Advances in Liver Disease 2018: A Year in Review. The Present and Future of Hepatitis B, C & E

Transcription

1 Advances in Liver Disease 2018: A Year in Review The Present and Future of Hepatitis B, C & E Eyob L. Feyssa, MD, MPH, FACP, Dipl. ABOM Director, Viral Hepatitis Program Einstein Healthcare Network

2 Disclosure of Conflicts of Interest Eyob L. Feyssa, MD, MPH, FACP, Dipl. ABOM has affiliations with Gilead Sciences, Merck, Abbvie, Salix Dova, and Conatus. I have included discussion on unlabeled uses of a commercial product or an investigational use of a product not yet approved for this purpose

3 Learning Objectives Interpret current evidence for individualizing antiviral therapy choices in chronic hepatitis B and C infections Review data on available evidence of benefits of antiviral therapy in unique at risk population Summarize the benefits of Hepatitis C therapy beyond virologic cure

4 Updates: Natural History and treatment of chronic HBV infection

5 Changes over time HBV is a life long, dynamic disease Risk of end stage liver disease and cancer increases with ongoing inflammation and viremia in adults Fibrosis can be reversible Drugs can decrease fibrosis progression HBV can be controlled but not cured Reactivation can occur even in those who have lost HBsAg Slide 2

6 Approved HBV treatments Interferon alfa-2b 1991 Lamivudine 1998 Adefovir 2002 Entecavir 2005 Peginterferon alfa-2a 2005 Telbivudine 2006 Tenofovir For HIV: Emtricitabine Tenofovir + emtricitabine (single pill coformulation) Tenofovir alafenamide (TAF) 2016 Novel, Targeted prodrug of Tenefovir 25 mg daily dosing vs TDF 300 mg daily Slide 13

7 HBV DNA <29 IU/mL, % HBV DNA <29 IU/mL at Week 144 (ITT) following TAF vs TDF for 24 weeks HBeAg-Negative HBeAg-Positive p= p= /285 63/74 428/ /178 0 TAF TDF TAF TDF No resistance to TAF and TDF was detected through Week 144 There were higher rates of ALT normalization by AASLD 2018 criteria in patients on TAF compared to TDF There were significantly smaller decreases in egfr CG and less decline in BMD with TAF compared to TDF at Week 144 Chan, AASLD 2018, 0381 and

8 Therapeutic endpoints over time Loss of HBeAg Loss of HBV DNA Anti-HBe+ Improved histology Anti-HBs+ Loss of HBsAg Improved survival TIME Slide 10

9 Incidence and predictors of HBsAg Seroclerance Retrospective Study 1 North American and 8 Asian centers 10,614 CHB patients treatment Naïve two undetectable HBsAg results six months apart. Low seroclearance rate annual rate of 1.33% (95% CI: ) 20-year cumulative incidence rate 25.49% Improved therapy is Needed Yee Hui Yeo et al; AASLD 2018: #212

10 Excluding Cirrhosis in CHB patients: Use of APRI and FIB-4 (Sonic-B Study) 8 global RCT that required baseline liver biopsy (n=3960) at study entry Derivation n=2926, Cirrhosis in 340 (12%) Validation n=1034, Cirrhosis in 155 (15%) Significant proportion of cirrhotic misclassified as no cirrhosis by conventional cut-offs (APRI <1.00; FIB-4 <1.45) 45% by APRI and 41% by FIB-4 New cut-off accurately excludes cirrhosis Sonneveld et al; AASLD 2018: #2072

11 Treatment benefit in minimal disease HBV infected patients Double Blind RCT of TDF vs Placebo in CHB HBV DNA >2,000IU/ml and ALT 1-2XULN with paired liver Bx at 0 and 3 years. (Taiwan) 132 paired liver biopsy data (65 TDF and 67 placebo) TDF treatment associated with Less progression of fibrosis and progression to cirrhosis Reduced inflammation score, HBV DNA and ALT. Clarify whether tenofovir disoproxil fumarate (TDF) could prevent disease progression in CHB patients with minimally raised ALT. Hsu et al; AASLD 2018: #264

12 Sustained Response after stopping antiviral therapy Inclusion HBeAg-neg with DNA neg > 3yrs (stat HBeAg-neg) >1yr post HBeAg loss (start HBeAG+) Intervention Randomized 2:1 stop vs continue NA F/U x 72 weeks Retreatment Criteria HBeAg seroconversion HBV DNA >2000 IU/ml + ALT.5ULN X2 HBV DNA >20,000 x 2 Result: Clinical relapse or Retreatment in >50% Liem et al; AASLD 2018: #268

