January 11, 2017 NTUH. Outline

Transcription

1 January 11, 217 NTUH Outline 2

2 3 High risk groups Persons with liver disease Persons needing immunosuppressive or cancer chemotherapy Injection drug users (IDU) Persons who have received unsafe injections Men who have sex with men (MSM) Persons with multiple sexual partners or history of sexually transmitted infection Family members, household contacts and sex partner of a person with hepatitis B Inmates of correctional facilities Dialysis patients HCV- or HIV-infected individuals Pregnant female Infants born to females with chronic HBV Blood or organ donors Health care workers Sarin et al., Hepatol Int. 216 Jan;1(1):1-98 4

3 Improve awareness 211, 45 (1966 ( ) ): HBsAg + anti-hcv HBsAg B Anti-HBs HBeAg E Ps. Pre-core/basal core HBeAg Anti-HBe E IgM anti-hbc IgM IgG anti-hbc IgG B 6

4 (HBV DNA) 7 REVEAL reveals the importance of HBV DNA in disease risk Biological gradient of HCC and cirrhosis risk across serum HBV DNA levels Patients (%) Cumulative Incidence of HCC at Year 13 Follow-up 1 (N = 3653) 1.3% 1.4% 3.6% < ,- 99, % 14.9% 1,- 999,999 1 million Cumulative Incidence of Cirrhosis at Year 13 Follow-up 2 (N = 3582) 4.5% 5.9% 9.8% Baseline HBV DNA (copies/ml) measured using the Roche COBAS assay < ,- 99, % 1,- 999, % 1 million 1 Chen et al. JAMA 26; 2 Iloeje et al. Gastroenterology 26

5 liver fibrosis Liver biopsy Non invasive tests APRI Fib4 Fibrotest BioFibroScore Elastography Trasient elastography MR elastography 9 HCC Risk calculators REACH-B score 1

6 Health care workers B C B C B C 1 HBV vaccination! Exposure prone procedures 1 Redd JT et al. J Infect Dis 27;195: Health-care provider-to-patient transmission of HBV CDC recommendation 212 exposure-prone invasive procedures HBV DNA HBV DNA 1 IU/mL HBV DNA 2 IU/mL 23 SHEA Society for Healthcare Epidemiology of America HBV DNA 2 IU/mL 1-2 B HBV B 3 1 Gunson et al., J Clin Virol 23;27: Henderson et al., Infect Control Hosp Epidemiol 21;31: Henderson et al., Clin Microbiol Rev 23;16:

7 13 Short-term immunomodulatory" treatment IFN Follow-up (mo/yrs) HBV DNA < 2 IU/ml (HBeAg seroconv.) HBV DNA < 2 IU/ml (HBeAg seroconv.) HBsAg Loss Long-term "suppressive" treatment NUC HBV DNA undetectable by PCR HBsAg seroconv. Years

8 Interferon- Antigen presenting cell Cytotoxic T cell T helper cell Natural killer cell B cell Liang TJ, et al. Hepatology 215;62(6):

9 (peginterferon alfa-2a, Pegasys) (lamivudine, LAM) (adefovir dipivoxil, ADV) (telbivudine, LdT) (entecavir, ETV) (Tenofovir, TDF) Peg-IFN alfa-2a 18 mcg/wk, 48 weeks

10 2

11 lamivudine, telbivudine Entecavir Tenofovir Entecavir Tenofovir Lamivudine Telbivudine Telbivudine Tenofovir

12 Sarin SK, et al Hepatol Int (216) 1:1 98

13 Sarin SK, et al Hepatol Int (216) 1:1 98 Sarin SK, et al Hepatol Int (216) 1:1 98

14 B HBeAg HBeAg HBsAg (+) > 6 HBeAg (+) > 3 ALT 5 ULN 2 ALT <5 ULN HBV DNA 2, IU/mL HBcAg (+ ) HBsAg (+) > 6 HBeAg (-) > 3 ALT 2 ULN (, 3 ) HBV DNA 2, IU/mL HBcAg (+ ) HBsAg (+) * 1. PT 3 2. T-Bil. 2 mg/dl Entecavir (.5 mg) Tenofovir Telbivudine Lamivudine HBeAg(-) 2 36 HBeAg (+) e 12 ( Entecavir 1mg) 3-6 Entecavir (.5 mg) Tenofovir Lamivudine Telbivudine

