Hepatitis B: Update from the 2017 Liver Meetings. Jama M. Darling, MD UNC High Impact Hepatology November 4, 2017

Transcription

1 Hepatitis B: Update from the 2017 Liver Meetigs Jama M. Darlig, MD UNC High Impact Hepatology November 4, 2017

2 Disclosure Slide Speakers Bureau: Noe Advisory board: Noe Grat Support: AbbVie This talk does cotai off label use of drugs.

3 Learig Objectives for HBV: Focused questios i 2017: How do we elimiate HBV by 2030? How does the practicig cliicia choose betwee FDA approved HBV therapies? Should we chage the treatmet paradigm from cotrol to fuctioal cure of HBV? Are we seeig reactivatio of HBV o HCV therapy with DAA s? What is the icidece of HBV i NC?

4 Chroic Hepatitis B is the Sigle Most Commo Cause of Cirrhosis ad HCC Worldwide I 2010, about 248 millio idividuals were HBsAg positive Lacet ;10003 p

5 Trasmissio of HBV Ifectio Trasfusio (blood, blood products) Child to Child Mother to Baby Fluids (blood, seme) HEPATITIS B Cotamiated Needles ad Syriges Orgas ad Tissue Trasplatatio Log term care facilities Diabetics i ursig homes Hemodialysis

6 WHO Viral Hepatitis Strategy Goal: Elimiate viral hepatitis as a major public health threat by Defiitio of Elimiatio: Reductio to zero of the icidece of ifectio caused by a specific aget i a defied geographical area as a result of deliberate efforts. MMWR 1999;48(SU01):23-7

7 WHO Viral Hepatitis Strategy Adapted from M. Ghay AASLD Post Grad Course 2017

8 Key US Strategies for Elimiatig HBV Adapted from Marc Ghay AASLD Post Grad Course 2017

9 Key Strategies to Elimiatig HBV What s Workig i US What Ca be Improved High ifat vacciatio coverage ACIP icorporates AASLD guidace o use of ativiral therapy i 3rd trimester USPSTF recommeds screeig for hepatitis B virus (HBV) ifectio i persos at high risk for ifectio (Grade B) Improve birth dose coverage Catch-up vacciatio i adults Screeig of high risk idividuals Traiig of physicias with expertise i maagig chroic HBV ifectio Ativirals ow geeric Adapted from Marc Ghay AASLD Post Grad Course 2017

10 Case #1 62 yo Korea female origially see i 2007 at UNC ad foud to be HBeAg(-), HBeAb(+) with a ALT of 22 ad HBV DNA of 1864 iu/ml. She was lost to follow-up ad retured i 2012 with ad ALT of 138 ad HBV DNA 1,000,000 iu/ml HBeAg(-) ad HBeAb(+). She was placed o teofovir (TDF) i 7/2012 ad has bee HBV DNA udetectable sice 5/2013 with a ALT i the 20 s. She had stage II fibrosis o Fibrosca. She also has T2DM ad osteopeia. Her Cr is 1.2. Her questio for me is: I m worried about my kideys with my diabetes. What are the optios for my HBV?

11 Curret therapeutic optios for chroic hepatitis B i US FDA-approved medicatios Pegiterfero alfa-2a, iterfero alpha-2b Lamivudie Adefovir Etecavir Teofovir disoproxil fumarate (TDF) Teofovir alafeamide (TAF) Telbivudie (discotiued)

12 Teofovir alafeamide (TAF): A ew optio i ucleos(t)ide therapy TAF: ovel prodrug of teofovir disoproxil fumarate (TDF) formulated to deliver active metabolite to hepatocytes at lower doses with lower systemic exposure I o-iferiority studies, TAF showed equally effective viral suppressio i eag+ ad eag- patiets as TDF at 96wks with o resistace Agarwal et al EASL 2017 Ab FRI-153; Bruetto et al EASL 2017 Ab PS-042

