CHB worldwide. HBeAg. Organ, blood, and semen donors HBV DNA. Hemodialysis ALT. Immune tolerant 1,2

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1 CHB worldwide Chronic Hepatitis B: Taming an Old Dog with New Tricks Approximately 35 million people worldwide have CHB 1,2 High prevalence areas include regions of 2,3 : Asia Africa Eastern Europe The Middle East Latin America The Caribbean Most people in the US who have CHB were born in regions of the world where the virus is common 2 George M. Abraham, MD, MPH, FACP, FIDSA Chief of Medicine, Saint Vincent Hospital Professor of Medicine, University of Massachusetts Medical School Chair, Board of Governors, and Regent, American College of Physicians (ACP) Chair, Infectious Disease Board, American Board of Internal Medicine (ABIM) 8% = High 2-7% = Intermediate <2% = Low 1. WHO. Hepatitis B Fact Sheet. Accessed October 11, CDC. Morb Mortal Wkly Rep. 28;57: CDC. Morb Mortal Wkly Rep. 25;54: Modes of HBV Transmission Course of HBV Infection Vertical transmission via mother HBV carrier Child Up to 9% of neonates will develop CHB if their mothers carry the virus 2 Horizontal transmission 1 Prolonged close contact (eg, household) IV drug use Sexual contact Exposure to blood or bodily fluid Organ, blood, and semen donors Hemodialysis HBV DNA ALT HBeAg Immune tolerant 1,2 This phase occurs in patients with perinatally acquired infection Minimal or no inflammation May last 1 to 4 decades High or fluctuating HBV DNA levels Persistent or intermittent fluctuation in ALT levels Active inflammation and liver damage Adapted with permission from: Yim HJ, Lok ASF. Hepatology. 26. HBsAg+ Anti-HBe Immune clearance 1,2 Inactive carrier1,2 Reactivation1,2 Low or undetectable HBV DNA levels Normal ALT levels Mild hepatitis, minimal fibrosis, but cirrhosis may be present from previous liver damage Some patients may have reactivation of HBV replication Usually older patients with more advanced liver disease Fluctuating levels of ALT and HBV DNA HBsAg Resolution 1 After many years, some patients may enter a resolution phase Not considered a cure as intracellular HBV DNA is still present CHB follows a nonlinear clinical course; not all patients will go through each phase HBV, hepatitis B virus. 1. CDC. Morb Mortal Wkly Rep. 28;57: CDC. Morb Mortal Wkly Rep. 25;54: HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B e antigen; Anti-HBe, antibody to HBeAg. 1. Keeffe EB et al. Gastroenterol Hepatol. 28;6: Yim HJ, Lok ASF. Hepatology. 26;43:S173-S

2 Natural History of Chronic HBV Infection Natural History of Chronic HBV Infection Immunotolerance HBV DNA Immune Clearance Immune Control (Nonreplicative) Immunotolerance HBV DNA Immune Clearance Immune Control (Nonreplicative) 1. Normal ALT 2. Low/undetectable HBV DNA 3. HBsAg+ and HBeAgor HBsAg-, anti-hbc+ HBeAg+ HBeAg- HBeAb+ HBeAg+ HBeAg- HBeAb+ HBsAg+ HBsAg- HBsAb+ HBsAg+ HBsAg- HBsAb+ ALT ALT 5-3 Yrs Infection Mos-Yrs Mos-Yrs 5-3 Yrs Infection Mos-Yrs Mos-Yrs Yim HJ, et al. Hepatology. 26;43:S173-S181. Yim HJ, et al. Hepatology. 26;43:S173-S181. CHB Management Algorithm HBeAg+ Anti-HBe Immune Clearance (HBeAg+ CHB) HBV DNA ALT HBeAg Anti-HBe+ Reactivation (HBeAg CHB) Treat HBsAg Positive CHB HBV DNA ALT Normal HBeAg+ Anti-HBe HBeAg Anti-HBe+ Immune Tolerant Inactive Carrier State Monitor Negative Anti-HBs Negative Positive Anti-HBc Negative Anti-HBc Positive Not Yet Exposed (Vaccinate) Immune from Vaccination Immune Control of Past HBV Infection* Do Not Treat *Patients who obtained immunity through natural exposure must be monitored if immunosuppressant therapy is initiated, and treatment may be indicated Keeffe EB, et al. Clin Gastroenterol Hepatol. 28;6: Yim HJ and Lok ASF. Hepatology. 26;43:S173-S181. 2

