. Alternative: glecaprevir/pibrentasvir for 16 weeks
a. Not recommended for patients with prior exposure to an NS5A inhibitor plus NS3/4 PI regimens
b. Not recommended for genotype 3 infection with sofosbuvir/NS5a inhibitor resistance
II. Glecaprevir/pibrentasvir treatment failures with or without compensated cirrhosis
A. Glecaprevir/pibrentasvir + sofosbuvir + weight-based Ribavirin for 16 weeks
B. Sofosbuvir/velpatasvir/voxilaprevir for 12 weeks
1. Weight-based ribavirin is recommended for patients with compensated cirrhosis
III. Multiple treatment failures (including sofosbuvir/velpatasvir/voxilaprevir or glecaprevir/pibrentasvir
+ sofosbuvir) with or without compensated cirrhosis
A. Glecaprevir/pibrentasvir + sofosbuvir + weight-based ribavirin for 16 weeks
B. Sofosbuvir/velpatasvir/voxilaprevir + weight based ribavirin for 24 weeks
Question 12: A patient with decompensated cirrhosis and HCV genotype 1a was previously treated with
SIM/SOF but experienced treatment failure. Which of the following 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
45
VIRAL HEPATITIS: HCV THERAPY FOR DECOMPENSATED CIRRHOSIS
I. HCV therapy for decompensated cirrhosis37
Table 35: HCV Therapy by Genotype