15 B HBsAg (+) * B HBsAg (+) HBV DNA 6 B ( HBV DNA 1 log IU/mL) Adefovir 3 Entecavir 1mg ( Lamivudine )3 Tenofovir 3 Interferon, pegylated interferon 1 Entecavir.5mg Tenofovir Telbivudine Lamivudine * Entecavir.5mg Tenofovir Telbivudine Lamivudine 6 ( ) HBsAg (+) HBV DNA 2, IU/mL Tenofovir 3 1 Tenofovir Tenofovir/Entecavir 1mg 3 ( ) 1. (Metavir F4 Ishak F5 ) 2. Entecavir Tenofovir 25 Entecavir Tenofovir Response at Wk (%) HBeAg seroconversion 2 3 HBsAg loss HBeAg Positive Entecavir Tenofovir < 1 HBsAg loss HBeAg Negative Log HBV DNA at Wk HBeAg positive HBeAg negative Genotypic resistance, % NUC naive 1.2 (Yr 5) (Yr 8) Lamivudine experienced 51 (Yr 5) NR Pregnancy rating Class C Class B AEs None Renal toxicity; BMD Lok AS. Hepatology. 21;52: Marcellin et al. AASLD 214

16 Entecavir Tenofovir Activity According to Resistance Entecavir Tenofovir LAM/LdT resistance Decreased Active ETV resistance -- Active ADV resistance Active Decreased TDF resistance Active -- Lok AS. Hepatology. 21;52: egfr Changes in Special Populations over 2 years in GLOBE Study (Telbivudine) (egfr at 6-9 ml/min/1.73 m 2 ) The egfr increased in Telbivudine treated patients with age older than 5 years (+11.4 %) The egfr increased in Telbivudine treated patients with baseline CKD stage 2 (+17.2%) Gane EJ, et al. Gastroenterology 214;146:

17 B Initial response HBeAg(+) patients Anti-HBe seroconversion Durable response HBV DNA undetectable HBeAg loss ALT normalization HBsAg loss Histology improved Prevent Complications (Cirrhosis, hepatocellular carcinoma) Prolong survival TIME Initiation of Primary aim of treatment: Permanently suppress HBV replication treatment Liaw YF et al. Asia Pacific Consensus Statement 28 Hepatol. Int

18 ( ) 1. AASLD. Lok & McMahon. Hepatol EASL. EASL Jury. J Hepatol APASL. Liaw, et al. Hepatology Int 212 Relapse rate after stopping NUC following APASL guideline: HBeAg-positive patients Study Kim SS et al., Hepatology Research 213 Dai CY., et a;. J Antimicrob Chemother 213 Chen CH., et al. AASLD 213. Abstract 937 Country Korea Taiwan Taiwan No. of patients NUC LAM 18, ADV 16, ETV 17 LAM ETV HBeAg status e (+) e (+) e (+) Treatment period (median) Consolidation period (median) 3.1 years ( 1.2) 2. years ( ) 3. years > 12 months > 12 months > 12 months Baseline HBV DNA (IL/mL) 24.6 x x 1 5 Not available Baseline HBsAg (IU/mL) Not available Time of assessment after EOT 1 year 6 months 1 year/2years Type of relapse Virological relapse Reappearance of HBeAg or HBV DNA detectable Virological relapse Clinical relapse Relapse rate 78.4% 5%* 36.3%/53.3% 31.1%/49.1% Virological relapse: HBVDNA >2, IU/mL Clinical relapse: HBVDNA >2, IU/mL and ALT > 2-fold ULN