3 Staging Liver Fibrosis: Common Scales Complications Associated With CHB Ishak, Knodell, and METAVIR are scales frequently used to characterize the extent of fibrosis 1 The relationship between Categorical Ishak Assignment score and extent of fibrosis is not linear 2 Fibrosis Measurement General Appearance 2 Ishak 2 Knodell 1,3 METAVIR 4 Categorical description (Ishak Stage) 2 (Ishak)* 2 Normal End-stage Fibrosis Cirrhosis Liver Disease HCC F No fibrosis (normal) 1.9% 1 1 F1 Fibrous expansion of some portal areas short fibrous septa 3.% 2 1 F1 3 3 F2 4 3 F3 Fibrous expansion of most portal areas short fibrous septa Fibrous expansion of most portal areas with occasional portal-to-portal (P-P) bridging Fibrous expansion of portal areas with marked bridging (P-P) as well as portal-to-central (P-C) 3.6% 6.5% 13.7% Healthy liver tissue Consequence of ongoing liver injury and repair 1 Risk of progression to cirrhosis is 2% to 6% annually 2 Typically presents 3 to 5 years after a diagnosis of CHB with cirrhosis 2 Average survival in patients with HCC is ~6 to 12 months, often due to late diagnosis F3 Marked bridging (P-P and/or P-C), with occasional nodules (incomplete cirrhosis) 24.3% 6 4 F4 Cirrhosis, probable or definite 27.8% Up to 4% of patients with CHB will develop cirrhosis, liver failure, or HCC 4 *Degree of fibrosis as measured by collagen proportionate area: proportion (%) of area of biopsy sample showing Sirius red staining for collagen 1. Brunt EM. Hepatology. 2;31: Standish R, et al. Gut. 26;55: Knodell RG, et al. Hepatology. 1981;1: Bedossa P, Poynard T. Hepatology. 1996;24: HCC, hepatocellular carcinoma. 1. Lim YS, Kim WR. Clin Liver Dis. 28;12: Weisberg IS, et al. Clin Liver Dis. 27;11: Asian Liver Center. 27 Physician s Guide to Hepatitis B. Accessed October 11, Lok ASF. N Engl J Med. 22;346: Host and Viral Risk Factors for HCC Male gender 1,2 Family history of HCC 1 Older age 1,2 Host Factors Coinfection with HCV, HDV, or HIV 1,2 Alcohol consumption 2 Cigarette smoking 2 Viral Factors HBV DNA levels >2, IU/mL (>1, copies/ml) 2,3 HBV genotype C 2,4,a Basal core promoter mutation 1,2 Precore mutation 2,3 Presence of HBeAg 2,4 Management of CHB HCV, hepatitis C virus; HDV, hepatitis D virus; HIV, human immunodeficiency virus. Although cirrhosis is a strong risk factor for HCC, 3% to 5% of HCC associated with HBV occurs in the absence of cirrhosis 1 a Asian Americans have a higher prevalence of HBV genotype C and a higher risk of HCC than Caucasian Americans. 4,5 1. Lok ASF, McMahon BJ. Hepatology. 29;5: Keeffe EB, et al. Clin Gastroenterol Hepatol. 28;6: Tong MJ, et al. Liver Int. 27; 27: Mahtab MA, et al. Hepatobiliary Pancreat Dis Int. 28;7: Lin SY, et al. Hepatology. 27;46:

4 CDC Recommendations for Routine CHB Testing Serologic Markers in HBV Infection Populations at high risk of CHB include: Foreign-born: People born in regions of high or intermediate prevalence of HBV infection Children of foreign-born parents: US-born people not vaccinated as infants, whose parents were born in regions of high prevalence of HBV infection Family and household members: People whose family or household members have HBV infection Infants born to mothers who have HBV infection Hemodialysis patients People with certain medical conditions: People who need cytotoxic or immunosuppression therapy for a medical condition such as: Cancer that requires chemotherapy Immunosuppression related to organ transplantation Immunosuppression related to rheumatologic and gastrointestinal disorders People with elevated ALT/AST of unknown causes All pregnant women HBsAg The HBV surface antigen is the standard marker of infection 1,2 Presence in serum >6 months defines CHB 2 Anti-HBs Antibody to HBsAg 3 Marker of immunity to HBV 2,3 Hepatitis B Virus HBV DNA Indicates ongoing viral replication 1,2 Levels correlate with replication and infectivity 1,2 Anti-HBc Antibody to the HBV core antigen can be used as a marker of infection 2 HBeAg Hepatitis B e antigen is used clinically as index of viral replication and infectivity 2,3 CDC. Morb Mortal Wkly Rep. 28;57: Dienstag JL. N Engl J Med. 28;359: Servoss JC, Friedman LS. Clin Liver Dis. 24;8: Hollinger FB, Lau DTY. Gastroenterol Clin North Am. 26;35: Vaccination Additional Recommended Screening in CHB Patients 1 month 5 months The hepatitis B vaccine provides long-term protection for people who have not been infected with the virus The hepatitis B vaccine is a series of 3 shots given over 6 months Alternative vaccination schedules given over 4 months demonstrate similar rates of seroprotection Recommended Screening 1 Hepatitis C Virus (HCV) 1% to 15% of patients with CHB are coinfected with HCV 2 Hepatitis D Virus (HDV) A higher proportion of persons with chronic HBV/HDV coinfection develop cirrhosis, hepatic decomposition, and HCC 2 Human Immunodeficiency Virus (HIV) Individuals with HBV and HIV coinfection tend to have more severe liver disease and increased rates of liver-related mortality 2 Immunity to Hepatitis A Virus (HAV) Persons with CHB who are not known to be immune to HAV should be vaccinated 1 CDC. Morb Mortal Wkly Rep. 26;55: CDC. Morb Mortal Wkly Rep. 28;57(RR8):1-2. Accessed September 19, Lok ASF, McMahon BJ. Hepatology. 29;5:

5 Expert Panel Consensus: US Treatment Algorithm Evaluation of CHB STEP 2 EVALUATE Order HBeAg, HBV DNA, and ALT for ALL patients with CHB Evaluation HBeAg HBV DNA ALT a Recommended Follow-Up + 2, IU/mL <2, IU/mL 2 IU/mL <2 IU/mL Elevated Treat Patient Normal Monitor Patient b,c Elevated Monitor Patient b Normal Monitor Patient b,d Elevated Treat Patient Normal Monitor Patient b,c Elevated Monitor Patient b Normal Monitor Patient b,d Patients with signs and symptoms suggestive of advanced liver disease or indicative of cirrhosis should be evaluated by a specialist. These patients frequently require ongoing evaluation and management of liver-related complications. a Normal serum ALT values are defined as 3 IU/L for men and 19 IU/L for women. b Patients with cirrhosis should be considered for treatment regardless of HBV DNA level. c Consider liver biopsy examination, particularly if patient is >35 to 4 years; treat if disease; in the absence of biopsy examination, observe for increase in ALT levels. d Consider therapy in patients with known significant histologic disease, even if low-level replication. Keeffe EB, et al. Clin Gastroenterol Hepatol. 28;6: Vibration Controlled Transient Elastography (Fibroscan ) 5

6 Bonder-Afdhal Score Diagnostic Performance of FibroScan for Assessing Liver Stiffness in NAFLD Expert Panel Consensus: US Treatment Algorithm Monitoring CHB in Patients not Recommended for Treatment Multicenter, prospective study evaluating diagnostic performance of FibroScan for liver stiffness measurement in pts undergoing biopsy for suspected NAFLD (N = 374 analyzed) Fibrosis (biopsy): F, 17%; F1, 23%; F2, 23%; F3, 29%; F4, 9% FibroScan LSM Correlation With Fibrosis Stage LSM (kpa) Both probes M probe XL probe Fibrosis Stage AUROC (95% CI) F2 F3 F4.77 ( ).8 ( ).89 ( ) By multivariate analysis, only factor significantly influencing LSM was fibrosis stage HBeAg HBV DNA ALT a Recommended Monitoring + 2, IU/mL Normal 2 IU/mL Normal Other Monitored Patients ALT every 3 to 6 months Consider liver biopsy or treatment if ALT becomes elevated ALT every 6 to 12 months for inactive carriers If ALT levels increase, check HBV DNA levels and rule out other causes of disease Significant fibrosis and damage can occur in patients with CHB despite normal ALT levels Patients with signs and symptoms suggestive of advanced liver disease or indicative of cirrhosis should be evaluated by a specialist. These patients frequently require ongoing evaluation and management of liver-related complications. Eddowes P, et al. AASLD 217. Abstract 184. Reproduced with permission. a Normal serum ALT values are defined as 3 IU/L for men and 19 IU/L for women. Keeffe EB, et al. Clin Gastroenterol Hepatol. 28;6:

7 Expert Panel Consensus: US Treatment Algorithm Recommendations for HCC Surveillance in Patients With CHB Alpha-fetoprotein and abdominal ultrasound every 6 months Recommended candidates for surveillance Asian men >4 years of age Asian woman >5 years of age Africans >2 years of age Patients with cirrhosis Patients with a family history of HCC Patients >4 years of age with ALT elevations and/or high HBV DNA levels (>2 IU/mL) Patients 3 to 35 years of age who were infected at birth or in early childhood Treatment Keeffe EB, et al. Clin Gastroenterol Hepatol. 28;6: Efficacy in Treatment-naïve HBeAg-positive CHB Patients Year 1 (%) Loss of Serum HBV DNA ^ IFN-α PegIFNα PegIFNα + LAM Oral Therapies LAM ADV LdT ETV Loss of HBeAg 33 3 / / na HBeAg Seroconversion 18% 27 / / Loss of HBsAg Normalization of ALT 23% Histologic Improvement NA Durability of Response 8-9 NA NA 5-8 ~9 ~8 69 NA # 48 weeks for LAM, ADV, ETV,, PegIFN, PegIFN+LAM, weeks for IFNa and 52 weeks for LdT. ADV= Adefovir dipivoxil, LdT=Telbivudine. ^ Hybridization or branched chain DNA assays (upper limit of detection 2,-2, IU/mL or 5-6 log 1 copies/ml) in standard IFN-α studies and some lamivudine studies and PCR assays (lower limit of detection ~5 IU/mL or 25 copies/ml) in other studies. NA=not available. Responses at week 48 / week 72 (24 weeks after stopping treatment) Post-treatment biopsies obtained at week 72 Lamivudine and entecavir: no or short duration of consolidation treatment; Adefovir and telbivudine: most patients had consolidation treatment Lok and McMahon, HEPATOLOGY 29;5(3):1-36. AASLD Practice Guidelines 29 7

8 Recommended Nucleos(t)ide Analogues for HBV Current Options in 218 Nucleos(t)ide Analogue Approval in HIV Approval in CHB QD Dose Lowest CrCl Without Dose Adjustment (ml/min) Entecavir N/A 25.5 mg 5 Tenofovir disoproxil fumarate Tenofovir alafenamide mg 5 (no dose recommendation at < 1 without dialysis) 215 (as part of fixeddose combination with antiretrovirals) mg 15 (not recommended at < 15 in HBV monoinfection) Entecavir [package insert] Tenofovir disoproxil fumarate [package insert] Tenofovir alafenamide [package insert] TAF vs : Mechanism of Action GI tract 3 mg TAF 25 mg Plasma Renal tubular cell 9% lower plasma TFV than with TFV Renal tubular cell Hepatocyte TFV HB V Tenofovir alafenamide: novel prodrug of tenofovir TAF: no dose adjustment needed in pts with CrCl > 15 ml/min TAF vs in Chronic HBV Infection: Wk 96 Efficacy HBV DNA: TAF noninferior to at Wks 48 and 96 in both studies; no resistance found in any arm HBeAg Negative [1] HBeAg Positive [2] HBV DNA < 29 IU/mL at Wk 96 (%) n/ N = Treatment difference (95% CI): -.6% (-7., 5.8), P =.84* / 285 TAF 127/ Treatment difference (95% CI): -2.2% (-8.3, 3.9), P =.47* ALT: significantly greater rate of ALT normalization at Wk 96 with TAF vs 423/ 581 TAF 218/ 292 *Adjusted for BL HBV DNA and PO antiviral treatment status. HBeAg-positive pts: higher rate of HBeAg seroconversion at Wk 96 vs Wk 48 with or TAF [2] HBeAg-negative pts: minimal decline in HBsAg with or TAF for (1 TAF-treated pt with GT A had HBsAg loss and seroconversion) [1] Arribas JR, et al. CROI 217. Abstract 453. Duarte-Rojo A. Therap Adv Gastroenterol. 21;3: Murakami E, et al. Antimicrob Agents Chemother. 215;59: Tenofovir disoproxil fumarate [package insert] Tenofovir alafenamide [package insert] Brunetto M, et al. EASL 217. Abstract PS Agarwal K, et al. EASL 217. Abstract FRI

