Hepatitis B: Update from the 2017 Liver Meetings

Jama M. Darling, MDUNC High Impact HepatologyNovember 4, 2017

Disclosure Slide

n Speakers Bureau: Nonen Advisory board: Nonen Grant Support: AbbVien This talk does contain off label use of

drugs.

Learning Objectives for HBV:

n Focused questions in 2017: ¨ How do we eliminate HBV by 2030?¨ How does the practicing clinician choose

between FDA approved HBV therapies?¨ Should we change the treatment paradigm

from control to functional cure of HBV?¨Are we seeing reactivation of HBV on HCV

therapy with DAA’s?¨What is the incidence of HBV in NC?

Chronic Hepatitis B is the Single Most Common Cause of Cirrhosis and HCC Worldwide

In 2010, about 248 million individuals were HBsAg positive

Lancet 2015 386;10003 p1546–1555

Transfusion(blood, blood

products)

Fluids(blood, semen)

Organs andTissue

Transplantation

ContaminatedNeedles

and Syringes

Mother to Baby

Hemodialysis

HEPATITIS B

Transmission of HBV Infection

Long term care facilities

Diabetics in nursing homes

Child to Child

WHO Viral Hepatitis Strategy

n Goal: Eliminate viral hepatitis as a major public health threat by 2030.

n Definition of Elimination: Reduction to zero of the incidence of infection caused by a specific agent in a defined geographical area as a result of deliberate efforts.

MMWR 1999;48(SU01):23-7

WHO Viral Hepatitis Strategy

Adapted from M. Ghany AASLD Post Grad Course 2017

Key US Strategies for Eliminating HBV

Adapted from Marc Ghany AASLD Post Grad Course 2017

Adapted from Marc Ghany AASLD Post Grad Course 2017

What’s Working in US

n High infant vaccination coverage

n ACIP incorporates AASLD guidance on use of antiviral therapy in 3rd trimester

n USPSTF recommends screening for hepatitis B virus (HBV) infection in persons at high risk for infection (Grade B)

n Antivirals now generic

What Can be Improved

n Improve birth dose coveragen Catch-up vaccination in adultsn Screening of high risk

individualsn Training of physicians with

expertise in managing chronic HBV infection

Key Strategies to Eliminating HBV

Case #1

n 62 yo Korean female originally seen in 2007 at UNC and found to be HBeAg(-), HBeAb(+) with an ALT of 22 and HBV DNA of 1864 iu/ml.

n She was lost to follow-up and returned in 2012 with and ALT of 138 and HBV DNA 1,000,000 iu/ml HBeAg(-) and HBeAb(+).

n She was placed on tenofovir (TDF) in 7/2012 and has been HBV DNA undetectable since 5/2013 with an ALT in the 20’s. She had stage II fibrosis on Fibroscan. She also has T2DM and osteopenia. Her Cr is 1.2.

n Her question for me is:¨ I’m worried about my kidneys with my diabetes. What are

the options for my HBV?

Current therapeutic options for chronic hepatitis B in US

n FDA-approved medications¨ Peginterferon alfa-2a, interferon alpha-2b¨ Lamivudine¨ Adefovir¨ Entecavir¨ Tenofovir disoproxil fumarate (TDF)¨ Tenofovir alafenamide (TAF)¨ Telbivudine (discontinued)

Tenofovir alafenamide (TAF): A new option in nucleos(t)ide therapy

n TAF: novel prodrug of tenofovir disoproxil fumarate (TDF) formulated to deliver active metabolite to hepatocytes at lower doses with lower systemic exposure

n In non-inferiority studies, TAF showed equally effective viral suppression in eAg+ and eAg- patients as TDF at 96wks with no resistance

Agarwal et al EASL 2017 Ab FRI-153; Brunetto et al EASL 2017 Ab PS-042

Switch to Tenofovir alafenamide (TAF) from Tenofovir (TDF) Improved Bone and Renal Safety Profile at 1 year.