13 HCC risk after the First 5 Years of ETV or TDF Therapy in Caucasian Chronic Hepatitis B (CHB) Patients of the PAGE-B Cohort 1951 adult Caucasians with CHB±compensated cirrhosis 1427 (73%) have completed followup >5 years without HCC until year 5 (age at year 5:57±13 years, males:70%, baseline cirrhosis:26%). After year 5, HCC developed exclusively in patients older than 50 years. HCC surveillance should continue in all patients >50 years old and probably in the few cirrhotics 50 years old. Papatheodoridis et al; AASLD 2018: #17

14 Summary of HBV in 2018 HBV is a lifelong and dynamic disease Spontaneous HBsAg clearance (functional cure) rate is low Virologic suppression with TAF is comparable with TDF offering lower effect / changes in egfr and bone mineral density. New threshold for excluding cirrhosis using APRI and FIB-4 Earlier antiviral intervention during the intermediate phase before ALT elevation may prevent unnecessary clinical events. Rate of sustained response is low after stopping therapy and warrants continuation of antiviral therapy. HCC occurs even with NA therapy. Surveillance recommended.

15 Present and Future considerations on HCV care

16 HCV in US Deadliest infectious disease 3.5 million Americans affected Multiple effective DAA therapies with SVR > 95% AASLD/IDSA recommends all patient with HCV be offered therapy ( HCV in 2018 and at the liver meeting Challenges in treating high-risk population Data on benefits of HCV therapy beyond SVR HCV, DAA therapy and HCC risk Introduction

17 Prevalence of Chronic HCV in the United States Analysis of NHANES HCV prevalence and National Vital Statistics System (NVSS) HCV and narcotic deaths to calculate state-level HCV prevalence Appalachian region has 3 of the 10 highest prevalent states HCV RNA Prevalence (100 persons) [ ] [ ] [ ] [ ] [ ] Estimated national prevalence of current HCV infection (RNA positive) = 1% (2.4 million persons)* Half of prevalent infections occur in 9 states and District of Columbia: Alaska, Arizona, DC, Kentucky, Louisiana, New Mexico, Oklahoma, Oregon, Tennessee, and West Virginia There is substantial variation in HCV prevalence among states, with the US west and Appalachian region containing more high-burden states Rosenberg, AASLD 2018, 88

18 HCV Linkage to Care in the United States: US laboratory database Linkage to HCV care remains a critical barrier in the HCV care cascade, especially in young patients at highest risk to transmit HCV Reau et al AASLD 2018: Abstract #1567.

19 Current therapy: Real world data

20 SVR12, % (PP) SOF/VEL Real World Outcomes in HCV Patients with GT1-6: TRIO study SOF/VEL / / / 152 Overall F0-3 F4 F0-3 F4 PPI 50/ 52 37/ 39 79/ 79 Treatment Naïve Treatment Experienced Curry, AASLD 2018, 678

21 SVR12, % (PP) SOF/VEL in GT 3 HCV with Compensated Cirrhosis: Real-World Integrated Analysis 100 SOF/VEL SOFVEL+RBV / 496 FibroScan, kpa GT 3 patients with CC from multiple real-world cohorts achieved a high SVR with SOF/VEL Fagiuoli, AASLD 2018, / / 53 47/ / 226 Overall TE < / / / 62

22 Efficacy of Glecaprevir/Pibrentasvir 8 weeks therapy in TN NC: US TRIO Real World Experience.

23 SVR12, % (PP) Real-World Efficacy of SOF/VEL/VOX: TRIO data Baseline Demographics Bacon, AASLD 2018, 706 Total N=196 Male, n (%) 144 (73) Mean Age, year (range) 61 (26 82) TE, n (%) 173 (88) Cirrhosis, n (%) 82 (42) Hypertension, n (%) CKD stage 1 3, n (%) Prior regimens, n (%) LDV/SOF±RBV SOF/VEL±RBV EBR/GZR±RBV Other SOF Other regimens 81 (41) 77 (43) 92/173 (53) 20/173 (12) 19/173 (11) 17/173 (10) 23/173 (13) 183/ / 183/ / 19/ / 163/ / 88/ Overall TN TE LDV/SOF ±RBV SOF/VEL/VOX for 12 weeks resulted in high real world efficacy, irrespective of genotype and prior treatment regimen 95 43/ 19/20 43 SOF/VEL ±RBV Prior treatmen