9 TAF vs in Chronic HBV Infection: Renal and Bone Outcomes Choosing Among Nucleos(t)ide Analogues Median Change in egfr (ml/min) (Q1, Q3) Significantly smaller effect on renal function with TAF at Wk 48 and Wk 96 in HBeAg-negative pts [1] TAF P = Significantly smaller effect on spine BMD with TAF at Wk 48 and Wk 96 HBeAg-negative pts [1] Mean (SD) Change From Baseline (%) Wk Wk Similar results seen with HBeAg-positive pts [2] P =.35 TAF P < If no comorbidities (for most pts) If risk of or preexisting bone or renal disease, prioritize ETV or TAF [2] Age > 6 yrs Bone disease Chronic steroids or other meds that affect bone History of fragility fracture Osteoporosis Renal abnormalities egfr < 6 ml/min/1.73 m 2 Albuminuria > 3 mg or moderate proteinuria Low phosphate (< 2.5 mg/dl) Hemodialysis Monotherapy with ETV,, or TAF [1,2] When to prioritize TAF over ETV Previous nucleoside exposure [2] Lamivudine with or without adefovir resistance HIV/HBV coinfection No dose adjustment for CrCl 15 ml/min When to prioritize ETV over TAF If less expensive (generic available) Dosing guidelines for CrCl < 15 ml/min 1. Brunetto M, et al. EASL 217. Abstract PS Agarwal K, et al. EASL 217. Abstract FRI Terrault NA, et al. Hepatology. 216;63: EASL. J Hepatol. 217;67: Chronic HBV Infection: Management of Pts With NA Resistance Switch to TAF vs Continuing in Chronic HBV Infection: Renal and Bone Outcomes Resistance Switch Strategy Add Strategy Adefovir Entecavir [1] Entecavir [1] Entecavir Tenofovir* [1,2] Tenofovir (or emtricitabine/tenofovir*) [1] Lamivudine Tenofovir* [1,2] Tenofovir (or emtricitabine/tenofovir*) [1] Telbivudine Tenofovir* [1,2] Tenofovir [1] Multidrug Tenofovir* [1] Tenofovir* + entecavir [1,2] *Includes either or TAF in EASL guidelines; AASLD guidelines not yet updated since approval of TAF. Median Change in egfr (ml/min) (Q1, Q3) Analysis of open-label extension data from 2 phase III trials in HBV-infected pts switching from to TAF at Wk 96 88% of pts achieved virologic suppression at Wk 96 (preswitch) and maintained to Wk 12 (post switch) Significantly higher proportion of pts achieved ALT normalization after switch to TAF CrCl Wk P = P =.36 Mean % Change From Baseline (g/cm 2 ) (SD) Spine BMD Wk P <.1 TAF (n = 361 at Wk ) (n = 18 at Wk ) à TAF P =.7 1. Terrault NA, et al. Hepatology. 216;63: EASL. J Hepatol. 217;67: Chan HLY, et al. EASL 217. Abstract PS-41. 9