Genotype 1 Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6
LDV/SOF
RBV eligible 12 weeks1 --- --- 12 weeksa 12 weeksa 12 weeksa
RBV ineligible 24 weeks --- --- 24 weeks 24 weeks 24 weeks
Prior SOF or 24 weeks1 --- --- 24 weeksa 24 weeksa 24 weeksa
NS5A failure
SOF/VEL
RBV eligible 12 weeks2 12 weeks 12 weeks 12 weeksb 12 weeksb 12 weeksb
RBV ineligible 24 weeks 24 weeks 24 weeks 24 weeks 24 weeks 24 weeks
Prior SOF or 24 weeks b
24 weeks b
24 weeks b
24 weeks b
24 weeksb 24 weeksb
NS5A Failure
a
Start with low dose RBV (600 mg) and increase as tolerated
b
Start with low dose RBV (600 mg) and increase as tolerated for Child-Turcotte-Pugh class C
46
VIRAL HEPATITIS: HIV/HCV CO-INFECTION
Everyone should be initiated on therapy (ideally); realistically, the most important factor is managing the drug-drug
interactions (usually try to control HIV first and then look at hepatitis C regimen)
I. Antiviral drug interactions
A. Elbasvir/grazoprevir
1. Do not use with cobicistat, efavirenz, etravirine, nevirapine, or HIV protease inhibitors
B. Glecaprevir/pibrentasvir
1. Do not use with atazanavir, ritonavir-containing regimens, efavirenz, etravirine
C. Ribavirin
1. Avoid use with didanosine, stavudine, zidovudine
D. Sofosbuvir
1. Avoid use with tipranavir
E. Ledipasvir/sofosbuvir
1. Use of TDF formulation increases tenofovir levels more than TAF, use with caution in eGFR <60
mL/min
F. Sofosbuvir/velpatasvir
1. Do not use with efavirenz, etravirine, or nevirapine
2. Use of TDF formulation increases tenofovir levels more than TAF, use with caution in eGFR <60
mL/min
G. Sofosbuvir/velpatasvir/voxilaprevir
1. Caution with darunavir/ritonavir and elvitegravir/cobicistat (no data)
2. TDF formulation increases tenofovir levels, use with caution in eGFR <60 mL/min
3. Do not use with ritonavir-boosted atazanavir, efavirenz, etravirine, or nevirapine
II. Conclusions
A. 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
B. Immunization is among the preventive strategies for viral hepatitis caused by HAV and HBV
C. Infectious diseases pharmacists play an important role in managing drug therapy for patients with or
at risk for viral hepatitis
47
ANSWER KEY TO CASE QUESTIONS
1. Correct answer = C (Initiate Havrix.)
Option C is correct since the patient would benefit from vaccination for HAV with the single-agent vaccination
based on the lack of antibody to HAV. In addition, vaccination is necessary due to travel to an area with high
prevalence of endemic hepatitis A. Option A is incorrect since the patient is not immune to hepatitis A virus and
would benefit from HAV vaccination since they are travelling to a remote area. Option B is incorrect since the
patient already has immunity to HBV, so the combo product of Twinrix is not needed. Option D is incorrect
because obtaining viral loads is not necessary for this patient unless there is concern for active infection.
2. Correct answer = B (Children <1 year of age)
Option B is correct; vaccination should be initiated at 12 months, so children under 1 year of age should not be
vaccinated. If travel is planned outside of the US, then vaccination should be performed. Individuals listed in
options A, C, and D should be vaccinated against hepatitis A. Men who have sex with men are at risk for
contracting HAV and should receive vaccination. Travel to endemic areas is a risk factor for contracting HAV and so
travelers to those regions receive vaccination. Injection drug use is a risk factor for contracting HAV and so those
individuals should receive vaccination.
3. Correct answer = D (HBsAg)
Option D is correct because HBsAg is the first and earliest serologic marker to appear in both acute and chronic
HBV. While Anti-HBc and HBV DNA do appear after HBsAg, HBeAg may or may not appear.
4. Correct answer = A (HBeAg (+) with HBV DNA 32,875 IU/mL and an ALT 152 U/L.)
Option A is correct. Based on both the AASLD and EASL guidelines, patients with a HBV VL ≥20,000 and ALT
>2xULN (AASLD) or HBV DNA >2000 and any ALT elevation and at least moderate fibrosis with HBeAg(+) meet
criteria for treatment initiation. Option B is incorrect becaue, while HBV DNA is elevated, the patient’s ALT are
WNL and the patient does not have fibrosis, which is a required criterion for treatment in those with HBeAg(+);
therefore, this patient does not meet that criterion. Option C is incorrect because for a patient with HBeAg (-)
infection, treatment should be initiated if HBV DNA >2000 in combination with any ALT elevation (EASL) or HBV
DNA >2000 with ALT ≥2xULN (AASLD). This patient does not meet those criteria. Option D is incorrect because,
based on the laboratory values patient does not meet criteria for treatment initiation.
5. Correct answer = D (Tenofovir disoproxil fumarate)
Option D is correct as this is a first-line recommendation for the management of HBV in the AASLD and EASL
guidelines. While tenofovir alafenamide (TAF) could be considered (Option C), the use of TAF with phenytoin is
contraindicated based on the reduction of TAF concentrations which may lead to decreased efficacy or the
development of resistance. Option A is considered an alternative agent as is option B. Lamivudine is noted to have
high rates of resistance after 1 year of use.
48
6. Correct answer = B (Do not stop taking this medication because it could result in worsening of hepatitis B
infection.)
Option B is correct since abrupt cessation could result in a flare-up or reactivation causing hepatitis B to return in a
worse way than before. Bone marrow suppression and worsened depression are routinely seen with pegylated
interferon but not with either formulation of tenofovir. The use of TDF may be taken without regard to
meals/food requirements. The use of TAF recommends taking it with food.
7. Correct answer = A (An individual actively injecting substances)
Option A is the best response since the patient has ongoing risk factors. Individuals listed in all other options are
eligible for one lifetime HCV screen given the most recent recommendations
8. Correct answer = D (A patient with HCV and metastatic HCC)
Option D is the best response; due to a short life expectancy, the initiation of HCV treatment is not recommended.
Option A is incorrect because prior non-response does not preclude a patient receiving HCV treatment. Levels of
SVR are high and retreatment should be encouraged. Option B is incorrect because patients with co-infection
should receive treatment as liver disease progression is often faster in this population. Option C is incorrect based