§Analysis of open-label extension data from 2 phase III trials in HBV-infected pts switching from TDF to TAF at Wk 96§88% of pts achieved virologic suppression at Wk 96 (pre switch) and maintained to Wk 120 (post switch)§Significantly higher proportion of pts achieved ALT normalization after switch to TAF

Significantly smaller effect on renal function and BMD with TAF

Agarwal et al EASL 2017 Ab FRI-153; Brunetto et al EASL 2017 Ab PS-042

What’s the best choice among Nucleos(t)ide Analogues?

n For most patients with no prior therapy and no significant medical comorbidities- ETV, TDF or TAF is fine (what’s on formulary with best co-pay).

n TAF or ETV are better choices for:¨ Age > 60¨ Renal dysfunction¨ Bone disease

n No dose adjustment with TAF for CrCl > 15n TAF or TDF with prior LAMr or HIV co-infection

Case #2

n 64 yo WM with CHB, HBeAg-, HBeAb+, with HBV DNA not detected on longstanding entecavir (ETV).

n Medical co-morbidities include HTN, DM and recent diagnosis of CAD requiring stenting. He has known cirrhosis based on imaging. He receives regular HCC screening with imaging q 6 months and AFP.

n He stopped drinking all alcohol about 12 yrs ago. He is retired from the Army.

n His question for me is:¨ Is my HBV medication going to lower my risk of

developing liver cancer?

TreatmentGoals

Normal ALT

UndetectableSerum

HBV DNA

HBeAg loss/seroconversion

ImprovedHistologyHBsAg

clearance

HBV Treatment Goals

Lower HCCRisk

LowercccDNA

n 1,951 adult Caucasian CHB patients without HCC at baseline who received ETV/TDF for ≥1 year were followed for 5-10 yrs.

n The yearly HCC incidence rate did not differ within and after the first 5 years in patients without cirrhosis (0.49% versus 0.47%, P = 0.931), but it significantly declined in patients with cirrhosis (3.22% versus 1.57%, P = 0.039).

n Older age (especially ≥50 years), lower platelets, and liver stiffness ≥12 kPa at year 5 represent the main risk factors for late HCC development.

Screening for HCC in HBV

n Asian males ≥40 yearsn Asian females ≥50 yearsn All cirrhotic hepatitis B carriersn Family history of HCCn Africans over age 20n For noncirrhotic hepatitis B carriers not listed above, the

risk of HCC varies depending on the severity of the underlying liver disease and HBV DNA levels. May institute earlier especially with vertical transmission.

n Ultrasound q 6 months (AFP if US unavailable)

Case #3

n 34 yo Asian female who has been suppressed on tenofovir since 2012. She presented with eAg+, immune active disease with a liver biopsy showing stage 3-4 fibrosis.

n She is otherwise healthy and is compliant with her TDF and abdominal US q 6 months.

n Her question for me is:¨Am I going to have to take this medication for the

rest of my life or is there a “cure” for HBV on the horizon?

Why is finite therapy a goal for HBV treatment?

Pregnancy issues

Younger patients find lifelong therapy

harder to accept

Long-term adherence

Cost-savings to healthcare system

Works days lost due to clinic visits

Reluctance to start therapy due to lack of safe stopping point Long-term safety

questions

New HBV Treatments

n Virology¨ Entry Inhibitors¨ cccDNA degradation/silencing¨ RNA interference (RNAi gene silencing)¨ Assembly inhibitors (Nucleocapsid)¨ sAg release inhibitors

n Immunology¨ Peg-interferon(s)¨ TLR or RIG-I agonists¨ Therapeutic vaccine¨ PD1-PDL1 blocking

Novel Targets for HBV “Cure”

Seto et al Clinical Liver Dis 2016 vol 8(4):83-88

HBcrAg, HBV-RNA Declines in A Phase 2a Study Evaluating the Multi-Dose Activity of ARB-1467 in HBeAg-Positive and Negative Virally SuppressedWith Hepatitis B