10 Guidelines: When to Start HBV Therapy Guidelines: What to Start as Initial HBV Therapy Guideline s HBV DNA, IU/mL HBeAg Positive ALT Liver Disease HBV DNA, IU/mL HBeAg Negative ALT Liver Disease [1] > 2, 2 x ULN N/A 2 2 x ULN N/A AASLD N/A N/A Cirrhosis N/A N/A Cirrhosis Continue indefinitely in HBeAg-negative pts with cirrhosis Treatment Preferred [1,2] Notes Entecavir Yes High potency, high genetic barrier to resistance Tenofovir alafenamide* Yes (EASL only) High potency, high genetic barrier to resistance Tenofovir disoproxil fumarate Yes High potency, high genetic barrier to resistance Peginterferon Should only be considered as initial therapy for pts with mild/moderate CHB or selected pts with compensated cirrhosis (no portal hypertension) Less safe in pts with cirrhosis, contraindicated in pts with decompensated cirrhosis Adefovir No Low genetic barrier to resistance Lamivudine No Low genetic barrier to resistance Telbivudine No Low genetic barrier to resistance *AASLD guidelines not yet updated since approval of TAF. Pts receiving : monitor renal function, consider monitoring BMD in pts at risk. [1] ETV,, TAF have very favorable safety profiles [2] 1. Terrault NA, et al. Hepatology. 216;63: Terrault NA, et al. Hepatology. 216;63: EASL. J Hepatol. 217;67: Expert Panel Consensus: US Treatment Algorithm Monitoring Treated Patients Expert Panel Consensus: US Treatment Algorithm Stopping Treatment Recommended Monitoring for Treated Patients When to Consider Stopping Treatment Assess HBV DNA and ALT levels every 3 months until complete virologic response is confirmed Monitor HBV DNA and ALT every 6 months thereafter Assess at 3 months: Primary treatment failure (HBV DNA decline from baseline <1 log 1 IU/mL) Reassess at 24 weeks: Complete response (HBV DNA <6 IU/mL) Partial response (HBV DNA 6 to <2 IU/mL) Assessing Treatment Failure/Resistance If patient is compliant, add more potent drug If noncompliant, counsel Continue therapy Monitor every 6 months Depending on drug profile, monitor every 3 months or add 2nd agent Inadequate response (HBV DNA 2 IU/mL) Add more potent drug; monitor every 3 months When possible, use agents with low risk for resistance as initial therapy Patients with signs and symptoms suggestive of advanced liver disease or indicative of cirrhosis should be evaluated by a specialist. These patients frequently require ongoing evaluation and management of liver-related complications. HBeAg+ (without cirrhosis) HBeAg (without cirrhosis) Cirrhosis Continue to treat after HBeAg seroconversion, until HBV DNA levels are undetectable by PCR; treatment then should be continued for an additional 12 months before considering stopping If HBV DNA levels are still detectable but stable, continue treatment for 6 months; if then HBV DNA levels are undetectable by PCR and HBeAg seroconversion is confirmed, treatment should be continued for an additional 12 months before considering stopping If no HBeAg seroconversion, treat indefinitely Definitive guidelines have not been established; however, long-term therapy is associated with lower rates of relapse Treatment should be long term Continue until patient becomes HBV DNA negative and has lost HBsAg Keeffe EB, et al. Clin Gastroenterol Hepatol. 28;6: PCR, polymerase chain reaction. Keeffe EB, et al. Clin Gastroenterol Hepatol. 28;6:

11 O- Translocation new (-) strand DNA synthesis dadadg 5 Cap (A)n 3 pgrna 9/17/18 Cure as a Goal of Therapy Why Is Cure Rare With Nucleos(t)ide Therapy? Actual cure True cure = all traces of HBV gone from the liver (like HCV) VERY difficult (if not impossible) à cccdna Functional cure Use the markers of pts who do well: 1. HBsAg loss (ideally with anti-hbs) 2. Possibly sustained off-treatment inactive disease without HBsAg loss (HBeAg negative, DNA undetectable, normal ALT, normal histology) HBsAg Attachment and penetration Golgi complex Release HBV virion Transport to cell nucleus cccdna Uncoating DNA repair Envelope proteins S, M, L Pregenomic RNA Core protein DNA synthesis HBV RNA transcripts Encapsidation of pg RNA HBeAg Polymerase protein Cure not so simple... reasons lie in the virology HBeAg Grimm D, et al. Hepatol Int. 211;5: Is Long-term HBV Therapy Required? HBV Therapy Reduces Risk of Disease Progression Systematic review of stopping nucleos(t)ide therapy in HBeAg-negative (n = 967) and HBeAgpositive (n = 733) pts Prospective cohort study in pts with HBV and first-onset complications of decompensated cirrhosis (N = 77) treated predominantly with lamivudine (n = 23) or entecavir (n = 198) Pts in Virologic Remission (%) HBeAg-negative Pooled HBsAg Loss: 1.7% (5/693) Durable biochemical remission: 57% (394/687) High rate of relapse to active disease Papatheodoridis GV, et al. Hepatol. 216;63: Months After Nucleos(t)ide Discontinuation 1 Low rate of HBsAg loss long-term therapy required HBeAg-positive Pooled HBsAg Loss: 1.% (17/341) Durable biochemical remission: 76% (268/43) Months After Nucleos(t)ide Discontinuation LT-Free Survival (%) *Nonresponders included pts with HBV rebound or genotypic resistance, primary nonresponse, NE due to early event (death, LT, LTFU). Antiviral therapy improved transplant-free survival over mean follow-up of 49 mos (P =.98 vs untreated) Jang JW, et al. Hepatology. 215;61: Bonferroni-adjusted P < Mos Treated, responder (n = 245) Treated, nonresponder* (n = 178) Untreated (n = 284) 11

