Hepatitis B: What You Need to Know Hepatitis B 2016

Transcription

1 Hepatitis B: What You Need to Know 2016 Tram T. Tran MD Medical Director, Liver Transplant Fellowship Program Director Cedars Sinai Medical Center Associate Professor of Medicine Hepatitis B 2016 New Guidelines Who to treat and who to monitor Special populations you shouldn't miss New therapies Page 1 of 18

2 Who to treat: Active viremia HBV Treatment 2016 >2,000-20,000 IU/ml Some evidence of liver injury Elevated ALT >2XULN Histologic injury Family history HCC Special populations FDA Approved Therapies First Line Therapy Peginterferon alfa-2a PEGASYS Roche Laboratories 2005 Entecavir BARACLUDETM Bristol-Myers Squibb 2005 Tenofovir VIREAD Gilead Sciences 2008 Second Line Therapy Adefovir dipivoxil HEPSERA Gilead Sciences 2002 Telbivudine TYZEKA Idenix and Novartis 2006 Third Line Therapy Lamivudine EPIVIR-HBV GlaxoSmithKline 1998 Available at Accessed 02/18/10. Page 2 of 18

3 We have succeeded at viral suppression Proportion of Subjects, % HBeAg- Patients TDF-TDF 70 ADV-TDF Weeks HBeAg+ Patients TDF-TDF ADV-TDF Weeks Observed response: 99.6% ITT* response: 75% Retention at Year 8: 71% (266/375) Observed response 98% ITT* response: 58% Retention at Year 8: 55% (146/266) *Missing/addition of FTC = failure (LTE-TDF) Marcellin, AASLD, 2014, Oral #229 We can regress fibrosis Patients with Ishak score 4: 38% at Baseline, 12% at Year 5 Patients with cirrhosis (Ishak score 5): 28% at Baseline, 8% at Year 5 P < P<0.001 Percentage of patients % 38% 63% 39% Baseline Year 1 Year 5 Ishak Fibrosis Scores Marcellin P, et al. Lancet. 6 Page 3 of 18

4 Treatments have LOW Resistance Cumulative Probability (%) Years ETVr = LVDr (M204V ± L180M) + T184, S202, and/or M250 substitutions n=663 2 n=278 3 n=149 4 n=120 5 n=108 6 n=99 HBV DNA <300 copies/ml in 94% of patients (n=99) in Year 6 Kitrinos. Hepatology 2014 We can LOWER Cancer Risk Analysis of 2,255 CHB patients from US cohort and 3,653 patients from REVEAL- HBV study (973 treated in US cohort) 273 incident cases of HCC (12/973 treated, 261/4935 untreated) 77% risk reduction in HCC in treated patients compared to untreated patients The reduced risk of HCC by antiviral therapy is independent of gender, age, cirrhosis, HBeAg, and ALT Lin, AASLD 2015, 207 Cumulative incidence of HCC REVEAL+US-No Treatment US-Treatment P< Years to follow-up Year Number at risk REVEAL + US-No treatment US-Treatment Page 4 of 18

5 HBeAg positive Treatment: how long? Seroconversion Consolidation 12 months after Cirrhotics: continue forever HBeAg negative indefinite Terrault 2015 Who should you NOT Treat? Oral therapy for normal ALT HBV 126 patients Mean age 33 High HBV DNA Mean 8.4 log10 IU/ml ALT <=43 U/L male, <=34 U/L female Endpoint: HBV DNA undetectable week 192 TDF n=64 Primary endpoint, n/n (%) HBV DNA <69 IU/mL 35/64 (55) TDF/FTC n=62 p- value* 47/62 (76) Secondary endpoints, n/n (%) HBeAg loss 4/63 (6) 1/62 (2) HBeAg seroconversion 3/63 (5) 0/62 (0) HBsAg loss 0 0 HBsAg seroconversion 0 0 Hui CK Hepatology Page 5 of 18

6 Then Now Page 6 of 18

7 Use of Preemptive Antiviral Therapy Reduces HBV-Related Hepatitis HBsAg+ patients with lymphoma treated with high-dose chemotherapy randomized to preemptive versus on-demand LAM Survival Free from Hepatitis Due to HBV Reactivation Patients at risk, n Preemptive LAM On-demand LAM P =.002 by log-rank test Preemptive LAM On-demand LAM (if HBV DNA increased) Week Lau GK, et al. Gastroenterology. 2003;125: Anti-HBc and reactivation FDA Boxed Warning 109 fatal cases of HBV acute liver injury 106 with rituximab, 3 with ofatumumab 69% cases were HBsAg negative prior to initiation of immune suppression Reactivation 63 days to 12 months after last dose Recommendation: Screen ALL patients before treatment with HBsAg, anti-hbc Refer to specialist Monitor for several months after treatment Page 7 of 18