on the AASLD guidelines, which recommend that all patients be treated for HCV regardless of disease severity.
Earlier treatment would reduce transmission along with progression of liver disease.
9. Correct answer = C (Glecaprevir/pibrentasvir for 8 weeks)
Option C is the best response since it is a preferred regimen in treatment-naïve individuals with non-cirrhotic
genotype 1b infection. In addition, no dosage adjustments are necessary in HD. Option A is not a recommended
regimen per the AASLD guidelines and a preferred option should be started initially. Additionally, there is minimal
data to support usage of sofosbuvir in HD. Although elbasvir/grazoprevir may be an option in ESRD/HD, the
duration of treatment should be 12 weeks. Although Option D is a recommended first-line option for this
population, there are minimal data to support usage of sofosbuvir in HD. Additionally, treatment of a patient with
viral load >6 million requires 12 weeks of therapy.
10. Correct answer = B (sofosbuvir/velpatasvir for 12 weeks)
Option B is the best response since it is a preferred regimen in treatment-naïve individuals with cirrhosis in
genotype 3 infection as long as the patient does not have any resistance-associated mutations. Option A is an
alternative regimen per the AASLD guidelines, and a preferred option should be started initially. Although
glecaprevir/pibrenstasvir may be an option in patients with cirrhosis with genotype 3 infection, the duration of
treatment should be 12 weeks. Option D is not recommended for genotype 3 virus since it is only indicated in all
genotypes except 2 and 3.
11. Correct answer = C (The patient may continue taking bictegravir/tenofovir alafenamide/emtricitabine while
on glecaprevir/pibrentasivir therapy.)
Option C is the best response since there are no drug-drug interactions associated with these treatments. While
dolutegravir may be safely used with glecaprevir/pibrentasvir, bictegravir may also be used safely with this
49
combination for the management of HCV. ART should ideally never be interrupted during treatment. There are no
known drug interactions between these combinations so they may be safely administered together. The use of
darunavir/cobicistat and glecaprevir/pibrentasvir is contraindicated. Therefore, these should not be given
together.
12. Correct answer = A (Ledipasvir/sofosbuvir with low initial dose of ribavirin x 24 weeks)
Option A is the best option since this is recommended as preferred therapy by the AASLD guidelines for the
management of genotype 1a. Option B is not recommended in the setting of decompensated cirrhosis in those
with previous SOF failure. Option C would be acceptable in the setting of NS5A treatment failure with a duration
of 24 weeks but not in the case of SOF failure. Option D is not recommended in this setting.
50
ANSWER KEY TO SELF-ASSESSMENT QUESTIONS (from front of the chapter)
1. Answer: D (No vaccination is needed.)
Since the patient has both hepatitis A and B antibodies present, the patient already has immunity to both
viruses and does not require vaccination. If the anti-HBc was positive, immunity to hepatitis B would be
secondary to exposure instead of previous vaccination.
2. Answer: A (Tenofovir alafenamide/emtricitabine/bictegravir)
Tenofovir, emtricitabine, and lamivudine all provide coverage against HIV/HBV co-infection but lamivudine
and emtricitabine should not be used alone for HBV as the development of resistance is relatively high.
Therefore, tenofovir alafenamide or tenofovir disoproxil fumarate is the recommended first-line option for the
management of HBV. The most appropriate answer is tenofovir alafenamide/emtricitabine/bictegravir.
Although lamivudine does provide coverage against HBV, the development of resistance is relatively high.
Abacavir, dolutegravir, and bictegravir do not provide any activity against HBV and, therefore, are not
appropriate choices. In addition, bictegravir is only available as a combination product. Neither rilpivirine nor
dolutegravir provide activity against HBV and is not an appropriate choice.
3. Answer: C (Glecaprevir/pibrentasvir – genotype 1)
Glecaprevir/pibrentasvir is a pan-genotypic HCV therapy that treats genotypes 1-6. Option A is incorrect
because ledipasvir/sofosbuvir provides coverage against HCV genotypes 1, 4-6. Option B is incorrect because
elbasvir/grazoprevir provides coverage against HCV genotypes 1 and 4. While
sofosbuvir/velpatasvir/voxilepravir does provide HCV coverage against genotype 4 as well as 1-3 and 5 and 6,
as a pan-genotypic regimen, it is not indicated for treatment-naïve patients but only for patients previously
treated with an HCV regimen containing either an NS5A inhibitor or sofosbuvir without an NS5A inhibitor;
therefore, option D is incorrect.
4. Answer: D (Sofosbuvir/velpatasvir)
Option D is correct because sofosbuvir/velpatasvir provides pan-genotypic coverage against HCV genotypes 1-
6. Option A is incorrect because ledipasvir/sofosbuvir is not indicated in genotype 3. Option B is incorrect
because elbasvir/grazoprevir is not indicated in genotype 3 nor should it be used is patients with
decompensated cirrhosis. Although glecaprevir/pibrentasvir can be used for the management of genotype 3
HCV, it should not be used in patients with decompensated cirrhosis; therefore, option C is incorrect.
5. Answer: B (Elbasvir/grazoprevir)
Option B is correct because elbasvir/grazoprevir does not have any dosing restrictions when combined with
proton pump inhibitors (PPIs) and may safely be used with them. Doses of PPIs comparable to 20 mg or lower
can be administered simultaneously with ledipasvir under fasted conditions (and this patient is receiving 40)
making option A incorrect. Doses greater than the dose equivalent of omeprazole 20 mg may reduce the
bioavailability of ledipasvir. The use of PPIs with velpatasvir is not recommended because PPIs can reduce the
serum concentration of velpatasvir, so options C and D are incorrect. If this combination cannot be avoided,
sofosbuvir/velpatasvir should be administered with food and 4 hours before omeprazole.
51
REFERENCES FOR FURTHER STUDY
Hepatitis A Virus
1. Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines,
2015. https://www.cdc.gov/std/tg2015/tg-2015-print.pdf (accessed 2021 Nov 18).
• Provides information on hepatitis A in various populations as well as on virus prevention.
2. Centers for Disease Control and Prevention (CDC). Viral hepatitis.