19 Relapse rate after stopping NUC following APASL guideline: HBeAg-negative patients Study Seto WA., et al. EASL 213. Abstract 773 Jeng WJ., et al. Hepatology Chen CH., et al. AASLD 213. Abstract 937 Country Hong Kong Taiwan Taiwan No. of patients NUC ETV ETV ETV HBeAg status e (-) e (-) e (-) Treatment period (median) 3.1 years (2. 6.) 2. years (1. 4.6) 3. years Baseline HBV DNA (IL/mL) Not available 12.5 x 1 5 Not available Baseline HBsAg (IU/mL) Not available Time of assessment after EOT 12 weeks 24 weeks 1 year 1 year/2years Type of relapse Virological relapse Virological relapse Clinical relapse Virological relapse Clinical relapse Relapse rate 11.2% 78.1% %/57.2% 31%/46.4% Virological relapse: HBVDNA >2, IU/mL Clinical relapse: HBVDNA >2, IU/mL and ALT > 2-fold ULN Predictors of relapse after stopping NUC treatment Baseline factors On-treatment factors High HBV DNA level 2x1 7 IU/mL 1 > 2x1 5 IU/mL 2 No cirrhosis 1 High qhbsag 7 Male, older 7 Prior ADV 7 End-of-treatment factors High qhbsag > 3 log IU/mL 3 > 567 IU/mL 6 > 25 IU/mL 7 3 rd month HBV DNA detectable 3,4 6 th month HBsAg decline <.5 log 5 Modifiable factors Shorter consolidation period <64 weeks 2 Shorter treatment duration 4 1. Park Y G et al, AASLD 212, abstract Jeng WJ., et al. Hepatology Liang et al., Aliment Pharmacol Ther 211; 34: Seto W.-K. et al. EASL 213, abstract Kim SS et al., Hepatology Research 213; 43: Park Y G et al, AASLD 212, abstract Chen CH., et al. AASLD 213. Abstract 937

20 39 Clinical goals of CHB therapy Short-term goal Mediumterm goal Long-term goal Mortality reduction Transplant need reduction HCC reduction Cirrhosis reduction Fibrosis regression HBsAg seroclearance Histologic improvement HBeAg loss/seroconversion (HBeAg-positive patients only) HBV DNA negative ALT normalization Treatment start Time 4 Su and Kao. Expert Rev. Gastroenterol. Hepatol. 215;9:

21 Untreated Entecavir Log-rank test P<.1 HR:.4 (95%CI: ) Years of follow-up Number at risk Untreated Entecavir Su and Kao et al., Liver Int. 216 Dec;36(12): Untreated Entecavir Log-rank test P= % HR:.38 (95%CI:.2-.74) Untreated Entecavir Log-rank test P=.97 94% HR:.6 (95%CI:.1-.32) Years of follow-up Number at risk Untreated Entecavir Years of follow-up Number at risk Untreated Entecavir Untreated Entecavir Log-rank test P<.1 86% HR:.14 (95%CI:.7-.3) Untreated Entecavir Log-rank test P<.1 85% HR:.15 (95%CI:.8-.29) Years of follow-up Number at risk Untreated Entecavir Years of follow-up Number at risk Untreated Entecavir Su and Kao et al., Liver Int. 216 Dec;36(12):

22 Cumulative Numbers of CHB/CHC Patients Received Reimbursed Therapy in Chiang CJ et al. Hepatology 215;61: Age-sex-specific Mortality and Incidence Rates Before and After the Launch of Chronic Viral Hepatitis Therapy Program in October 23 in Taiwan Year CLD Mortality HCC Mortality HCC Incidence (referent) 1. (referent) 1. (referent) (.9-.94).95 ( ).98 ( ) (.76-.8).76 ( ).86 ( ) Chiang CJ et al. Hepatology 215;61:

23 Monitoring in longterm NUC therapy AASLD 215 APASL 215 Renal parameters Renal monitoring frequency Lactic acidosis monitoring BMD monitoring ADV or TDF Serum Cre, Phosphorus Urine glucose, protein Periodically (at lease annually) NUCs in pts with advanced decompensated cirrhosis No recommendation (insufficient evidence) ADV or TDF Renal function At least every 3 months ETV In pts with severe decompensated disease ADV or TDF At least every 3 months Lampertico et al., AP&T 216; 44:

24 47 Liver Damage due to HBV Reactivation During intense cytotoxic or immunosuppressive therapy, there is a markedly enhanced viral replication withdrawal of cytotoxic or immunosuppressive therapy With the subsequent restoration of immune function. There is Rapid immune-mediated destruction of HBVinfected hepatocytes increases in serum levels of HBV DNA, HBeAg, and HBV DNA polymerase, resulting in widespread infection of hepatocytes. hepatitis, hepatic failure, and even death. Lau GKK. Hepatol Int 28; 2:

25 Risk groups (Low, Moderate) Risk Group HBVr Drug Risk Estimates Diseases Low risk group < 1% Traditional immunosuppressive agents: azathioprine, 6 mercaptopurine, methotrexate o HBsAg pos/anti HBc pos: < 1% (A) o HBsAg neg/anti HBc pos: << 1% (A) Inflammatory bowel disease, psoriasis, sarcoidosis, autoimmune liver disease, arthritis Moderate risk group 1% to 1% Corticosteroids for 1 week o HBsAg pos/anti HBc pos: < 1% (B) o HBsAg neg/anti HBc pos: << 1% (A) TNF alpha inhibitors: (etanercept, adalimumab, infliximab) o HBsAg pos/anti HBc pos: 1 1% (B) o HBsAg neg/anti HBc pos: 1% (C) Tyrosine kinase inhibitors (imatinib, nilotinib) o HBsAg pos/anti HBc pos: 1 1% (B) o HBsAg neg/anti HBc pos: 1% (C) Corticosteroids ( 4 weeks) o HBsAg pos/anti HBc pos: 1 1% (C) (low dose) o HBsAg neg/anti HBc pos: 1 1% (C) (any dose) Asthma, contact dermatitis Inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis Chronic myelogenous leukemia, gastrointestinal stromal tumors Inflammatory bowel disease, vasculitis, sarcoidosis, autoimmune disorders Perrillo RP, AGA Risk groups (High) esp. RITUXIMAB Risk Group HBVr Drug Risk Estimates Diseases High risk group > 1% Corticosteroids ( 4 weeks) o HBsAg pos/anti HBc pos: >1% (B) (high dose*) Anthracycline derivatives such as doxorubin and epirubicin o HBsAg pos/anti HBc pos: 15 3% (A) o HBsAg neg/anti HBc pos: >1% (B) Inflammatory bowel disease, vasculitis, sarcoidosis, autoimmune disorders Breast, ovarian, uterine, and lung cancers; lymphoma and leukemias; TACE B cell depleting agents such as rituximab and ofatumumab o HBsAg pos/anti HBc pos: 3 6% (A) o HBsAg neg/anti HBc pos: >1% (A) Lymphoma/leukemia, rheumatoid arthritis, idiopathic thrombocytopenic purpura, cryoglobulinemia Confidence in evidence: (A) High confidence that the estimate lies within group risk boundaries (B) Moderate confidence that the estimate lies within group risk boundaries (C) Little or no confidence that the estimate lies within group risk boundaries *High dose steroids: prednisone 2 mg or equivalent Perrillo RP, AGA 214 5

26 A management algorithm for patients with HBV infection prior to starting immunosuppressive therapy Hwang JP, Lok AS. Nat Rev Gastroenterol Hepatol. 214 Apr;11(4): Tenofovir alafenamide 52

