Post on 01-Sep-2020
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Sponsorship and Support
This activity is supported by an educational grant from Gilead Sciences, Inc.
This educational activity is provided by the North Carolina Academy of Family Physicians in collaboration with Med‐IQ.
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This live activity Moving Toward Elimination Through Better HBV Screening and Treatment has been reviewed and is acceptable for up to 1.0 Prescribed credit by the American Academy of Family Physicians. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
AMA/AAFP Equivalency:AAFP Prescribed credit is accepted by the American Medical Association as equivalent to AMA PRA Category 1 Credit(s)™ toward the AMA Physician’s Recognition Award. When applying for the AMA PRA, Prescribed credit earned must be reported as Prescribed credit, not as Category 1.
Accreditation / Designation Statement: Family Physicians
Richard R. Andrews, MD, MPH (Co‐chair and Presenter)Board‐Certified Family MedicineHouston, TX
Su Wang, MD, MPH (Co‐chair)Medical DirectorCenter for Asian HealthSaint Barnabas Medical CenterLivingston, NJ
Faculty
Marietta SaundersCME Specialist NC Academy of Family PhysiciansRaleigh, NC
Amy Burdette, PhDManager, Educational Strategy & ContentMed‐IQBaltimore, MD
Activity Planners
Disclosure StatementThe content of this activity has been peer reviewed and has been approved for compliance. The faculty and contributors have indicated the following financial relationships, which have been resolved through an established COI resolution process and have stated that these reported relationships will not have any impact on their ability to give an unbiased presentation.
Richard R. Andrews, MD, MPH, has indicated no real or apparent conflicts.
Su Wang, MD, MPH, has indicated no real or apparent conflicts.
The peer reviewers and activity planners have no financial relationships to disclose.
Learning Objectives
Upon completion, participants should be able to:• Outline risk factors for HBV infection, including country of origin, that raise
the need for HBV testing among patients and their families• Interpret results from HBV testing and identify appropriate next steps based
on the test results• Discuss current treatment recommendations and realistic treatment
expectations
Epidemiology and Public Health Burden
• Worldwide, ~290 million people with chronic HBV infection
• Estimated 887,000 deaths from HBV‐related liver disease and HCC in 2015
WHO. www.who.int/news‐room/fact‐sheets/detail/hepatitis‐b;Polaris Observatory Collaborators. Lancet Gastroenterol Hepatol. 2018;3:383‐403; Jefferies M, et al. World J Cases. 2018;6:589‐99.
High: ≥ 8%High Intermediate: 5%‐7%Low Intermediate: 2%‐4%Low: < 2%No Data Available.
HBV in the US
• Between 550,000 and 2 million people have chronic HBV infection
National Academics of Science, Engineering, and Medicine. www.nap.edu/catalog/23407/eliminating‐the‐public‐health‐problem‐of‐hepatitis‐b‐and‐c‐in‐the‐united‐states; Kowdley KV, et al. Hepatology. 2012;56:422‐33.
Age‐Adjusted Annual Incidence Rate(Cases per 100,000)
7.7 to 12.86.9 to 7.76.3 to 6.95.4 to 6.33.3 to 5.4Data not available
US (SEER + NFCR) Rate (95% CI)7.4 (7.3‐7.4)AK
VT
HI
CO
TN
WA
OR
CA
NV
UT
NM
TX
OK
KS
SD
NDMT
ID
LA
AR
MO
IA
MN
WI
IL IN
MI
OH
ME
PA
NY
VAWV
KY
ALMS
SC
NC
GA
FL
MA
DE
DC
NJMD
NE
NH
RICT
AZ
WY
Chronic HBV Infection
WHO. https://apps.who.int/iris/bitstream/handle/10665/255016/9789241565455‐eng.pdf;jsessionid=E1539B18505F6F7F473E18A1A0192070?sequence=1; Jayalakshmi M, et al. Viral Replication. 2013.