https://www.cdc.gov/hepatitis/hav/index.htm (accessed 2021 Nov 19).
• Resources on not hepatitis A as well as on hepatitis B, C, D, and E. Provides surveillance

information and statistics along with educational resources and vaccination information for
healthcare providers.
Hepatitis B Virus
1. Department of Health and Human Services. Panel on antiretroviral guidelines for adults and adolescents.
Guidelines for the use of antiretroviral agents in adults and adolescents living with
HIV. https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/AdultandAdolescentGL.pdf
(accessed 2021 Nov 18).
• Provides management resources and information about interacting medications that treat these
disease states.
2. European Association for the Study of the Liver. EASL 2017 clinical practice guidelines on the
management of hepatitis B virus infection. J Hepatol. 2017;67:370-398.
• Updated European guidelines that provide a comprehensive overview on epidemiology,

diagnosis, management, and monitoring. Provides information on both acute and chronic
infection.
3. Terrault NA, Lok AS, McMahon BJ et al. Update on prevention, diagnosis, and treatment of chronic
hepatitis B: AASLD 2018 hepatitis B guidance. Hepatol. 2018;67:1560-1599.
• United States guidelines that provide a comprehensive overview of the management of chronic
hepatitis.
52
Hepatitis C Virus
1. American Association for the Study of Liver Diseases (AASLD), Infectious Diseases Society of America
(IDSA). HCV guidance: recommendations for testing, managing, and treating hepatitis C.
https://www.hcvguidelines.org/ (accessed 2021 Nov 18).
• Comprehensive overview providing information on the management of treatment-naïve and

treatment-experienced patients with HCV and genotypes 1-6.
2. European Association for the Study of the Liver. EASL-ALEH clinical practice guidelines: non-invasive tests
for evaluation of liver disease severity and prognosis. J Hepatol. 2015;63:237-264.
• Overview on non-invasive tests used to determine liver disease severity, prognosis, and extent of
fibrosis.
53
MODULE REFERENCES
1. Centers for Disease Control and Prevention (CDC). Viral hepatitis.