27 Tenofovir alafenamide (TAF) A Novel Prodrug of Tenofovir GI TRACT RENAL TUBULAR CELL TFV DIANION ESTER TFV (tenofovir) TDF (tenofovir disoproxil fumarate) 3 mg TAF (tenofovir alafenamide) 25 mg PLASMA short plasma half-life ~9% LOWER PLASMA TFV TFV longer plasma half-life - greater plasma stability OAT 1 & 3 TFV HEPATOCYTE TFV-DP HBV AMIDATE RENAL TUBULAR CELL 53 T 1/2 based on in vitro plasma data - TDF =.4 minutes, TAF = 9 minutes. Lee W et. Antimicr Agents Chemo 25;49(5): Birkus G et al. Antimicr Agents Chemo 27;51(2): Babusis D, et al. Mol Pharm 213;1(2): Ruane P, et al. J Acquir Immune Defic Syndr 213; 63: Sax P, et al. JAIDS Sep 1;67(1):52-8. Sax P, et al. Lancet 215. Jun 27;385(9987): Agarwal K et al. J Hepatology 215; 62: ; Buti EASL 216, Oral GS6; Chan, EASL 216, Oral 53 GS12 OAT 1 & 3 TFV Study 18 and 11: Phase 3 CHB Studies: TAF vs TDF TAF HBV Phase 3 clinical trial Primary Endpoint* Baseline Wk 48 Wk 96 Wk 144 Double-blind Study 18 HBeAg- (N=425) Study 11 HBeAg+ (N=873) Randomized 2:1 TAF 25mg TDF 3mg Open-label TAF 25 mg Two phase 3, randomized, double-blind studies Inclusion criteria HBV DNA 2, IU/mL; ALT >6 U/L (males), >38 U/L (females) Primary endpoint (non inferiority margin of 1%): HBV DNA <29 IU/mL at Week 48 Key secondary safety endpoints Bone mineral density and renal parameters at Week 48 Amendment to extend double-blind to Week 144 and open-label phase to Week 384 (Year 8) is currently underway *Non-inferiority margin of 1% Buti EASL 216, Oral GS6; Chan, EASL 216, Oral GS12 5 4

28 Study 18 and 11: Phase 3 CHB Studies: TAF vs TDF Demographics Study 18 (HBeAg-) (N=425) TAF n=285 TDF n=14 Mean age, y (range) 45 (19 8) 48 (25 72)* Male, n (%) 173 (61) 86 (61) Asian, n (%) 25 (72) 11 (72) Mean BMI, kg/m 2 (SD) 25 (4) 25 (4) Treatment experienced, n (%) 6 (21) 31 (22) East Asia region, n (%) 114 (4) 64 (46) Mean HBV DNA, log 1 IU/mL (SD) 5.7 (1.34) 5.8 (1.32) Study 11 (HBeAg+) (N=873) TAF n=581 TDF n= (18 69) 38 (18 68) 371 (64) 189 (65) 482 (83) 232 (79) 24 (4) 24 (4) 151 (26) 77 (26) 287 (49) 145 (5) 7.6 (1.3) 7.6 (1.4) Elevated HBV DNA, n (%) HBeAg- ( 7 log 1 IU/mL) HBeAg+ ( 8 log 1 IU/mL) 55 (19) 24 (17) 272 (47) 142 (49) Median ALT, U/L (Q1, Q3) 67 (44, 12) 67 (47, 12) FibroTest score.75, n/n (%) 31/28 (11) 2/139 (14) 85 (61, 139) 86 (57, 137) 45/566 (8) 22/282 (8) *P=.11 East Asia region denotes Hong Kong, Japan, Singapore (Study 11 only), South Korea, and Taiwan Q, quartile; SD, standard deviation Buti EASL 216, Oral GS6 Chan, EASL 216, Oral GS12 Study 18: Phase 3 CHB Study: TAF vs TDF HBV DNA Response at 48 Weeks HBV DNA <29 IU/mL (%) Log 1 HBV DNA Change 1 Treatment difference +1.8% (-3.6, +7.2); p=.47 Study 18 (HBeAg-subjects) P atients, % (95% C I) TAF: 94% (Wk 48) TDF: 93% (Wk 48) Log 1 HBV DNA Change IU /m L, M ea n (9 5% C I) TAF TDF Study W eek Study W eek Similar and non-inferior rates of virologic suppression with TAF and TDF at Week 48 No resistance detected in either treatment group Buti, EASL 216, Oral GS6