Normal Liver
Chronic Liver Inflammation Liver Cirrhosis
HCC
• If left untreated, viral hepatitis infection (HBV and HCV) can lead to cirrhosis (720,000 deaths) and HCC (470,000 deaths)
Global Deaths From Viral Hepatitis Now Exceed HIV, TB, or Malaria
WHO. www.who.int/hepatitis/publications/global‐hepatitis‐report2017/en.
0.0
Dea
ths, m
illions
0.5
1.0
1.5
2.0
2.5
2000 2005 2015
HepatitisHIVMalariaTB
2010Year
HBV: Disproportionate Toll on Minorities
• Although anyone can get HBV, some people are at greater risk– Of the estimated 2 million chronically infected in the US, 1.32 million are foreign born, with 58% immigrating from high or intermediate endemic areas
• Asian Americans and Pacific Islanders – Represent 5% of total US population– Represent ~50% of HBV cases in US– 8 times more likely to die of HBV compared with non‐Hispanic whites
• African immigrants– 2 in 10 have HBV – < 20% are aware of their infection
CDC. Viral hepatitis surveillance ‐ United States, 2016; Hepatitis B Foundation. www.hepb.org/blog/raising‐awareness‐hepatitis‐b‐african‐immigrant‐communities‐us; Kowdley KV, et al. Hepatology. 2012;56:422‐33.
The Era of Viral Hepatitis Elimination
• In 2016, WHO adopted the goal of viral hepatitis elimination by 2030• In 2018, the US National Academy of Science (formerly IOM) convened a committee for national strategy, which concluded: “We have the tools to eliminate, but it will require significant resource allocation, commitment, and strategy”
• Selected levers for change: 1) education, 2) advocacy, 3) scaling up screening and treatment, and 4) anti‐stigma and discrimination
WHO. https://apps.who.int/iris/bitstream/handle/10665/206453/WHO_HIV_2016.04_eng.pdf?sequence=1; National Academies of Sciences, Engineering, and Medicine. www.nap.edu/catalog/23407/eliminating‐the‐public‐health‐problem‐of‐hepatitis‐b‐and‐c‐in‐the‐united‐state; NOhep. www.nohep.org.
National Progress on HBV Prevention Has Stalled
CDC. www.cdc.gov/hepatitis/statistics/2016surveillance/pdfs/2016HepSurveillanceRpt.pdf.
0
Num
ber o
f Cases
7,000
8,000
9,000
2001 2004 20132010
6,000
5,000
4,000
3,000
2,000
1,000
2007 2016Year
Reported Number of Acute HBV Cases—US, 2001‐2016
HBV Screening
Impact of Screening Strategies: HBV Care Cascade
Hutin Y, et al. MMWR Morb Mortal Wkly Rep. 2018;67:773‐7.
Care cascadea for hepatitis B treatment, by WHO region, 2016.aThe sequential steps or stages of HBV care that persons living with HBV infection go through from diagnosis through viral suppression.
0
Num
ber o
f Persons
250,000,000
300,000,000
HBV Diagnosis and Treatment Status
200,000,000
150,000,000
100,000,000
50,000,000
Western PacificSouth‐East AsiaEuropeanEastern MediterraneanAmericanAfrican
Infected
Infection Diagnosed
On Treatment Viral Suppression Achieved
Patient‐Related Barriers to HBV Screening and Care • Limited awareness and lack of knowledge about HBV infection
– In a survey among 301 US patients (~50% Asian American), 36% believed that HBV is transmitted by sharing utensils, and 20% were unaware of HBV consequences
– Low socioeconomic and educational backgrounds have lowest screening rates • Limited proficiency in English • Cultural values/beliefs • Denial• Stigma and discrimination
– For example, in China, there is discrimination against people with HBV infection—they are frequently expelled from schools, terminated from jobs, and shunned by their community; many immigrants may remain reluctant to undergo testing due to deeply ingrained stigma
• Concern regarding cost • Misconceptions • Limited knowledge of healthcare system
Hu KQ, et al. Dig Dis Sci. 2011;56:3163‐71; Lee H, et al. Asia Pac J Oncol Nurs. 2016;3:324‐34.
