10/27/2016
State-of-the-Art Prevention and Management of Hepatitis B Virus Infection Kenneth E. Sherman, MD, PhD Gould Professor of Medicine University of Cincinnati Cincinnati, Ohio
FORMATTED: 10/11/16 New York, New York: November 4, 2016
Learning Objectives After attending this presentation, learners will be able to: Describe the principles of hepatitis B virus (HBV) prevention through vaccination Describe current and emerging therapies for HBV infection Describe the known risk factors of hepatocellular carcinoma (HCC) and summarize the available approaches for screening and surveillance for early detection and management Slide 3 of 40
CASE • A 47 yo MSM with history of HIV for 11 years develops acute onset of jaundice, abdominal pain, nausea and anorexia. He reports having one partner in stable relationship – HIV regimen changed 6 months ago due to rising creatinine attributed to TDF. cART efavirenz/tenofovir/emtricitibine changed to efavirenz/abacavir/lamivudine – ALT 847 AST 755 Bilirubin 11.7 Creatinine 1.47 mg/dl HIV< 50 copies/ml HLA-B*5701 negative Slide 4 of 40
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TOPICS • • • • •
EPIDEMIOLOGY VIROLOGY PREVENTION TREATMENT OTHER MANAGEMENT
Slide 6 of 40
Prevalence of Hepatitis B Virus • Globally 2 billion people have been exposed • 350 million people with chronic HBV infection
Slide 7 of 40
HBV/HIV Disease Burden Worldwide Prevalence of Chronic Hepatitis B and HIV
HIV 50 million
HBV 350 million
4-8 million HBV/HIV coinfected Slide 8 of 40
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Increased Liver Mortality in HIV/HBV Coinfected Men: MACS 16
14.2
14 Liver MR/1000 PYs
• 5293 men (326 HBsAg+ baseline) followed 10.5 years
12 10 8 6 4 2
Slide 9 of 40
VB /H VHI
Thio C et al. Lancet. 2002;360:1921-26.
1.7
0.8
0.0
0
+ BV /H VHI
BV /H V+ HI
+ BV /H V+ HI
D:A:D Study: Independent Predictors of Liver-Related Death in HIV Latest CD4 Cell Count (cells/µL)
16.06
500
2.01
HIV Acquisition via IDU Hepatitis C Status Negative
6.66
Positive
Hepatitis B Status Negative
3.73
Positive 0.2
D:A:D: Data Collection on Adverse Events of Anti-HIV Drugs.
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1.0
10
100
Relative Risk of Death
Weber R, et al. Arch Intern Med. 2006;166:1632-1641.
ESLD NA-ACCORD
Marina B. Klein et al. Clin Infect Dis. 2016
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HCC RISK REVEAL COHORT Baseline HBV DNA ≥106 copies/mL
RR 6.6
105– 2.0 indicates cirrhosis
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Sarin et al., HEPATOL INT, 2016
HBV MANAGEMENT APASL
Liver stiffness > 8 kPa (by transient elastography) or APRI > 1.5 indicates significant fibrosis; Liver stiffness > 11 kPa (by transient elastography) or APRI > 2.0 indicates cirrhosis
Slide 28 of 40
Sarin et al., HEPATOL INT, 2016
HBV MANAGEMENT APASL
Consider LT if no stabilization
* Cirrhosis by non-invasive markers means Liver stiffness > 11 kPa (by transient elastography) or APRI > 2.0
Slide 29 of 40
Sarin et al., HEPATOL INT, 2016
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HBV/HIV COINFECTION TREATMENT GUIDELINES •
•
•
Prior to initiation of antiretroviral therapy (ART), all patients who test positive for hepatitis B surface antigen (HBsAg) should be tested for hepatitis B virus (HBV) DNA using a quantitative assay to determine the level of HBV replication (AIII). Because emtricitabine (FTC), lamivudine (3TC), and tenofovir (TDF) have activity against both HIV and HBV, if HBV or HIV treatment is needed, ART should be initiated with the combination of TDF + FTC or TDF + 3TC as the nucleoside reverse transcriptase inhibitor (NRTI) backbone of a fully suppressive antiretroviral (ARV) regimen (AI). If HBV treatment is needed and TDF cannot safely be used, the alternative recommended HBV therapy is entecavir in addition to a fully suppressive ARV regimen (BI). (BII).
Slide 30 of 40
DHHS Guidelines for Use of Antiretroviral Agents in HIV-1 Infected Adults And Adolescents. Accessed 2/9/2016 at www.aidsinfo.nih.gov
TDF TO TAF REGIMEN SWITCH • Two Study Reports Available – Assess HIV Suppression Efficacy • N= 663 – Assess HBV Suppression Efficacy • N= 72
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100 90 80 70 60 50 % 40 30 20 10 0
Switch No Switch
Gallant JE, et al. CROI 2016 Gallant JE, et al. IAS 2015
HBV Mutation • Arises due to the relatively low fidelity of the HBV polymerase • Mutation rate of approximately 3x10-4 (Park et al., Eur J Biochem, 2004)
• 10-fold higher than most DNA viruses
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HBV Polymerase Key Mutations
Slide 33 of 40
Koziel and Peters, NEJM, 2007
HBV/HIV Coinfection Lamivudine Breakthrough 1200
LAMIVUDINE Anti-HBc IgM
+
+
-
ALT (U/L)
1000 800 600 400 200 0 0
4
8
12
16
20
ALT Slide 34 of 40
Bessesen et al., CID, 1999
RISK OF RESISTANCE
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Sarin et al., HEPATOL INT, 2016
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HBV Targets HBV HBeAg
Core particle plus strand synthesis
Recycling
HBsAg
Entry of HBV into cell Core particle minus strand synthesis Core assembly and RNA packaging
Vesicular transport to cell membrane Translation
Transcription
Repair
cccDNA Slide 36 of 40
THERAPEUTIC APPROACHES
VIROLOGIC
IMMUNOLOGIC VIRION ASSEMBLY INHIBITION THERAPEUTIC VACCINE
ENTRY/UNCOATING INHIBITION
DNA PROCESSING INHIBITION Slide 37 of 40
REVERSE TRANSCRIPTION INHIBITION IMMUNE STIMULATION cccDNA INHIBITION OR CLEAVAGE
BIOMARKERS OF RESPONSE Beyond HBV DNA and Serology • • • •
Quantitative HBsAg HBV RNA in SERUM cccDNA Elimination of Integrated HBV DNA
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HCC SURVEILLANCE • Who? – Asian male over 40 – Asian Female over 50 – Any with family history of HCC – African/North American Blacks – ALL Patients with Cirrhosis – HIV???
• How?
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– US every 6 months but some might need CT/MRI – ?AFP
Conclusions • Vaccination is a critical element of prevention but current methods are imperfect, particularly in those with HIV infection • Treatment goal is complete suppression of HBV viral replication • Long term suppression will rarely lead to functional cure (HBsAg negative state) • Other modalities are needed to clear cccDNA reservoir or to achieve functional cure • Don’t forget HCC screening/surveillance Slide 40 of 40
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