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ANTIVIRAL TREATMENT

VIRAL HEPATITIS author by

eLibrary Prof. MojcaBern Matičič, 2017 MD, PhD

Clinic for Infectious Diseases and Febrile Illnesses, University Medical Centre Ljubljana ESCMIDFaculty of Medicine, University of Ljubljana © Slovenia

Ljubljana: April 15, 2019 Global number of deaths due to infectious dieases, period 2000-2015

• Text here authorBy the year 2030: • Text here by 20 million • Text here new deaths

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WHO Global hepatitis report, 2017. Available at: http://apps.who.int/iris/bitstream/10665/255017/1/WHO-HIV-2017.06-eng.pdf. Global number of deaths due to viral hepatitis in 2015

96% ofauthordeaths due to byHBV and HCV

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WHO. Global hepatitis report, 2017. http://apps.who.int/iris/bitstream/10665/255017/1/WHO-HIV-2017.06-eng.pdf. Global number of deaths due to viral hepatitis in 2015 – hepatitis B and C are the major problems in Europe

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WHO Global hepatitis report, 2017. Available at: http://apps.who.int/iris/bitstream/10665/255017/1/WHO-HIV-2017.06-eng.pdf. A lifecycle of the three viruses

HBV HCV HIV

Lifelong persistance Does NOT enter authorLifelong persistance in hepatocyte nucleus the hepatocyte nucleus integrated in cellular genome (cccDNK) by of memory cells

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Soriano V, et al. J Antimicrob Chemother 2008;62:1–4. A lifecycle of the three viruses and their treatment

HBV HCV HIV

TREATMENT: TREATMENT: authorTREATMENT: No reservoir of infection Lifelong supression Clearance by Lifelong supression CURE

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Soriano V, et al. J Antimicrob Chemother 2008;62:1–4. A lifecycle of the three viruses and treatment

HBV HCV HIV

TREATMENT: TREATMENT: authorTREATMENT: No reservoir of infection Lifelong supression Clearance by Lifelong supression CURE

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Soriano V, et al. J Antimicrob Chemother 2008;62:1–4. The global burden of HBV and HCV infections

HBV HCV author Chronically by infected 257 million 71 million eLibrary Infection 9% 20% diagnosed ESCMID Infection© 8% 7% treated

WHO. Global hepatitis report, 2017. http://apps.who.int/iris/bitstream/10665/255017/1/WHO-HIV-2017.06-eng.pdf. author by

HEPATITISeLibrary C

ESCMID © Hepatitis C is a sistemic disease that may lead to life-threatening conditions

Extrahepatic manifestations Liver author40-73% by Immune Metabolic

HCV induces crioglobulins – HCV induces insulin eLibraryClinical features : resistance – risk for Chronic hepatitis type 2 diabetes • Fatigue mellitus: • Arthralgias/arthritis • T2DM associated with • Purpura metabolic syndrome • Decompensated cirrhosis • Sicca syndrome HCV may contribute to other metabolic complications: • Peripheral neuropathy ESCMID - Coronary artery disease – Acute • Membranoproliferative coronary stroke glomerulonephritis Hepatocellular© - Cerebral vascular diseae - Stroke • B-cell Non-Hodgkin lymphoma carcinoma - Chronic kidney disease – End Stage Renal Disease

Ramos-Casals M et al. J Hepatol 2017; 66:1282-99. Timeline of HCV Therapy

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Sofosbuvir+Velpatasvir+Voxilaprevir ESCMID ©

P/R=pegylated nterferon+ribavirin RBV=ribavirin Sustained virological response (SVR) rates of HCV treatment (GT1, treatment naive)

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ESCMID ©

Adapted from Strader DB, et al. Hepatology 2004;39:1147-71. INCIVEK [PI]. Cambridge, MA: Vertex Pharmaceuticals; 2013. VICTRELIS [PI]. Whitehouse Station, NJ: Merck & Co; 2014. Jacobson I, et al. EASL 2013. Amsterdam. The Netherlands. Poster #1425. Manns M, et al. EASL 2013. Amsterdam. The Netherlands. Oral #1413. Lawitz E, et al. APASL 2013. Singapore. Oral #LB-02; Afdhal N, et al. N Engl J Med 2014; 370: 1889-98; Kowdley K, et al. N Engl J Med 2014; 370: 1879-88. Sustained virological response (SVR) rates of HCV treatment (GT1, treatment naive)