Increasing Awareness: Patient Education Tool• Developed 3 videos to convey information about HBV risk factors, transmission, testing, and treatment
• More than 4,000 video views• https://youtu.be/VAk65Of7qHI• https://youtu.be/Y23KephMQu8• https://youtu.be/rtnA8MqFF2Q
Who Are We Missing?• 68‐year‐old retired librarian found to have 12‐cm HCC (Chinese) • 65‐year‐old with primary CNS lymphoma and fulminant liver failure due to HBV reactivation from chemotherapy (Taiwanese)
• 54‐year‐old with diabetes mellitus, history of cerebrovascular accident (twice), found incidentally to have stage 2 cirrhosis and HBV (Haitian)
• 28‐year‐old woman from Equatorial Guinea with HBV, elevated liver enzymes, and low platelets
Slide courtesy of Dr. Su Wang.
HBV Infection in Global Population, 2015
WHO. www.who.int/hepatitis/publications/global‐hepatitis‐report2017/en.
Num
ber o
f Persons, in Millions
120
WesternPacific Region
100
80
60
40
20
0AfricanRegion
South‐EastAsia Region
Eastern Mediterranean
Region
EuropeanRegion
Region of the Americas
Geographic Regions With High or Intermediate HBV Prevalence (≥2%)
Region Countries Africaa AllAsiaa AllAustralia and South Pacific All except Australia and New Zealand Middle East All except Cyprus and IsraelEastern Europe All except HungaryWestern Europe Malta, and indigenous populations in GreenlandNorth America Alaska natives and indigenous populations in northern CanadaMexico and Central America Guatemala and HondurasSouth America Ecuador; Guyana; Suriname; Venezuela; and Amazonian areas of
Bolivia, Brazil, Colombia, and PeruCaribbean Antigua and Barbuda, Dominica, Grenada, Haiti, Jamaica, St. Kitts
and Nevis, St. Lucia, and Turks and Caicos Islands
US Preventive Services Task Force. Final recommendation statement hepatitis B virus infection: screening, 2014; Weinbaum CM, et al. MMWR Recomm Rep. 2008;57:1‐20.aRegions with highest prevalence.
AALSD: High‐Risk Groups Who Should Be Screened• Persons born in HBV endemic regions of the world
(HBsAg prevalence of ≥ 2%)• US‐born persons not vaccinated as infants whose parents
were born in regions with HBsAg prevalence ≥ 8%a
• Persons who have ever injected drugsa• Men who have sex with mena• Persons needing immunosuppressive therapy• Persons not in long‐term monogamous relationship
(eg, > 1 sexual partner in previous 6 mos)a• Persons evaluated for or on treatment for STDa
• Travelers to countries with intermediate or high prevalencea
• Persons with elevated ALT/AST of unknown etiologya• Unvaccinated persons with diabetes aged 19‐59 yearsa• Blood, plasma, organ, tissue, or sperm donors
• Pregnant women• Infants born to HBsAg‐positive mothersa• Persons with chronic liver diseasea• End‐stage renal disease and hemodialysis patientsa• Household, needle‐sharing, and sexual contacts of
HBV‐infected individualsa• People with HIVa• Healthcare and public safety workers exposed to blood
or blood‐contaminated bodily fluidsa• Persons who are source of blood or body fluid exposure
that may require post‐exposure prophylaxis • Residents/staff of facilities for developmentally disabled
personsa• Inmates of correctional facilitiesa
aIf seronegative.
HBV screening must be covered by most insurance plans under ACA rules (as a preventive service with no cost sharing to patient)
Terrault N, et al. Hepatology. 2018;67:1560‐99.
HBV Screening Algorithm
McMahon BJ. Med Clin North Am. 2014;98:39‐54.Terrault NA, et al. Hepatology. 2018;67:1560‐99.