13 Switch to Teofovir alafeamide (TAF) from Teofovir (TDF) Improved Boe ad Real Safety Profile at 1 year. Aalysis of ope-label extesio data from 2 phase III trials i HBV-ifected pts switchig from TDF to TAF at Wk 96 88% of pts achieved virologic suppressio at Wk 96 (pre switch) ad maitaied to Wk 120 (post switch) Sigificatly higher proportio of pts achieved ALT ormalizatio after switch to TAF Sigificatly smaller effect o real fuctio ad BMD with TAF Agarwal et al EASL 2017 Ab FRI-153; Bruetto et al EASL 2017 Ab PS-042

14 What s the best choice amog Nucleos(t)ide Aalogues? For most patiets with o prior therapy ad o sigificat medical comorbidities- ETV, TDF or TAF is fie (what s o formulary with best co-pay). TAF or ETV are better choices for: Age > 60 Real dysfuctio Boe disease No dose adjustmet with TAF for CrCl > 15 TAF or TDF with prior LAMr or HIV co-ifectio

15 Case #2 64 yo WM with CHB, HBeAg-, HBeAb+, with HBV DNA ot detected o logstadig etecavir (ETV). Medical co-morbidities iclude HTN, DM ad recet diagosis of CAD requirig stetig. He has kow cirrhosis based o imagig. He receives regular HCC screeig with imagig q 6 moths ad AFP. He stopped drikig all alcohol about 12 yrs ago. He is retired from the Army. His questio for me is: Is my HBV medicatio goig to lower my risk of developig liver cacer?

16 HBV Treatmet Goals HBeAg loss/ serocoversio Udetectable Serum HBV DNA Lower cccdna Treatmet Goals Lower HCC Risk Normal ALT HBsAg clearace Improved Histology

17 1,951 adult Caucasia CHB patiets without HCC at baselie who received ETV/TDF for 1 year were followed for 5-10 yrs. The yearly HCC icidece rate did ot differ withi ad after the first 5 years i patiets without cirrhosis (0.49% versus 0.47%, P = 0.931), but it sigificatly declied i patiets with cirrhosis (3.22% versus 1.57%, P = 0.039). Older age (especially 50 years), lower platelets, ad liver stiffess 12 kpa at year 5 represet the mai risk factors for late HCC developmet.

18 Screeig for HCC i HBV Asia males 40 years Asia females 50 years All cirrhotic hepatitis B carriers Family history of HCC Africas over age 20 For ocirrhotic hepatitis B carriers ot listed above, the risk of HCC varies depedig o the severity of the uderlyig liver disease ad HBV DNA levels. May istitute earlier especially with vertical trasmissio. Ultrasoud q 6 moths (AFP if US uavailable)

19 Case #3 34 yo Asia female who has bee suppressed o teofovir sice She preseted with eag+, immue active disease with a liver biopsy showig stage 3-4 fibrosis. She is otherwise healthy ad is compliat with her TDF ad abdomial US q 6 moths. Her questio for me is: Am I goig to have to take this medicatio for the rest of my life or is there a cure for HBV o the horizo?

20 Why is fiite therapy a goal for HBV treatmet? Cost-savigs to healthcare system Youger patiets fid lifelog therapy harder to accept Pregacy issues Log-term adherece Reluctace to start therapy due to lack of safe stoppig poit Log-term safety questios Works days lost due to cliic visits

21 New HBV Treatmets Virology Etry Ihibitors cccdna degradatio/silecig RNA iterferece (RNAi gee silecig) Assembly ihibitors (Nucleocapsid) sag release ihibitors Immuology Peg-iterfero(s) TLR or RIG-I agoists Therapeutic vaccie PD1-PDL1 blockig