https://www.cdc.gov/hepatitis/hav/havfaq.htm#general (accessed 2021 Nov 18).
2. World Health Organization (WHO). Hepatitis A. https://www.who.int/en/news-room/fact-

sheets/detail/hepatitis-a (accessed 2021 Nov 18).
3. Centers for Disease Control and Prevention. The ABCs of hepatitis.

https://www.cdc.gov/hepatitis/resources/professionals/pdfs/ABCTable.pdf (accessed 2021 Nov 18).
4. Centers for Disease Control and Prevention. Diagnosis and management of foodborne illnesses.
https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5304a1.htm (accessed 2021 Nov 18).
5. Centers for Disease Control and Prevention. Infectious diseases related to travel.
https://wwwnc.cdc.gov/travel/yellowbook/2018/infectious-diseases-related-to-travel/hepatitis-a (accessed
2021 Nov 18).
6. Nelson NP, Link-Gelles R, Hofmeister MG. Update: recommendations of the Advisory Committee on
Immunization Practices for use of hepatitis A vaccine for postexposure prophylaxis and for preexposure
prophylaxis for international travel. MMWR Morb Mortal Wkly Rep 2018; 67:1216.
7. Centers for Disease Control and Prevention (CDC). Hepatitis B questions and answers for health professionals.
https://www.cdc.gov/hepatitis/hbv/hbvfaq.htm#overview (accessed 2021 Nov 18).
8. Gonzalez SA. Hepatitis B. http://www.antimicrobe.org/v22.asp#t5 (accessed 2021 Nov 18).
9. World Heath Organization (WHO). Hepatitis B. https://www.who.int/en/news-room/fact-

sheets/detail/hepatitis-b (accessed 2021 Nov 18).
10. D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a
systematic review of 118 studies. J Hepatol. 2006;44:217-31.
11. MDCalc. Child-Pugh score for cirrhosis mortality. https://www.mdcalc.com/child-pugh-score-cirrhosis-

mortality (accessed 2021 Nov 18).
12. Terrault NA, Lok ASF, McMahon BJ et al. Update on prevention, diagnosis, and treatment of chronic hepatitis
B: AASLD 2018 hepatitis B guidance. Hepatol. 2018;67:1560-99.
13. European Association for the Study of the Liver (EASL). EASL 2017 clinical practice guidelines on the
management of hepatitis B virus infection. J Hepatol. 2017;67:370-98.
14. European Association for the Study of the Liver (EASL), Asociacion Latinoamericana para el Estudio del Higado
(ALEH). EASL-ALEH clinical practice guidelines: non-invasive tests for evaluation of liver disease severity and
prognosis. J Hepatol. 2015;63:237-64.
15. Centers for Disease Control and Prevention (CDC). Viral hepatitis training.
https://www.cdc.gov/hepatitis/resources/professionals/training/serology/training.htm (accessed 2021 Nov
18).
16. Mast EE, Margolis HS, Fiore AE et al. A comprehensive immunization strategy to eliminate transmission
of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on
Immunization Practices (ACIP) part 1: immunization of infants, children, and adolescents. MMWR Recomm
Rep. 2005;54:1-31.
54
17. Centers for Disease Control and Prevention (CDC). Interpretation of hepatitis B serologic test results.
https://www.cdc.gov/hepatitis/hbv/pdfs/serologicchartv8.pdf (accessed 2021 Nov 18).
18. Brunetto M, Lim YS, Gane E et al. A phase 3 study comparing tenofovir alafenamide (TAF) to tenofovir
disoproxil fumarate (TDF) in patients with HBeAg-negative, chronic hepatitis B (CHB): efficacy and safety
results at week 96. EASL 2017. Abstract PS-042.
19. Agarwal K, Fung S, Seto WK et al. A phase 3 study comparing tenofovir alafenamide to tenofovir disoproxil
fumarate in patients with HBeAg-positive, chronic hepatitis B: efficacy and safety results at week 96. EASL
2017. Abstract FRI-153.
20. Baraclude (entecavir) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; December 2018.
21. Vemlidy (tenofovir alafenamide) [prescribing information]. Foster City, CA: Gilead Sciences; August 2020.
22. Viread (tenofovir) [prescribing information]. Foster City, CA: Gilead Sciences Inc; April 2019.
23. Pegasys (peginterferon alfa-2a) [prescribing information]. South San Francisco, CA: Genentech, Inc; October
2017.
24. Hepsera (adefovir) [prescribing information]. Foster City, CA: Gilead Sciences Inc; November 2012.
25. Epivir HBV (lamivudine) [prescribing information]. Research Triangle Park, NC; GlaxoSmithKline; August 2020.
26. Ghany MG, Doo EC. Antiviral resistance and Hepatitis B therapy. Hepatology. 2009;49: S174–84.
27. Department of Health and Human Services, Panel on Antiretroviral Guidelines for Adults and Adolescents.
Guidelines for the use of antiretroviral agents in adults and adolescents living with
HIV. https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/AdultandAdolescentGL.pdf
(accessed 2021 Nov 18).
28. Centers for Disease Control and Prevention (CDC). https://www.cdc.gov/vaccines/acip/meetings/slides-