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NS5A ihibitors

Ombitasvir (OBV) Ledipasvir (LDV) Daclatasvirauthor (DCV) by Elbasvir (EBR) Pibrentasvir (PIB) Velpatasvir (VEL) eLibrary MK-8408 ruzasvir (RZR)* Polymerase inhibitors NS5B

Protease inhibitors Sofosbuvir (SOF) NS3/4A ESCMID Dasabuvir (DSV) Voxilaprevir (VOX) Grazoprevir (GZR) Glecaprevir (GLE) © MK-3682 uprifosbuvir (UPR)* Asunaprevir (ASV) Paritaprevir (PTV) Boceprevir (BOC) Narlaprevir (NAR) Simeprevir (SMV) * Investigational drugs. Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000. DAA combinations of 2nd generation

Pangenotypic author by

SOFOSBUVIR/ eLibrary SOFOSBUVIR/ VELPATASVIR GLECAPREVIR/ VELPATASVIR/ PIBRENTASVIR VOXILAPREVIR ESCMID ©

MAV—VHC—MED—164—nov17—R—A—DLU déc18 v1 Resistance-associated substitutions (RASs))

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EASL. Recommendations on Treatment of Hepatitis C 2018..J Hepatol 2018 (in press);https://doi.org/10.1016/j.jhep.2018.03.026 Efficacy of SOF/VEL/VOX for 12 Weeks in DAA-Experienced Patients

SVR12 in DAA-Experienced Patients With and Without RASs By HCV GT author by

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Sarrazin et al. EASL 2017; Poster THU-248. Which combination to choose?

Drug-drug interactions

Frequency of Underlyingauthor dosing diseasesby

Special Treatment conditions duration eLibrary (Tx)

Adverse Cirrhosis events ESCMID © Life style

DDI, drug–drug interaction. author by EASL Recommendations on Treatment of Hepatitis C 2018 eLibrary Chair: Jean-Michel Pawlotsky

EASL govrning board Representative : Francesco Negro Panel: AlessioESCMID Aghemo , Marina Berenguer, Olav Dalgard, Geoffrey Dusheiko, Fiona © Marra, Massimo Puoti, Heiner Wedemeyer

Presented on April 14, 2018 at EASL, in press in J Hepatology DAAs approved in Europe in 2018 and recommended by EASL guidelines 2018

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EASL. Recommendations on Treatment of Hepatitis C 2018..J Hepatol 2018 (in press);https://doi.org/10.1016/j.jhep.2018.03.026 INDICATIONS for Treatment of HCV infection

• All HCV infected patients UNIVERSAL ACCESS TO THERAPYauthor by • DAA based regimen without IFN and without ribavirine • For all patients: eLibrary • Those without and with cirrhosis (Child Pugh A)

• Those naive and pretreated ESCMID • Same© regimen for those with HIV infection

EASL. Recommendations on Treatment of Hepatitis C 2018..J Hepatol 2018 (in press);https://doi.org/10.1016/j.jhep.2018.03.026 EASL treatment recommendations 2018: no cirrhosis or compensated cirrhosis

Pangenotypic regimens Genotype-specific regimens Genotype SOF/VEL/ SOF/VEL GLE/PIB SOF/LDV GZR/EBR 3D VOX author Genotype 1a Yes Yes No* byYes a Yesb No Genotype 1b Yes Yes No* Yes Yes Yes

Genotype 2 Yes Yes No* No No No Genotype 3 Yesc eLibraryYes Yesd No No No Genotype 4 Yes Yes No* Yesa Yese No