8 High Risk Immune Suppression HBsAg-positive or anti-hbc positive patients B cell depleting agents (eg, rituximab, ofatumumab) Anthracycline derivatives (eg, doxorubicin, epirubicin) Moderate-dose (10 20 mg prednisone daily or equivalent) or high-dose (>20 mg prednisone daily or equivalent) corticosteroids daily for 4 weeks Reddy 2015 Management Strategy Screening: HBsAg, anti-hbc HBsAg positive HBsAg negative; anti-hbc positive Initiate prophylaxis High risk treatment? Yes No Initiate prophylaxis Monitor Page 8 of 18

9 Risk Factors Associated With Perinatal HBV Infection Due to Immunoprophylaxis Failure Immunoprophylaxis failure rate Overall: 4.9% Maternal HBV DNA >6 log 10 copies/ml: 5.7% Independent risk factor for vertical transmission of HBeAg positive mothers Maternal HBV DNA levels Immunoprophylaxis failure occurred in a significant proportion of infants born to mothers with anti-partum hemorrhage, meconium-stained amniotic fluid, independently Infants (%) Immunoprophylaxis Failure 4.9% Overall (n=1242) 0% <6 (n=174) 3.0% (n=298) 5.5% (n=531) 9.6% 8 (n=531) Han G, et al. Hepatology. 2011;54(suppl):444A. Abstract 170. Maternal HBV DNA (log 10 copies/ml) Page 9 of 18

10 Prevalence of Birth Defects With NUCs: Antiretroviral Pregnancy Registry Antiretroviral Pregnancy Registry is a large ongoing database of many antiretroviral drugs Regimen 1 st trimester Prevalence % (95% CI) 2 nd and 3 rd trimester Prevalence % (95% CI) Birth defects in a general population a 2.7 (2.7, 2.8) LAM 142/ ( ) 207/ ( ) TDF 58/ ( ) 25/ ( ) ADV 0/48-0/0 - ETV 2/58-0/2 - LdT 0/10-0/9 - a Centers for Disease Control and Prevention birth defects surveillance system (MACDP) 1989 through Potential limitations of registries such as this should be recognized. The limitations include, but are not limited to, underreporting, differential reporting, underascertainment of birth defects, differential ascertainment of birth defects, and loss to follow-up. Adapted from Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989 through 31 January Wilmington, NC: Registry Coordinating Center, Available from URL: Page 10 of 18

11 Antiviral Options for HBV: Pregnancy Category Category B Telbivudine Tenofovir DF Category C Interferon alfa Peginterferon alfa-2a Peginterferon alfa-2b Lamivudine Adefovir Entecavir Pregnancy category B: Animal studies do not indicate a risk to the fetus and there are no controlled human studies, or animal studies do show an adverse effect on the fetus but well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus Pregnancy category C: Studies have shown that the drug exerts animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in either animals or women BMD in Infants 74 infants tenofovir in late pregnancy vs 69 tenofovir-unexposed infants Bone mineral content at one month post delivery Tenofovir-exposed newborns did not differ from unexposed newborns Mean gestational age (38.2 vs 38.1) length ( 0.41 vs 0.18) or weight ( 0.71 vs 0.48) The mean (standard deviation) BMC of tenofovir-exposed infants was 12% lower than for unexposed infants (56.0 [11.8] vs 63.8 [16.6] g; P =.002) The adjusted mean bone mineral content was 5.3 g lower (95% confidence interval, 9.5, 1.2; P =.013) in the tenofovir-exposed infants need for minimization of exposure and assessment and discussion of clear risk and benefit George K. Siberry. Clin Infect Dis Sep 15;61(6): doi: /cid/civ437. Epub 2015 Jun 9. Page 11 of 18

12 Suggested Management of HBV Infection During Pregnancy HBsAg+ Yes HBV DNA >10 6 copies/ml (200,000 IU/ml) HBV DNA <10 6 copies/ml a Refer for consideration for treatment with 3TC, TDF, or TBV at Week 32 Infant receives HBIG + HBV vaccine at birth a May consider treatment if previous child HBV+. Tran TT. Cleve Clin J Med. 2009;76(Suppl 3):S25-S29. Tenofovir Alafenamide (TAF) Reduces Circulating TFV DIANION ESTER GI PLASMA TRACT TFV (tenofovir) TDF (tenofovir disoproxil fumarate) 300 mg TAF (tenofovir alafenamide) 25 mg RENAL TUBULAR CELL PLASMA short plasma half-life 92% lower plasma TFV TFV TFV long plasma half-life - greater plasma stability OAT 1 & 3 TFV HEPATOCYTE HBV AMIDATE RENAL TUBULAR CELL OAT 1 & 3 TFV T 1/2 based on in vitro plasma data - TDF = 0.4 minutes, TAF = 90 minutes. Lee W et. Antimicr Agents Chemo 2005;49(5): Birkus G et al. Antimicr Agents Chemo 2007;51(2): Babusis D, et al. Mol Pharm 2013;10(2): Ruane 24 P, - et GILEAD al. J Acquir CONFIDENTIAL Immune Defic Syndr 2013; AND 63: PROPRIETARY Sax P, et al. JAIDS DRAFT Sep FOR 1;67(1):52-8. INTERNAL Sax P, et USE al. Lancet ONLY NOT Jun 27;385(9987): FOR DISTRIBUTION Agarwal K OR et al. PROMOTION. J Hepatology 2015; 62: Page 12 of 18