2021-11-2-3.html (accessed 2021 Nov 18).
29. Centers for Disease Control and Prevention (CDC). https://www.cdc.gov/vaccines/pubs/pinkbook.html

(accessed 2022 Mar 1)
30. Centers for Disease Control and Prevention (CDC). CDC guidance for evaluating health-care personnel for
hepatitis B virus protection and for administering postexposure management. MMWR Recomm Rep.
2013;62:1-19.
31. Spradling P. Hepatitis C. Travelers health: chapter 4: travel-related infectious diseases. Centers for Disease
Control and Prevention (CDC). https://wwwnc.cdc.gov/travel/yellowbook/2020/travel-related-infectious-
diseases/hepatitis-c (accessed 2021 Nov 18).
32. Gower E, Estes C, Blach S et al. Global epidemiology and genotype distribution of the hepatitis C virus
infection. J Hepatol. 2014;61:S45–57.
33. Messina JP, Humphreys I, Flaxman A et al. Global distribution and prevalence of hepatitis C virus genotypes.
Hepatol. 2015;61:77–87.
34. Sklan EH, Charuworn P, Pang PS et al. Mechanisms of HCV survival in the host. Nat Rev Gastroenterol Hepatol.
2009; 6:217-27.
35. Centers for Disease Control and Prevention (CDC). Hepatitis C questions and answers for health professionals.
https://www.cdc.gov/hepatitis/hcv/hcvfaq.htm#section3 (accessed 2021 Nov 18).
55
36. Centers for Disease Control and Prevention (CDC). Interpretation of results of tests for hepatitis C virus (HCV)
infection and further actions. https://www.cdc.gov/hepatitis/hcv/pdfs/hcv_graph.pdf (accessed 2021 Nov 18).
37. American Association for the Study of Liver Diseases (AASLD), Infectious Diseases Society of America (IDSA).
HCV guidance: recommendations for testing, managing, and treating hepatitis C.
https://www.hcvguidelines.org/ (accessed 2021 Nov 18).
38. Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative
Study Group. Hepatol. 1996;24:289-93.
39. Loaeza-del-Castillo A, Paz-Pineda F, Oviedo-Cárdenas E et al. AST to platelet ratio index (APRI) for the
noninvasive evaluation of liver fibrosis. Ann Hepatol. 2008;7:350-357.
40. Wai CT, Greenson JK, Fontana RJ et al. A simple noninvasive index can predict both significant fibrosis and
cirrhosis in patients with chronic hepatitis C. Hepatol. 2003;38:518-526.
41. Sovaldi [package insert]. Foster City, CA: Gilead Sciences, Inc.; March 2020.
42. Rebetol (ribavirin capsules) prescribing information. Whitehouse Station, NJ: Merck & Co., Inc.; May 2019.
43. Copegus (ribavirin capsules) [package insert]. South San Francisco, CA: Genentech USA, Inc.; August 2011.
44. Zepatier [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; December 2019.
45. Mavyret [package insert]. North Chicago, IL: AbbVie Inc.; May 2020.
46. Harvoni [package insert]. Foster City, CA: Gilead Sciences, Inc.; March 2020.
47. Epclusa [package insert]. Foster City, CA: Gilead Sciences, Inc.; July 2020.
48. Vosevi [package insert]. Foster City, CA: Gilead Sciences, Inc.; November 2019.
56