HBsAg (+)
HBsAg, anti‐HBs, and anti‐HBc IgG Tests
Collect Baseline Data:• ALT• HBeAg, anti‐HBe• HBV DNA level
– AND –Go to evaluation and monitoring algorithm
HBsAg (‐)
Anti‐HBs (+)
Immune to HBV;
no follow‐up needed
Vaccinate
Anti‐HBs (‐)
Chronic HBV Infection HBeAg Positive HBeAg Negative
Chronic HBVInfection
Phase 1 Phase 2 Phase 3 Phase 4 Phase 5
Chronic HBV Infection
Chronic HBV Infection
Chronic HBV Infection
Chronic HBV Infection
Resolved HBVInfection
HBsAg High High/intermediate
Low Intermediate Negative
HBeAg Positive Positive Negative Negative NegativeHBV DNA > 107 IU/mL 104–107 IU/mL < 2,000 IU/mLa > 2,000 IU/mL < 10 IU/mLc
ALT Normal Elevated Normal Elevatedb Normal
Liver disease None/minimal Moderate/severe
None Moderate/severe
Noned
Old terminology Immune tolerant Immune reactive HBeAg positive
Inactive carrier HBeAg negative chronic hepatitis
HBsAg negative/ anti‐HBc positive
New Nomenclature for Chronic Phases
• The natural history of chronic HBV infection has been schematically divided into 5 phases
aHBV DNA levels can be between 2,000 and 20,000 IU/mL in some patients without signs of chronic hepatitis infection.bPersisitently or intermittently, based on traditional ULN (~40 IU/L).ccccDNA can frequently be detected in the liver.dResidual HCC risk only if cirrhosis has developed before HBsAg loss. EASL. J Hepatol. 2017;67:370‐98.
HBV Care
Primary Care HBV Evaluation/Monitoring Algorithm
Terrault NA, et al. Hepatology. 2018;67:1560‐99;McMahon BJ. Med Clin North Am. 2014;98:39‐54.aNew norms establish elevated ALT as ≥ 25 IU/L for women and ≥ 35 IU/L for men.
HBeAg (+)
HBV DNA > 20,000 IU/mL
ALT normal
HBeAg (‐)Anti‐HBe (+)
HBV DNA > 2,000 IU/mL
ALT elevateda
HBV DNA > 2,000 IU/mL
ALT normal
HBeAg (+)
HBV DNA > 20,000 IU/mL
ALT elevateda
Immune active
Inactive phase
RetestHBeAg, HBV DNA, and ALT
every 6 months
Consult with specialist for consideration of liver
biopsy and/or treatment
RetestHBeAg, HBV DNA, and ALT
every 6 months
Immune tolerant
HBV Medical Care • Chronic HBV infection is usually lifelong
– Asymptomatic even with ongoing inflammation – Increased risk of HCC and cirrhosis
• All HBsAg+ need routine monitoring – Every 3‐12 months– HBV viral load and liver enzymes – Liver cancer screening: ultrasound or CT and AFP Can occur in noncirrhotics
• HBV “carrier” is overused– False sense of security that condition is benign– HBV can fluctuate between “active” and “inactive”– “Carrier state” should only apply to HBeAg ‐, HBV DNA < 2,000 IU/mL, and normal ALT (< 25 IU/L women, < 35 IU/L men)
CDC. www.cdc.gov/hepatitis/hbv/bfaq.htm; Terrault NA. Hepatology. 2016; El‐Serag HB. Gastroenterology. 2012;142:1264‐73; McMahon BJ.Med Clin North Am. 2014;98:39‐54. Slide courtesy of Dr. Su Wang.
Evaluation of HBV+ Patients• History/physical examination– Family history of HBV, liver cancer, or other liver disease
–Examine for stigmata of liver disease (late finding)
• Test for the following:– HBeAg / anti‐HBe– HBV DNA quantification Viral load
– CBC with platelets – Liver panel (AST/ALT, total bilirubin / direct bilirubin)
– PT/INR and serum albumin – AFP– Hepatitis D (pt origin, PWID)– Screen for HAV, HCV, and HIV
• Provide vaccination against HAV
Terrault NA, et al. Hepatology. 2018;67:1560‐99.