Genotype 5 Yes Yes No* Yesa No No

Genotype 6 Yes Yes No* Yesa No No

*Triple combination therapy efficacious but not useful due to the efficacy of double combination regimens. aTreatment-naïve patients withoutESCMIDcirrhosis or with compensated (Child-Pugh A) cirrhosis. bTreatment-naïve and treatment-experienced patients without cirrhosis or with compensated (Child-Pugh A) cirrhosis with an HCV RNA level ≤800,000 IU/mL (5.9©Log IU/mL). 10 cTreatment-naïve and treatment-experienced patients without cirrhosis. dTreatment-naïve and treatment-experienced patients with compensated (Child-Pugh A) cirrhosis. e Treatment-naïve patients without cirrhosis or with compensated (Child-Pugh A) cirrhosis with an HCV RNA level ≤800,000 IU/mL (5.9 Log10 IU/mL) EASL. Recommendations on Treatment of Hepatitis C 2018..J Hepatol 2018 (in press);https://doi.org/10.1016/j.jhep.2018.03.026 EASL treatment recommendations 2018: decompensated cirrhosis

• No protease inhibitors +++ author • Sofosbuvir/Ledipasvir + RBV for 12 weeksby

• Sofosbuvir/Velpatasvir + RBV for 12 weeks eLibrary • Treatment for 24 weeks without ribavirin (contra-indications or poor tolerance to ribavirin) ESCMID ©

EASL. Recommendations on Treatment of Hepatitis C 2018..J Hepatol 2018 (in press);https://doi.org/10.1016/j.jhep.2018.03.026 EASL treatment recommendations 2018: other special groups

• Renal impairment • HBV coinfection author • Immune-complex mediated manifestationsby of chronic hepatitis C • Non-hepatic solid organ transplant recipients • PWIDs eLibrary • Haemoglobinopathies and bleeding disorders • Adolescents and children ESCMID ©

EASL. Recommendations on Treatment of Hepatitis C 2018..J Hepatol 2018 (in press);https://doi.org/10.1016/j.jhep.2018.03.026 DAAs and Drug-Drug Interactions

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EASL. Recommendations on Treatment of Hepatitis C 2018..J Hepatol 2018 (in press);https://doi.org/10.1016/j.jhep.2018.03.026 Benefits of Curing HCV infection

Cure author

Decreased Improved clinical by HCV transmission outcomes

Hepatic Extrahepatic Reduction in: eLibrary Improvement in: Cirrhosis All-cause mortality Decompensation Quality of life HCC Lymphoproliferative disorders Transplantation Diabetes, insulin resistance, ESCMID renal/cardiovascular outcomes © Neurocognition

Smith-Palmer J, et al. BMC Infect Dis. 2015;15:19. Negro F, et al. Gastroenterology. 2015;149:1345-1360. George SL, et al. Hepatology. 2009;49:729-738. TAKE HOME MESSAGE

• Potent and simplified therapies for HCV infection author by – Short duration, > 95% efficacy – No ribavirin – Not affected by genotype,eLibrary fibrosis, mutations – Resistance rare – Manageable risk of interactions ESCMID © author by

HEPATITISeLibrary B

ESCMID © Phases of chronic HBV infection

HBeAg Anti-HBeauthor by

eLibrary Phase 1 Phase 2 Phase 3 Phase 4

ESCMID New © HBeAg-positive HBeAg-positive HBeAg-negative HBeAg-negative nomenclature chronic HBV infection chronic hepatitis B chronic HBV infection chronic hepatitis B

Lok A, et al. J Hepatol 2017;67:847–61. EASL. J Hepatol 2017;67:370–98. Timeline of HBV Therapy

INTERFERON alpha author

ADV ETV TDFby TAF

1998 2002 2005 2006 2008 2017 eLibrary

LAM Peg-IFN LdT

ADV = adefovir ETV = entekavir ESCMID LAM = lamivudin LdT = telbivudin © Peg-IFN = pegylated interferon TAF = tenofovir alafenamid TDF = tenfovir dizoproksil fumarat HBV treatment approved in Europe in 2017

Approved Interferons: s.c. Interferon alpha-2a author Interferon alpha-2-b 24-48 weeks Peginterferon alpha-2a by

Nucleoside analogues: p.o. Lamivudine Entecavir eLibrary Telbivudine Lifelong? Nucleotide analogues: p.o. Adefovir ESCMID Tenofovir© alafenamid (TAF) Tenfovir disoproksil fumarat (TDF) Objectives of HBV therapy