13 TAF HBV Phase 3 Program Baseline Wk 48 Wk 96 Wk 144 Double-blind Open-label Study 108 HBeAg- (N=425) Study 110 HBeAg+ (N=873) Randomized 2:1 TAF 25mg TDF 300mg TAF 25 mg Primary endpoint*: HBV DNA < 29 IU/mL at Week 48 Two phase 3, randomized, double-blind studies Primary endpoint (non inferiority margin of 10%) HBV DNA <29 IU/mL at Week 48 Key secondary safety endpoints Bone mineral density at Week 48 Renal parameters at Week 48 * Non-inferiority margin of 10% Gilead Announces Top-Line Results From Two Phase 3 Studies Evaluating Tenofovir Alafenamide (TAF) for Patients With Chronic Hepatitis B Infection [press release]. Gilead Sciences; Jan 5 th, Study 108 and 110: Phase 3 CHB Studies Safety Summary at Week 48 AEs leading to study drug discontinuation, % (n) The most commonly reported AEs TAF 25mg Study 108 HBeAg- TDF 300mg TAF 25mg Study 110 HBeAg+ TDF 300mg 0.7% (n=2) 0.7% (n=1) 1.0% (n=6) 1.0 (n=3) Headache URI Nasopharyngitis Cough Occurred at similar rates among TAF vs TDF arms In both Studies 108 and 110, patients receiving TAF had smaller mean percentage decreases in BMD in the hip and spine from baseline to Week 48 compared to TDF (p<0.001) Median egfr change from baseline to Week 48 favored TAF in both Studies 108 and 110 (p<0.01) Smaller increases in serum creatinine were observed in patients on TAF in Study 110 (p=0.02) Gilead Announces Top-Line Results From Two Phase 3 Studies Evaluating Tenofovir Alafenamide (TAF) for Patients With Chronic Hepatitis B Infection [press release]. Gilead Sciences; Jan 5 th, Page 13 of 18

14 Tram T. Tran, MD, FACG Changes (%) in Quantitative Proteinuria at Week 48 Studies 104 and 111: HIV+ ART-Naïve Adults, Week 48 Combined Analysis Urine [protein]:creatinine Ratio Median % Change from Baseline (Q1, Q3) Protein (UPCR) Retinol Binding Protein Albumin (UACR) Beta2microglobulin E/C/F/TAF E/C/F/TDF p <0.001 for all Baseline mg/g 44 mg/g Sax P, et al. Lancet Sax P, et al. CROI Seattle, WA. Oral #143LB 5 mg/g 5 mg/g 64 μg/g 67 μg/g 101 μg/g 103 μg/g ß-2- µglobulin, beta-2 microglobulin New Targets for HBV Cure Immunodulators TLR agonists T-cell vaccines PD-1/PD-L1 blockade Entry Inhibitors Myrcludex cccdna silencing RT Pol Inhibitors Nucleotide analogues Non-Nuc analogues RNAseH inhibitrs HBsAg release Inhibitor NAP Inhibit protein translation by sirna Arrowhead Tekmira Alnylam GSK Core inhibitors Novira Bayer Assembly Gilead Janssen Roche Zoulim F, Durantel D. Cold Spring Harb Perspect Med. 2015;5:a Page 14 of 18

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16 ARC 520 Liver targeted Reduce cccdna derived HBV transcripts, HBeAg and HBsAg implicated in immune tolerance Host immune reconstitution Study Design Yuen Late Breaker #9 AASLD 2015 Page 16 of 18

17 HBeAg negative ETV experienced HBsAg reduction HBcrAg reduction HBcrAg and HBeAg >HBsAg HBeAg positive had better HBcrAg and HBeAg responses than HBsAg Best response HBsAg response was in the naïve HBeAg positive patients Page 17 of 18

18 What to Do Now? Keep treating hepatitis B under current guidelines: Elevated HBV DNA plus elevated ALT or significant disease on liver biopsy or family history of HCC Screen appropriately for HCC (US every 6 months ± AFP level) New therapies that will allow cure will likely involve multiple mechanisms (as does treatment for hepatitis C) Page 18 of 18