ID RC Viral Hep Workbook 2022 FINAL T229150

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ID RC Viral Hep Workbook 2022 FINAL T229150

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VIRAL HEPATITIS

David E. Koren, Pharm.D., M.P.H., BCPS, AAHIVP, FIDSA

Answer key is provided at the end of this chapter.

Anti-HAV IgM: negative

Anti-HAV IgG: positive

HCV Ab: negative

Which of the following is the most appropriate recommendation?

A. Hepatitis A vaccination is needed.

B. Hepatitis B vaccination is needed.

C. Hepatitis A and B vaccination is needed.

I. Just the facts1-3

A. Enveloped RNA virus

B. 24,900 new cases annually in the U.S.

2. Contaminated food or water

D. Incubation period: 15-50 days (Average = 28 days)

1. Abdominal pain, jaundice, pale stools, dark urine, loss of appetite

2. Considered an acute and not chronic infection

a. Chronic hepatitis is defined as inflammation of the liver lasting >6 months

3. Much more severe in adults vs. children

F. Also can be transmitted through sex or IV drug use

Patient Case #1:

II. Risk factors for hepatitis A virus1-3

A. Travel to or living in an area with poor sanitation or lacking safe water

B. Men who have sex with men

C. Recreational drug use

D. Direct contact with an infected person

E. Clotting factor disorders

F. Working with non-human primates

Table 1. Hepatitis A Serologies

A. Total hepatitis A antibody is not useful for acute infection diagnosis

B. Diagnosis is established by the detection of serum IgM hepatitis A antibodies—indicates whether

IV. Clinical course of hepatitis A virus4

Figure 1: Hepatitis A: Clinical Illness

C. Phase 1: viral replication

D. Phase 2: prodromal phase (anorexia occurs here)

E. Phase 3: icteric phase (dark urine, pale stools, upper GI pain)

2. Fluids to replete volume loss from vomiting and diarrhea

A. Improved sanitary conditions

B. Safe access to water

C. Ensuring that appropriate food safety procedures are followed

D. Vaccination is going to be the most beneficial prevention technique

1. 2 doses given at least 6 months apart

Question 2: Hepatitis A vaccination is recommended in all of the following groups EXCEPT:

VII. Who should be immunized against HAV3

A. All children ≥1 year of age

B. Persons with travel to areas with intermediate to high rates of infection

D. Illegal and injection drug users

F. Persons with clotting-factor disorders

G. Persons working with HAV-infected primates or with HAV in a research laboratory

H. Persons with chronic liver disease, including HBV- and HCV-infected

I. Persons exposed as result of an outbreak

J. Persons who require post-exposure prophylaxis

VIII. Available vaccines5

B. Hepatitis A vaccines considered interchangeable

D. Intramuscular (IM) injection in deltoid muscle

E. If the second dose is delayed, series does not need to be restarted

Table 3: Pre-Exposure Prophylaxis

XI. Post-exposure management6

B. Administer as soon as possible and within 2 weeks of exposure

Table 4: Post-Exposure Agents by Age

I. Incidence of hepatitis B virus infection7

II. Hepatitis B lifecycle8

Figure 2: Hepatitis B Lifecycle

A. cccDNA: covalently closed circular double-stranded DNA