Goals - Improve survival - Prevent disease progression and developmentauthorof HCC by Endpoints

HBV DNA ALT/ASTeLibrary HBeAg/HBsAg negativity normalisation loss

ESCMIDAnti-HBs cccDNA © appearance loss EFFICACY of one-year treatment of chronic hepatitis B in randomised clinical studies

HBeAg-positive author by

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HBeAg-negative ESCMID ©

EASL. J Hepatol 2017; 66:153–94. Most common mutants and cross-resistance to NA treatment

author by

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Panel members Kosh Agarwal, Thomas Berg, Maria Buti, Harry LA Janssen, GeorgeESCMID Papatheodoridis, Fabien Zoulim, Frank Tacke (EASL Governing Board representative) © Reviewers Maurizia Brunetto, Henry Chan, Markus Cornberg

EASL. J Hepatol 2017; 66:153–94. New classification of chronic HBV infection phases

• The natural history of chronic HBV infection has been schematically divided into ﬁve phases

HBeAg positive HBeAg negativeauthor Phase 1 Phase 2 Phase 3 Phase 4 Phase 5 Chronic HBV by infection Chronic HBV Chronic Chronic HBV Chronic Resolved HBV infection hepatitis B infection hepatitis B infection High/ HBsAg High Low Intermediate Negative intermediate HBeAg Positive PositiveeLibraryNegative Negative Negative HBV DNA >107 IU/mL 104–107 IU/mL <2,000 IU/mL* >2,000 IU/mL <10 IU/mL‡ ALT Normal Elevated Normal Elevated† Normal Moderate/ Moderate/ Liver disease None/minimal None None§ severe severe HBsAg negative Old ESCMIDImmune reactive HBeAg negative Immune tolerant Inactive carrier /anti-HBc terminology HBeAg positive chronic hepatitis © positive

*HBV DNA levels can be between 2,000 and 20,000 IU/mL in some patients without signs of chronic hepatitis; †Persisitently or intermittently, based on traditional ULN (~40 IU/L). ‡cccDNA can frequently be detected in the liver; §Residual HCC risk only if cirrhosis has developed before HBsAg loss. EASL. J Hepatol 2017; 66:153–94. Treatment of HBV

• The natural history of chronic HBV infection has been schematically divided into ﬁve phases

author by

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EASL. J Hepatol 2017; 66:153–94. Target populations for HVB therapy for EASL 2017

HBV chronic Special groups HBV chronic HBV acute hepatitis of patients infection? hepatitis?

Chronic Pregnant women Age > 30 author hepatitis HBV-DNA > by 2.000 UI/ml ALT> N Patients Former undergoing “inactive Fibrosis > F1 suppressive carrier” therapy (HBeAg- infection) eLibraryif family history Health care HBV-DNA > of HCC, workers 20.000 IU/ml extra hepatic + ALAT > 2N signs

EASL. J Hepatol 2017; 66:153–94. Real-life outcomes of HBV treatment in patients with bridging fibrosis and cirrhosis after one-year treatment

Significant reduction in: HCC, varriceal bleeding, renal impairement, spontaneous bacterial peritonitis, death due to liver disease author 50 by 40

30 P = .001 (%) 20 eLibrary17.7

Bolniki 10 7.8

Liaw YF, et al. N Engl J Med. 2004;351:1521-31. Clinical management of suspected HBV infection

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EASL. J Hepatol 2017; 66:153–94. HBV reactivation in patients undergoing immunosuppressive therapy

author by

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ESCMID ©

Reviews in Medical Virology 2001; 11: 287-99. PREVENTION of HBV reactivation in patients undergoing immunosuppressive therapy

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Duration of chemoprophylaxis: - continue at leastESCMID 12 months after the end of immunosuppression (18 months© if hematological disease) - and stop only if underlying disease is in remission and there is no liver disease

; Reviews in Medical Virology 2001; 11: 287-99. Cholongitas st al. World J Gastroenterol 2015. Vigano et al. Expert Opin Biol Ther, 2016. The risk of HBV reactivation can be classified as high, moderate, low - depending on the drug