12 Long-term Oral HBV Therapy is Highly Effective Long-term Oral HBV Therapy: Downsides Suppresses HBV DNA [1,2] Normalizes ALT [2,3] Prevents fibrosis progression [3,4] Promotes fibrosis regression, even in cirrhosis [4] Prevents and even reverses hepatic decompensation [1] Reduces, but does not eliminate, the risk of HCC [1,5] Long-term therapy is effective... but low rates of HBsAg loss [6] Toxicity Potential for renal, bone complications with Resistance High with lamivudine (not preferred by guidelines) [1] Very low with entecavir unless already LAM resistant [2] None with in clinical trials (similar expected with TAF) [3] Cost Adherence 1. Hadziyannis SJ, et al. Hepatology. 2 ;32: Gish SR, et al. Gastroenterology. 27;133: Buti M, et al. Dig Dis Sci. 215;6: Lim YS, et al. Gastroenterology. 214;147: Chang TT, et al. Hepatology. 21;51: Zoutendijk R, et al. Gut. 213;62: Marcellin P, et al. Lancet. 213;381: Papatheodoridis GV, et al. J Hepatol. 215;62: Papatheodoridis GV, et al. Hepatol. 216;63: Do You Ever Really Get Rid of HBV? cccdna Immune control not clearance Resolved HBV a misnomer still HBV DNA in liver Werle-Lapostolle B, et al. Gastroenterology. 24;126:

13 Do You Ever Really Get Rid of HBV? Do You Ever Really Get Rid of HBV? T cell cccdna cccdna T cell T cell Immune control not clearance Resolved HBV a misnomer still HBV DNA in liver Werle-Lapostolle B, et al. Gastroenterology. 24;126: Immune control not clearance Resolved HBV a misnomer still HBV DNA in liver Werle-Lapostolle B, et al. Gastroenterology. 24;126: Along Comes Immune Suppression Along Comes Immune Suppression T cell T cell cccdna T cell HIV Steroids Chemotx cccdna T cell HIV Steroids Chemotx T cell T cell Immune control can be lost Immune-mediated liver damage with immune reconstitution Werle-Lapostolle B, et al. Gastroenterology. 24;126: Immune control can be lost Immune-mediated liver damage with immune reconstitution Werle-Lapostolle B, et al. Gastroenterology. 24;126:

14 HBV Reactivation HBV Reactivation Definition HBeAg+ HBeAg- HBeAb+ Immunotolerance Immune Clearance HBV DNA ALT Immune Suppression 5-3 Yrs Mos-Yrs Mos-Yrs Infection Hoofnagle JH. Hepatology. 29;49(5 suppl):s156-s165. HBeAg+ Immune Reconstitution Loss of HBV immune control in a patient with inactive or resolved HBV infection Abrupt reappearance or increase in viral replication with liver damage occurring during and/or following immune reconstitution Clinically Range from subclinical to severe/fatal hepatitis Rise in HBV DNA ± return of HBeAg ALT increase (may be mild or very dramatic) May progress to liver failure/death despite antiviral therapy Hoofnagle JH. Hepatology. 29;49(5 suppl):s156-s165. Subset of Agents Reported to Cause HBV Reactivation Steroids Increase Risk of HBV Reactivation Class Corticosteroids Antitumor antibiotics Plant alkaloids Alkylating agents Antimetabolites Monoclonal antibodies Others Agents Dexamethasone, methylprednisolone, prednisolone Actinomycin D, bleomycin, daunorubicin, doxorubicin, epirubicin, mitomycin-c Vinblastine, vincristine Carboplatin, chlorambucil, cisplatin, cyclophosphamide, ifosfamide Azauridine, cytarabine, fluouracil, gemcitabine, mercaptopurine, methotrexate, thioguanine Alemtuzumab, rituximab Colaspase, docetaxel, etoposide, fludarabine, folinic acid, interferon, procarbazine 5 patients with NHL who were HBsAg positive randomized to epirubicin, cyclophosphamide and etoposide (ACE) ± prednisolone (P) HBsAg Patients (%) * 44* 28* HBV ALT Jaundice Reactivation > 1 x ULN * Complete Remission Survival at 4 Yrs Prednisolone increased risk and severity of HBV reactivation but trend toward improved NHL outcome ACE PACE *P <.5 Yeo W, et al. Hepatology. 26;43: Cheng AL, et al. Hepatology. 23;37:

15 Who Should Be Screened? AASLD recommends screening high-risk individuals [1] Immigrants CDC [2,3] & EASL [4] recommend screening ALL patients prior to starting chemotherapy Asia, Africa, Pacific Islands, Middle East, Eastern Europe, South/Central America, Caribbean, Aboriginal Children of immigrants Men who have sex with men HIV/HCV positive History of IDU, incarceration Hemodialysis patients 1. Lok AS, et al. Hepatology. 29;5: Weinbaum CM, et al. MMWR Recomm Rep. 28:57 (RR-8): Weinbaum CM, et al. Hepatology. 29:49(suppl 5):S35-S EASL. J Hepatol. 29; 5: Significance of Lone Anti-HBc Positive Marker Indicates exposure to HBV Usually persists lifelong but may lose after yrs May be false positive if truly no HBV risk factors No guidelines for management Risk for reactivation Low risk for most standard solid tumor regimens Consider preemptive HBV therapy if cirrhosis Consider preemptive HBV therapy if the following treatment strategies are used Rituximab Bone marrow/stem cell transplantation Manzano-Alonso ML, et al. World J Gastroenterol. 211;17: Rituximab: A Particular Problem Monoclonal antibody against CD2 (B-cell marker) Reduces B-cell numbers and antibody levels Increasingly used as part of CHOP-R, EPOCH-R Increased risk of HBV reactivation, including HBsAgnegative patients Reverse seroconversion: reappearance of HBsAg in previously HBsAg-negative patient due to loss of immune control Management of Anti-HBc Positive Patients Receiving Rituximab No consensus, limited data Options Start antiviral therapy before chemotherapy Follow HBV DNA closely on chemotherapy treat if HBV DNA positive Follow HBsAg closely on chemotherapy treat if HBsAg positive Combination approach: follow HBsAg and HBV DNA Yeo W, et al. Hepatology. 26;43: Papamichalis P, et al. Clin Res Hepatol Gastroenterol. 212;36:

16 Agents Reported to Cause HBV Reactivation Summary of Management Strategies Other (rituximab, cyclosporine) Steroids (prednisone, budesonide) Anti-TNF (infliximab, adalimumab, etanercept) Immunomodulatory Therapy Antimetabolite (methotrexate) Purine Analogues (azathioprine/6mp) No clear consensus on management of lone anti-hbc positive receiving rituximab Preemptive treatment if HBV DNA positive may be considered if anti-hbs negative and/or if there is a concern about compliance with follow-up testing Close follow-up of HBV DNA likely effective but costly and requires compliance Following HBsAg alone may be adequate for most cases but clearly associated with some risk Roche B, et al. Liver Int. 211;31(suppl 1):

17 Phase IIb Study of HBV/HDV Entry Inhibitor, Myrcludex B + in Pts With Chronic HBV/HDV Interim results from an open-label, randomized phase IIb study HBeAg-negative patients with chronic HDV infection (N = 12) Wk -12 Wk Wk 24 MyrB 2 mg SC QD + (N = 3) (N = 3) MyrB 5 mg SC QD + (N = 3) (N = 3) MyrB 1 mg SC QD + (N = 3) (N = 3) (N = 3) (N = 3) All patients received until Wk 48 Allweiss L, et al. EASL 218. Abstract PS

18 Activity of Myrcludex B + in Patients With Chronic HBV/HDV Infection Median Change at Wk 24 vs BL, log IU/mL MyrB 2 mg + (n = 3) MyrB 5 mg + (n = 3) MyrB 1 mg + (n = 3) All MyrB + Arms (n = 9) (n = 3) HBV pgrna Total HBV DNA cccdna/cell Liver HBV DNA Serum HBsAg HDV RNA HDAg+ hepatocytes NTCP CYP7A CXCL IL Allweiss L, et al. EASL 218. Abstract PS

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20 Applause!! QUESTIONS?? 2