• NoapparentcorrelationwasobservedbetweendeclinesinHBV-RNAorHBcrAg anddeclinesinHBsAg

• BaselineHBsAg andIL28bgenotypeCCweresignificantlyassociatedwithresponse

• ARB-1467waswelltolerated

LB17 Agarwal et al AASLD 2017

Safety, Tolerability, Pharmacokinetics and Antiviral Activity of JNJ-56136379, a Novel HBV Capsid Assembly Modulator, in Non-cirrhotic, Treatment-naïve Subjects with Chronic Hepatitis B.

n JNJ-56136379 (JNJ-379): potent capsid assembly modulator (CAM)

n JNJ-379 binds to the HBV core protein and interferes with the HBV capsid assembly, and prevents cccDNA formation during de novo infection, by interfering with capsid disassembly

ThreepatientswithHBVDNA<LLOQoftheHBVDNAassay.

Zoulim et al LB15 AASLD 2017 (slide from Paul Kwo)

New HBV Treatments: Prospects for Cure

n NA’s are safe, effective and difficult to replace. Long-term therapy usually required as durable remission with NA’s is about 57% eAg-and 76% eAg+ (Hepatology 2016;63:1481)

n There is a shift in end points from control to functional cure with HBsAg seroconversion.

n Destruction of cccDNA for complete cure is possible but difficult.

n New anti-viral therapies and immune modulators are being developed for HBV.

n Combination therapy will likely be required for “cure”.

Combination therapy for HBV “Cure”

Seto et al Clinical Liver Dis 2016 vol 8(4):83-88

Case #4

n 55 yo Caucasian male with chronic HBV eAg-, eAb+, HBV DNA detected <10iu/ml co-infected with HCV genotype 1a VL 587,000 iu/ml

n He has a remote history of drug and alcohol abuse-none in > 10 yrs.

n His ALT is 57 and Fibroscan is 7.3 kPa (F1-F2).n His questions for me is:

¨ I’m excited about having my HCV treated but will it make my HBV worse?

hcvguidelines.org (AASLD/IDSA)

Hepatology. 2016;63:261-283

AB122: Hepatitis B Reactivation is Uncommon in Persons Treated with Directly Acting Antiviral Agents Against HCV: Results from ERCHIVES

Butt et al AASLD 2017

HBV reactivation (defined as new detectable HBV DNA or increase of more than 1 log10), ALT flare (defined as serum ALT >5X from baseline in presence of HBV reactivation

Case #5

n 36 yo WM with a 6 yr h/o IVDU. He is brought in by his Mom because he looks yellow. He has noted some malaise, dark urine and mild RUQ discomfort as well as decreased appetite. He remembers being told he tested positive for HCV in the past.

n Labs show AST 958 ALT 1174 AP 139 TB 6.9 INR 1.0, HCV Ab+, HCV RNA neg, HBsAg+, HBcIgM+, HBV DNA 889,000 iu/ml, HIV neg

n His question for me is:¨Do I need treatment for hepatitis C?

2015 State Acute HBV Incidence Compared to Healthy People 2020 National Goal

21,900 acute hepatitis B cases in the US in 2015

www.cdc.gov/hepatitis/statistics/2015surveillance/commentary.ht

Chr

onic

Infe

ctio

n (%

)Sym

ptomatic Infection (%

)

100100

Birth 1-6 mos 7-12 mos 1-4 yrs Older Childrenand Adults

0

20

40

60

8080

60

40

20

0

90%

25-30%

<5%

Outcome of Hepatitis B Virus Infectionby Age of Transmission

Predominantly adult infection

in Western countries

Chronic infectionSymptomatic infection

Predominantly neonatal infection

in Asia

Acute Hepatitis B

n Care is usually supportiven Consider therapy if INR > 1.5, Tbili > 10 or

encephalopathyn Consider therapy if other underlying liver

disease or cirrhosis or immunosuppressed

n Ask yourself why this patient wasn’t vaccinated?

AASLD Washington DC 2017

Which presidential memorial in DC prominently features his dog?