Risk Drugs Disorders for receiving the drugs B cell–depleting agents : anti CD20, CD56 - Lymphoma/leukemia - Rheumatoid arthritis/ Idiopathic thrombocytopenic purpura, High Anthracycline derivatives doxorubicin, epirubicin Cryoglobulinemia (> 10%) Breast, ovarian, uterine, and lungauthor cancers; lymphoma and leukemias; Corticosteroid therapy for 4 wk (moderate/high transarterial chemoembolization dose) Inflammatory bowel disease, vasculitis, sarcoidosis, autoimmune IST for transplantation (stem cell, solid organ) disorders by TNF-a inhibitors: etanercept, adalimumab, Inflammatory bowel disease, rheumatoid arthritis, ankylosing certolizumab, infliximab spondylitis Moderate Other cytokine inhibitors and integrin inhibitors: Plaque psoriasis, inflammatory bowel disease (1-10%) abatacept, ustekinumab, natalizumab, vedolizumab Breast, ovarian, uterine, and lung cancers; lymphoma and leukemias; Tyrosine kinase inhibitors: imatinib, nilotinib transarterial chemoembolization; Chronic myelogenous leukemia, eLibrarygastrointestinal stromal tumors Corticosteroid therapy for 4 wk (low dose > 10 mg Inflammatory bowel disease, vasculitis, sarcoidosis, autoimmune QD) disorders Other IST without steroids Traditional immunosuppressive agents: Inflammatory bowel disease, psoriasis, sarcoidosis, autoimmune liver azathioprine, 6-mercaptopurine, methotrexate disease, arthritis Low Intra-articularESCMID corticosteroids Arthritis (< 1 %) Corticosteroid for 1 wk Asthma, contact dermatitis Corticosteroid© therapy for 4 wk if HBsAg-/Anti HBc+ Inflammatory bowel disease, vasculitis, sarcoidosis, autoimmune (low dose < 10 mg/d) disorders

Perillo et al. Gastroenterology 2015. Tenofovir to prevent HBV transmission in mothers with high Viral Load

• 200 pregnant women, HBV DNA > 200.000 UI/mL • Randomized for tenofovir or placebo from 30-32 wk gestation until 4w post delivery author • All infants received passive+active immunoprophylaxisby

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Pan CQ et al. N Engl J Med, 2016. Targets for possible future anti-HBV drugs

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. Petersen J et al. J Hepatol 2016; 65: 835–48. TAKE HOME MESSAGE

• Indication to HBV therapy have beenauthor expanded – Classical indication : cirrhosis, chronicby hepatitis (decreased HBV DNA threshold) – Additional indications : • PMTCT in mothers with high viremia • Prevention of reactivationeLibrary in immunosuppressed patients • Coinfection with HIV, HDV, HCV patients (under DAA) • Extrahepatic manifestations • Health care workers • HBVESCMID chronic infection (age > 30, familial history of HCC) •©Severe acute hepatits Management of patients not clearing HEV infection

Chronic HEV infection

Reduction of immunosuppression author HEV clearance Noby HEV clearance 3-month course of ribavirin monotherapy

Serum and stool Relapse after HEV RNA negative ceasingeLibrary ribavirin

6-month course of No response to ribavirin monotherapy ribavirin or intolerant

Persistent HEV replication ESCMIDin serum or HEV relapse © Pegylated interferon for 3 months in LTx patients No alternative available therapy in other transplant patients

EASL CPG HEV. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.005 [Epub ahead of print] CONCLUSIONS

• Antivirals for HCV make hepatitis C a curable disease author by • Antivirals for HBV make hepatitis B a well controlled chronic disease • No antivirals for HEVeLibrary exist so far – new drugs are needed for hepatitis E GT3 with severe clinical course (acute, chronic) ESCMID © Literature

• http://www.easl.eu/medias/cpg/2018/EASL%20Recommenda tions%20on%20Treatment%20of%20Hepatitis%20C%202018/author English-report.pdf by • http://www.easl.eu/medias/cpg/management-of-hepatitis-B- virus-infection/English-report.pdf • http://www.easl.eu/medias/cpg/2018/EASL%20Recommenda tions%20on%20Treatment%20of%20Hepatitis%20C%202018/eLibrary English-report.pdf ESCMID ©