HBV Counseling
• Discuss symptoms of hepatitis flares and the importance of regular visits• Suggest partners and household contacts receive testing • Educate regarding strategies to reduce transmission risk:
– Vaccinate household and sexual contacts– Use barrier protection during sexual intercourse if partner is not vaccinated – Do not share toothbrush, razors, injection equipment, or glucose testing equipment– Cover open cuts and scratches– Clean blood spills with diluted bleach – Do not donate blood, organs, or sperm
Terrault NA, et al. Hepatology. 2018;67:1560‐99.
HBV Counseling• Advise regarding prescription/nonprescription drugs
– Although, in general, most medications are safe unless liver is cirrhotic, many medications are metabolized by the liver; thus, ask patients to check with their healthcare provider before starting a new medication
– No complementary and alternative treatment has been proven to improve outcomes in patients with HBV; some can cause liver toxicity
• Provide support – Have patients share their fears/concerns – Invite family members to discuss HBV risks and long‐term care– Connect patients with support groups (local or online), counselors, social workers, etc.
• Reiterate that there is no shame; we could all be affected by HBV
Terrault NA, et al. Hepatology. 2018;67:1560‐99.
Should HBV‐Infected Persons Be Restricted from Working in Certain Occupations or Settings?• CDC recommendations for prevention and control of HBV infection specify that persons should not be excluded from work, school, play, childcare, or other settings on the basis of their HBV infection status
• Healthcare students and workers should not be excluded from training or practice (if they perform exposure‐prone procedures, counseling and advice from expert review panel is recommended)
• There is no evidence of HBV transmission from food handlers, teachers, or other service providers in the absence of blood‐to‐blood contact
Holmberg SD, et al. MMWR Recommendations and Reports. 2012;61:542.
HCC Surveillance• Screen with ultrasound with or without AFP every 6 months
AASLD Indications for Surveillance HBsAg‐Positive Persons• All patients with cirrhosis• Patients at high risk of HCC:
– Asian or black men > 40 years old– Asian women > 50 years old– First‐degree family member with history of HCC– Person with HDV
• Children and adolescents with advanced fibrosis (F3) or cirrhosis and those with first‐degree family member with HCC may require HCC surveillance
Additional Risk Factors to Consider • Basal core promoter mutation• Genotype C• Coinfection with HCV, HIV, HDV• Persistently high HBV DNA• Late HBeAg loss (40+ years)• Elevation of liver inflammation testsa
• Alcohol use, smoking• Fatty liver • African individuals > 20 years old
Terrault NA, et al. Hepatology. 2018;67:1560‐99.aAbnormal ALT: male ≥ 30 U/L or female ≥ 19 U/L.
HBV Treatment
Goals and Endpoints of Therapy
Goals• Improve survival and quality of life by preventing disease progression and HCC• Prevent mother‐to‐child transmission and HBV reactivation and prevent and treat HBV‐associated extrahepatic manifestations
aOften represents a partial immune control of the chronic HBV infection.bAchieved in most patients with long‐term suppression of HBV replication.cIndicates profound suppression of HBV replication and viral protein expression.
RecommendationsGrade of Evidence
Grade of Recommendation
Main endpointInduction of long‐term suppression of HBV DNA I 1
Valuable endpointInduction of HBeAg loss (± anti‐HBe seroconversion)in HBeAg‐positive patients with chronic HBV infectiona
II‐1 1
Additional endpoint ALT normalization (biochemical response)b II‐1 1
Optimal endpoint HBsAg loss (± anti‐HBs seroconversion)c II‐1 1
EASL. J Hepatol. 2017;67:370‐98.
Grade of evidence: 1: Randomized, controlled trialsII‐1: Controlled trials without randomization
Grade of recommendation:1: Strong recommendation
Goal of HBV Therapy: Suppress Virus to Prevent Cirrhosis, HCC, and Death
Slide courtesy of Dr. Su Wang.
Durable Suppression of HBV Replication
Treatment Begins
Time
HBV
Rep
lication
Drug‐resistant variant
Naturally occurring viral variants
Drug‐susceptible virus
Incomplete Suppression of Viral Replication Allows the Selection of Resistant Virus
Adapted from Locarnini S, et al. Antivir Ther. 2004;9:679‐93; Fung SK, et al. Antivir Ther 2004;9:1013‐26.