22 Novel Targets for HBV Cure Seto et al Cliical Liver Dis 2016 vol 8(4):83-88

23 HBcrAg, HBV-RNA Declies i A Phase 2a Study Evaluatig the Multi-Dose Activity of ARB-1467 i HBeAg-Positive ad Negative Virally Suppressed With Hepatitis B No apparet correlatio was observed betwee declies i HBV- RNA or HBcrAg ad declies i HBsAg Baselie HBsAg ad IL28b geotype CC were sigificatly associated with respose ARB-1467 was well tolerated LB17 Agarwal et al AASLD 2017

24 Safety, Tolerability, Pharmacokietics ad Ativiral Activity of JNJ , a Novel HBV Capsid Assembly Modulator, i No-cirrhotic, Treatmet-aïve Subjects with Chroic Hepatitis B. JNJ (JNJ-379): potet capsid assembly modulator (CAM) JNJ-379 bids to the HBV core protei ad iterferes with the HBV capsid assembly, ad prevets cccdna formatio durig de ovo ifectio, by iterferig with capsid disassembly Three patiets with HBV DNA <LLOQ of the HBV DNA assay. Zoulim et al LB15 AASLD 2017 (slide from Paul Kwo)

25 New HBV Treatmets: Prospects for Cure NA s are safe, effective ad difficult to replace. Log-term therapy usually required as durable remissio with NA s is about 57% eagad 76% eag+ (Hepatology 2016;63:1481) There is a shift i ed poits from cotrol to fuctioal cure with HBsAg serocoversio. Destructio of cccdna for complete cure is possible but difficult. New ati-viral therapies ad immue modulators are beig developed for HBV. Combiatio therapy will likely be required for cure.

26 Combiatio therapy for HBV Cure Seto et al Cliical Liver Dis 2016 vol 8(4):83-88

27 Case #4 55 yo Caucasia male with chroic HBV eag-, eab+, HBV DNA detected <10iu/ml co-ifected with HCV geotype 1a VL 587,000 iu/ml He has a remote history of drug ad alcohol abuseoe i > 10 yrs. His ALT is 57 ad Fibrosca is 7.3 kpa (F1-F2). His questios for me is: I m excited about havig my HCV treated but will it make my HBV worse?

28 Hepatology. 2016;63: hcvguidelies.org (AASLD/IDSA)

29 AB122: Hepatitis B Reactivatio is Ucommo i Persos Treated with Directly Actig Ativiral Agets Agaist HCV: Results from ERCHIVES HBV reactivatio (defied as ew detectable HBV DNA or icrease of more tha 1 log10), ALT flare (defied as serum ALT >5X from baselie i presece of HBV reactivatio Butt et al AASLD 2017

30 Case #5 36 yo WM with a 6 yr h/o IVDU. He is brought i by his Mom because he looks yellow. He has oted some malaise, dark urie ad mild RUQ discomfort as well as decreased appetite. He remembers beig told he tested positive for HCV i the past. Labs show AST 958 ALT 1174 AP 139 TB 6.9 INR 1.0, HCV Ab+, HCV RNA eg, HBsAg+, HBcIgM+, HBV DNA 889,000 iu/ml, HIV eg His questio for me is: Do I eed treatmet for hepatitis C?

31 2015 State Acute HBV Icidece Compared to Healthy People 2020 Natioal Goal 21,900 acute hepatitis B cases i the US i

32 Outcome of Hepatitis B Virus Ifectio by Age of Trasmissio Chroic Ifectio (%) % Predomiatly eoatal ifectio i Asia Chroic ifectio Symptomatic ifectio 25-30% Predomiatly adult ifectio i Wester coutries <5% Symptomatic Ifectio (%) Birth 1-6 mos 7-12 mos 1-4 yrs Older Childre ad Adults

33 Acute Hepatitis B Care is usually supportive Cosider therapy if INR > 1.5, Tbili > 10 or ecephalopathy Cosider therapy if other uderlyig liver disease or cirrhosis or immuosuppressed Ask yourself why this patiet was t vacciated?

34 AASLD Washigto DC 2017 Which presidetial memorial i DC promietly features his dog?