29 Study 11: Phase 3 CHB Study: TAF vs TDF HBV DNA Response at 48 Weeks HBV DNA <29 IU/mL (%) Log 1 HBV DNA Change 1 Study 11 (HBeAg+ subjects) Proportion of Patients, % Treatment difference -3.6% (-9.8, +2.6); p=.25 TAF: 64% (Wk 48) TDF: 67% (Wk 48) M ean IU /m L (95% C I) TAF TDF Study Week Study W eek Similar and non-inferior rates of virologic suppression with TAF and TDF at Week 48 No resistance detected in either treatment group Chan, EASL 216, Oral GS12 Study 18 and 11: Phase 3 CHB Studies: TAF vs TDF ALT Normalization at 48 Weeks 1 Central Laboratory 1 AASLD Study 18 Proportion of Patients, % P=.76 83% 75% Proportion of Patients, % P<.1 5% 32% Study W eek TAF TDF Study W eek 1 1 Study 11 Proportion of Patients, % TAF TDF P=.18 72% 67% Proportion of Patients, % P=.14 45% 36% Study W eek Study W eek TAF showed statistically significant increased ALT normalization rates utilizing AASLD ALT criteria Central lab upper limit of normal (ULN): males 43 U/L, females 34 U/L ( 69 y, males 35 U/L, females 32 U/L); AASLD ULN: males 3 U/L, females 19 U/L. Buti EASL 216, Oral GS6 Chan, EASL 216, Oral GS12

30 Study 18 and 11: Phase 3 CHB Studies: TAF vs TDF Overall Safety Adverse Events Laboratory Abnormalities, 1% Patients, n (%) TAF n=866 TDF n=432 AE 68 (7) 291 (67) Grade 3 4 AE 39 (5) 17 (4) Serious AE 36 (4) 21 (5) D/C due to AE 9 (1) 5 (1) Death 1 * 1 HCC 1 (<1) 5 (1) Grade (31) 126 (29) ALT 7 (8) 4 (9) AST 28 (3) 23 (5) Amylase 23 (3) 1 (2) Fasting LDL cholesterol 37 (4) 1 (<1) Fasting glucose (hyperglycemia) 9 (1) GGT 3 (<1) 6 (1) * 54-year old Asian woman died due to H1N1 influenza at \week 14 (non-treatment-emergent) 51-year old Asian man with cirrhosis died due to HCC at Week 56 (non-treatment-emergent) Buti, EASL 216, Oral GS6 Chan, EASL 216, Oral GS12 Gilead Sciences, Data on File Study 18 and 11: Phase 3 CHB Studies: TAF vs TDF Results: Renal Safety Mean (±SD) change in egfr CG (ml/min) Mean (SD) change in egfr CG (ml/min) Study Week TAF n= TDF n=432 TAF TDF p <.1 P-value Change in scr, mg/dl.1 (.11).24 (.1).12 Subjects receiving TAF experienced significantly less change in egfr CG scr at Week 48 compared to TDF Continuous data are expressed as mean (SD) scr, serum creatinine; egfr CG, creatinine clearance by Cockcroft-Gault Buti EASL 216, Oral GS6 Chan, EASL 216, Oral GS12 Gilead Sciences, Data on File and 6

31 Study 18 and 11: Phase 3 CHB Studies: TAF vs TDF Changes in Spine and Hip BMD Through Week 48 Spine Hip P< Study 18 Mean (SD) % Change Mean (SD)% from Baseline Change from Baseline P< Week Week TDF TAF -6 Study 11 Mean (SD)% Change from Baseline P<.1 P< Decreases in hip and spine BMD were significantly smaller with TAF compared to TDF Buti, EASL 216, Oral GS6 Chan, EASL 216, Oral GS12 B

32 Studies 12/13 Predicted HCC Incidence Using Risk Scores vs. Actual Cases HBeAg+ and HBeAg- patients treated with TDF for up to 8 years Cumulative No. HCC Cases Observed REACH-B CU-HCC GAG-HCC PAGE-B *While 5-year projections are available for the CU-HCC, GAG-HCC, and PAGE-B scores, yearly incidence data were available for calculations of REACH-B as well as actual observed HCC incidence data through 8 years in Studies 12 and 13. All four risk scores predicted similar number of patients experiencing HCC at the end of 5 years, which was higher than what was observed in TDF-treated patients Kim, EASL, 215, P644