DrugDose
in Adults Potential Side Effects CommentsFirst LineEntecavir (ETV) 0.5 mg/1.0
mg po qdLactic acidosis (decompensated cirrhosis only) Generic, high potency, high genetic barrier to
resistanceTenofovir disoproxil (TDF)
300 mg po qd Nephropathy, Fanconi syndrome, osteomalacia, lactic acidosis
Generic, high potency, high genetic barrier to resistance
Tenofovir alafenamide (TAF)
25 mg po qd Lactic acidosis Less bone and renal toxicity, high potency, high genetic barrier to resistance
Peginterferon alfa‐2a (PEGIFN alfa‐2a)
180 ugSQ every week
Flu‐like symptoms, fatigue, mood disturbances, cytopenia, autoimmune disorders (adults), anorexia and weight loss (children)
Finite treatment of 48 weeks, less safe in patients with cirrhosis, contraindicated for decompensated cirrhosis
Second LineAdefovir dipivoxil (ADV)
10 mg po qd Acute renal failure, Fanconi syndrome, lactic acidosis
Low potency, low genetic barrier to resistance
Telbivudine (TBV) 600 mg po qd Creatine kinase elevation, myopathy, peripheral neuropathy, lactic acidosis
High potency, low genetic barrier to resistance
Third LineLamivudine (LAM) 100 mg po qd Pancreatitis, lactic acidosis Low potency, low genetic barrier to resistance
HBV Treatments
Terrault NA, et al. Hepatology. 2018;67:1560‐99; Hepatitis B Foundation. www.hepb.org/treatment‐and‐management/treatment/approved‐drugs‐for‐adults; McMahon B. Med Clin N Am. 2014;98:39‐54.
Therapy for Treatment‐Naïve Patients
• Long‐term administration of a potent NA with a high barrier to resistance is the treatment of choice– Regardless of severity of liver disease
EASL. J Hepatol. 2017;67:370‐98.
RecommendationsGrade of Evidence
Grade of Recommendation
Treatment of choice Long‐term administration of a potent NA with high barrier to resistance (regardless of severity of liver disease)
I 1
Preferred regimens ETV, TDF, and TAF as monotherapies I 1
NOT recommended LAM, ADV, and TBV I 1
Grade of evidence: 1: Randomized, controlled trialsGrade of recommendation: 1: Strong recommendation
Definitions of Response to Treatment
EASL. J Hepatol. 2017;67:370‐98.
Responses NA Therapy PegIFN Alfa TherapyVirological (on‐treatment)
Response: HBV DNA < 10 IU/mLPrimary nonresponse: < 1 log10 decrease in HBV DNA after 3 months of therapyPartial response: HBV DNA decreased by > 1 log10 but still detectable after ≥ 12 months of therapy in compliant patientsBreakthrough: confirmed HBV DNA increase of > 1 log10 above on‐therapy nadir
Response: HBV DNA < 2,000 IU/mL
Virological (off‐treatment)
Sustained response: HBV DNA < 2,000 IU/mL for ≥ 12 months after end of therapy
Serological HBeAg loss and development of anti‐HBea
HBsAg loss and development of anti‐HBsBiochemical ALT normalizationb (confirmed by ALT determination at least every 3 months for at least 1 year
post‐treatment)Histological Decrease in necroinflammatory activityc without worsening in fibrosis compared with pre‐treatment
histological findings
aOnly for HBeAg‐positive patients. bBased on traditional ULN (~40 IU/L).cBy ≥ 2 points in HAI or Ishak’s system.
Preventing Vertical Transmission
• To prevent perinatal (vertical) transmission:–Antivirals for pregnant woman with HBV DNA > 106
– TDF, TBV, LAM (TDF preferred)
Terrault NA, et al. Hepatology. 2018;67:1560‐99; EASL. J Hepatol. 2017;67:370‐98.
