Toward Elimination HBV Recognition: A Combined Strategy · 2019. 11. 1. · 12 Saturday General...

12

Saturday General Session

MovingTowardEliminationThroughBetterHBVRecognition:ACombinedPatient/ProviderStrategy

RichardAndrews,MD,MPHBoard-certified Family Physician Hope Clinic Houston, Texas EducationalObjectivesBy the end of this educational activity, participants should be better able to:

1. Improve awareness of HBV among at-risk patient groups and reduce stigma about the disease.

2. Increase healthcare provider recognition of who and how to test for HBV in the primary care setting.

SpeakerDisclosure Dr. Andrews has disclosed that he has no actual or potential conflict of interest in relation to this topic. SupporterDisclosureThis educational activity is supported by an educational grant from Gilead. It has been planned and produced by North Carolina Academy of Family Physicians and Med-IQ with the Texas Academy of Family Physicians strictly as an accredited continuing medical education activity.

1

Instructions to Receive Credit

• Please refer to the Texas’s Chapter instructions on how to redeem credit for this lecture.

• The surveys and evaluation being handed out during this lecture are not related to credit redemption and are optional, however your completion of them is greatly appreciated.

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.

Copyright

© 2019 Med‐IQ, Inc.

Statement of Evidence‐Based Content

Educational activities that assist physicians in carrying out their professional responsibilities more effectively and efficiently are consistent with the ACCME definition of continuing medical education (CME). As an ACCME‐accredited provider of CME, it is the policy of Med‐IQ to review and ensure that all the content and any recommendations, treatments, and manners of practicing medicine in CME activities are scientifically based, valid, and relevant to the practice of medicine. Med‐IQ is responsible for validating the content of the CME activities it provides. Specifically, (1) all recommendations addressing the medical care of patients must be based on evidence that is scientifically sound and recognized as such within the profession; (2) all scientific research referred to, reported, or used in CME in support or justification of a patient care recommendation must conform to generally accepted standards of experimental design, data collection, and analysis.

Med‐IQ is not liable for any decision made or action taken in reliance upon the information provided through this activity.

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

2

Marietta SaundersCME Specialist NC Academy of Family PhysiciansRaleigh, NC

Amy Burdette, PhDManager, Educational Strategy & ContentMed‐IQBaltimore, MD

Activity Planners Disclosure Statement

The 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

VA

WV

KY

ALMS

SC

NC

GA

FL

MA

DE

DC

NJ

MD

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)

3

Global Deaths From Viral Hepatitis Now Exceed HIV, TB, or Malaria

WHO. www.who.int/hepatitis/publications/global‐hepatitis‐report2017/en.

0.0

Deaths, 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

Number of Cases

7,000

8,000

9,000

2001 2004 20132010

6,000

5,000

4,000

3,000

2,000

1,000

2007 2016

Year

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

Number of 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

4

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.

Number of 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 All

Asiaa All

Australia and South Pacific All except Australia and New Zealand

Middle East All except Cyprus and Israel

Eastern Europe All except Hungary

Western Europe Malta, and indigenous populations in Greenland

North America Alaska natives and indigenous populations in northern Canada

Mexico and Central America Guatemala and Honduras

South America Ecuador; Guyana; Suriname; Venezuela; and Amazonian areas of Bolivia, Brazil, Colombia, and Peru

Caribbean 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.

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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 (‐)


HBeAg Positive HBeAg Negative

Chronic HBVInfection

Phase 1 Phase 2 Phase 3 Phase 4 Phase 5





Resolved HBVInfection

HBsAg High High/intermediate

Low Intermediate Negative

HBeAg Positive Positive Negative Negative Negative

HBV 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 (+)


ALT elevateda


ALT normal

HBeAg (+)


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.

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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


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


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

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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 Comments

First Line

Entecavir (ETV) 0.5 mg/1.0 mg po qd

Lactic acidosis (decompensated cirrhosis only) Generic, high potency, high genetic barrier to resistance

Tenofovir 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 Line

Adefovir 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 Line

Lamivudine (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 Therapy

Virological (on‐treatment)

Response: HBV DNA < 10 IU/mL

Primary nonresponse: < 1 log10 decrease in HBV DNA after 3 months of therapy

Partial response: HBV DNA decreased by > 1 log10 but still detectable after ≥ 12 months of therapy in compliant patients

Breakthrough: 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‐HBs

Biochemical 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.

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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.

9

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

6770

03

1118

29

4

17

0.50.21.2

0 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

Blood

No treatment

Liver

Blood

NA induced virus suppression

(HBe seroconversion ~20%)

Liver

BloodDecreased viral RNA and

protein synthesis HBsAg loss and seroconversion

Liver

Blood

Elimination of cccDNA but persistence of integrated

viral DNA

Virus suppression Functional care Complete care

Infectiousparticles

HBsAg

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: [email protected]

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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

Toward Elimination HBV Recognition: A Combined Strategy · 2019. 11. 1. · 12 Saturday General...

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