Reactivation and Cure
What Is Reactivation of HBV?• Occurs in patients with active (HBsAg+) and resolved (HbsAg‐, anti‐HBc+) HBV infection
– ccc‐DNA remains in liver (patient can test immune)
• Can occur during treatment with immunosuppressive agents • Characterized by abrupt increase in HBV DNA and increase in ALT/AST
– Leads to hepa s flare and can cause fulminant liver failure → death
Hwang, et al. J Clin Oncol. 2015;33:2212‐20.
HBsAg+/anti‐HBc+ HBV DNA+
Rise in HBV DNA level compared with baseline
Baseline HBV Status ReactivationInitiation of Immunosuppressive
Therapy
HBsAg+/anti‐HBc+ HBV DNA‐
Appearance of HBV DNA: HBV DNA‐ to HBV DNA+
HBsAg‐/anti‐HBc+ HBV DNA‐
Reverse seroconversion: HBsAg‐ to HBsAg+ (HBV DNA ±)
Appearance of HBV DNA withoutHBsAg: HBV DNA‐ to HBV DNA+
HBV Reactivation in the Setting of Chemotherapy
Slide courtesy of Dr. Su Wang. Lok ASF, et al. Ann Intern Med. 2012;156:743‐45.
Pre‐Chemo HBsAg+ HBV DNA +/‐ ALT Normal
X
X XHBV‐Specific B & T Cells
Controlled HBV Replication
During Chemo HBsAg+ HBV DNA +++ ALT Abnormal
Loss of HBV‐Specific B & T Cells
Uncontrolled HBV Replication
Post‐Chemo HBsAg+ HBV DNA +++
ALT Flare
Immune Activation HBV Clearance
Hepatocyte Damage
HBV DNAin nucleus
cccDNA
HBV DNAin nucleus
cccDNA
HBV DNAin nucleus
cccDNA
XX
ASCO Guidelines for HBV Reactivation
Hwang JP, et al. JCO. 2015;33:2212‐20.
Results: Positive
Conduct HBsAg and anti‐HBc Screening
Results: Positive
HBsAg‐/anti‐HBc+ Immunosuppressive therapy associated with
high risk of HBV reactivation
Prophylactic antiviral therapy or monitor HBV DNA and ALT with on‐demand antiviral therapy; consult hepatitis B specialist
Risk Factors Associated With HBV infection• Born in ≥ 2% HBV prevalence country• Parents born in high‐prevalence region• Household or sexual contact with HBV+ person • HIV+• Injection drug use•Men who have sex with men
Therapies Associated With High Risk of HBV• B cell–depleting agents• Stem‐cell transplantation
HBsAg‐/anti‐HBc+ Immunosuppressive therapy not associated
with high risk of HBV reactivation
HBsAg+/anti‐HBc+ Immunosuppressive therapy
Prophylactic antiviral therapy and monitor HBV DNA and ALT;
consult HBV specialist
Monitor HBV DNA and ALT with on‐demand antiviral therapy
HBV Reactivation in Patients With HCV Receiving DAAs• Reports of HBV reactivation in patients receiving treatment with DAAs• In an observational study of Chinese patients receiving DAAs for HCV infection (N = 327):
– 10 patients positive for HBsAg 3 of 10 patients with HBV reactivation
– Of 124 patients with HBsAg‐/HBeAb+, none experienced HBV reactivation
• Phase 3b study in Taiwan patients with HCV/HBV infection (N = 111) received DAAs– Of 37 patients with baseline HBV DNA < 20 IU/mL, 31 patients had > 1 quantifiable HBV DNA– Of 74 patients with baseline HBV DNA > 20 IU/mL, 39 had increases of HBV DNA > 1 log10 IU/mL– 5 patients had increased levels of HBV DNA and ALT
• FDA requires boxed warning for certain DAAs regarding the risk of HBV reactivation and the need for screening/monitoring patients treated with DAAs for HCV
Collins JM, et al. Clin Infect Dis. 2015;61:1304‐6; Ende AR, et al. J Med Case Rep. 2015;9:164; Hayashi K, et al. Clin J Gastroenterol. 2016;9:252‐6; Wang C, et al. Clin Gastroenterol Hepatol. 2017;15:132‐6; Liu CJ, et al. Gastroenterology. 2018;154:989‐97; FDA. www.fda.gov/media/100702/download32.
Guidance on HBV Reactivation in Patients Receiving DAAs for HCV • HBV vaccination recommended for susceptible individuals • All patients starting HCV DAAs should be screened for HBV infection
– If HBsAg+, test HBV DNA prior to, during, and immediately after HCV treatment For > 20,000 IU/mL, start HBV treatment For low or undetectable HBV DNA, one of two approaches are recommended:
» Initiate prophylactic antiviral therapy (continued until 12 weeks after completion of DAA therapy)
»Monitor HBV DNA levels during and after DAA therapy; antiviral therapy should be initiated if HBV DNA > 10‐fold increase above baseline or > 1,000 IU/mL in those with previously undetectable HBV DNA levels
AASLD/IDSA HCV Guidelines. 2018.
Prevention of Resistance Should Rely on the Use of First‐Line NAs With a High Barrier to Resistancea
EASL. J Hepatol. 2017;67:370‐98.
Cumulative incidence of HBV resistance to NAs in pivotal trials in NA‐naïve patients with chronic HBV infectionb
24
38
49
67 70
0 311
18
29
4
17
0.50.2 1.20 0 0 0 0 0 00
10
LAM
20
30
40
50
ADV TBV ETV TDFb TAF
60
70
80
aEvidence level I, grade of recommendation 1. bCollation of currently available data—not from head‐to‐head studies.No evidence of resistance has been shown after 8 years of TDF treatment.
1 year2 years3 years4 years5 years
What Does HBV Cure Look Like? Viral Suppression vs. Functional Cure vs. Sterilizing Cure
Reprinted from Durantel D, et al. J Hepatol. 2016;64:S117‐31. © 2016, with permission from Elsevier.
Liver
BloodNo treatment
Liver
BloodNA induced virus
suppression (HBe seroconversion ~20%)
Liver
BloodDecreased viral RNA and
protein synthesis HBsAg loss and seroconversion
Liver
BloodElimination of cccDNA but persistence of integrated
viral DNA
Virus suppression Functional care Complete care
InfectiousparticlesHBsAg
Mature nucleocapsid
IntegratedDNA
Viral RNA
cccDNA
HBeAg
Anti‐HBe
Anti‐HBs
Contact Information
For questions or comments about this activity, please contact Marietta Saunders.
Call (toll‐free): (919) 833‐2110 Email: msaunders@ncafp.com
Please visit us online at www.Med‐IQ.com for additional activities provided by Med‐IQ®.
Unless otherwise indicated, photographed subjects who appear within the content of this activity or on artwork associated with this activity are models; they are not actual
patients or doctors.
HBV Screening: Abbreviations and Acronyms
ADV = adefovir dipivoxil AFP = alpha‐fetoprotein ALT = alanine transaminase Anti‐HBc = antibody to hepatitis B core antigen Anti‐HBe = antibody to hepatitis B e antigen Anti‐HBs = antibody to hepatitis B surface antigen AST = aspartate aminotransferase CBC = complete blood count cccDNA = covalently closed circular DNA CNS = central nervous system DAA = direct‐acting antiviral ETV = entecavir HBV = hepatitis B HAV = hepatitis A virus HBeAb = hepatitis B e antibody HBeAg = hepatitis B e antigen HBsAg = hepatitis B surface antigen HCC = hepatocellular carcinoma HCV = hepatitis C virus HDV = hepatitis D virus HIV = human immunodeficiency virus INR = international normalized ratio LAM = lamivudine LFT = liver function test NA = nucleos(t)ide analogue PegIFN = pegylated interferon PWID = people who inject drugs TAF = tenofovir alafenamide fumarate TB = tuberculosis TBV = telbivudine TDF = tenofovir disoproxil fumarate ULN = upper limit of normal US = United States