24 Current therapy: New data / application

25 8 Weeks therapy with G/P in Compensated cirrhotic patients: Expedition-8 study 5 no SVR 12 1 DC No virological failures No Safety concerns Brown et al; AASLD 2018: LB7

26 HCV reinfection and injection risk behavior following Elbasvir/Grazoprevir therapy in OAT centers: C-EDGE CO-STAR PART B

27 HCV reinfection and injection risk behavior following Elbasvir/Grazoprevir therapy in OAT centers: C-EDGE CO-STAR PART B

28 Benefits of HCV therapy beyond SVR

29 Durability of SVR % Durability of SVR Following Treatment with DAAs 3-year registry of patients treated in Gilead-sponsored trials who achieved SVR Treatment Regimens (%) SOF+RBV±PegIFN 80 LDV/SOF±RBV SOF/VEL±RBV SOF/VEL/VOX Other / patients had detectable HCV RNA during their participation in the SVR registry 8 (0.1%) had virologic evidence of relapse 15 (0.2%) had virologic evidence of reinfection with phylogenetically distinct virus of same genotype 7 (0.1%) had reinfection with different genotype Schwabe, AASLD 2018, 595 SVR is durable and late relapses (beyond SVR12) are rare

30 Benefits of SVR Liver-related and All-cause mortality is lower in patients with SVR vs patients who failed therapy SVR associated with substantial reduction in the incidence of extrahepatic manifestations Mood disorders (21%), CKD (53%), HTN, osteoporosis, HIV infection Mental health, Fatigue and substance use Reduced incidence rate of Type-2 DM following completion of DAA therapy Reduced Cardiovascular event after HCV therapy Janjua et al; AASLD 2018: #145, Rossi et al; AASLD 2018: #148, Butt et al; AASLD 2018: #1566, Singer et al; AASLD 2018: #589

31 Reduction in Cardiovascular Events After HCV Treatment: ERCHIVES VA HCV Database Treated n=17,103 Butt, AASLD 2018, 1566 Untreated n=17,103 Age, median Race, % White Black Male, % Alcohol abuse/ dependence, % Drug abuse/ dependence, % BMI, % >30 kg/m FIB-4 >3.25, % Median total cholesterol, mg/dl Baseline Characteristics Diabetes, % 8 9 Hypertension, % SVR, % 76 - PegIFN+RBV treated per study criteria n=4,436 Untreated, matched controls n=4,436 Study Flow Exclude If CVD at baseline n=151,593 n=13,536 DAA treated per study criteria n=12,667 Untreated, matched controls n=12,667 CV Events: acute myocardial infarction, angina, cardiac failure, peripheral vascular disease, bypass, angioplasty, stroke Atherosclerotic Cardiovascular Disease

32 Probability of CVD-free survival Probability of CVD-free survival HR (95% CI) Reduction in Cardiovascular Events After HCV Treatment: ERCHIVES VA HCV Database Treated Untreated Log-Rank p< CVD-Free Survival Time in years Factors Associated with a Diagnosis of an Incident of CVD Events Treated with SVR Treated no SVR Untreated Log-Rank p< Time in years Butt, AASLD 2018, 1566 HCV treatment significantly reduced CVD events

33 Summary of HCV in 2018 DAA therapy option available for all group HCV infected individuals HCV treatment rate is low vs number of patients diagnosed Available data support that high risk population can be treated with low risk of relapse or reinfection rates SVR is associated with reduced rates of liver related and all-cause morbidity

34 Few points on Hepatitis E (HEV) HEV common cause of acute viral hepatitis but least diagnosed RNA virus member of the genus Hepevirus Variability in reported prevalence By geography high in developing world Also reported variability in sensitivity and specificity of different serologic tests Genotype 1 4 Transmission: contaminated food and water blood transfusions through mother-to-child transmission. Purcell and Emerson J Hepatol 2008 Donnelly et al,. Aliment Pharmacol Ther. 2017; 1-6.

35 Hepatitis E (HEV) acute vs chronic Acute hepatitis E generally self-limiting but can also lead to acute liver failure in small proportion of patients Often misdiagnosed usually DILI In first 300 cases of DILIN, 16% (50) reactive IgM anti-hev 9 cases (3%) genotype 3. Chronic hepatitis E almost exclusively occurs in immunosuppressed patients (eg, those with HIV infection, following solid organ or bone marrow transplantation) Typically genotype 3 HEV Acute on chronic hepatitis pre-existing liver disease Extrahepatic manifestations Eg. Neurologic manifestations: Guillain-Barre Syndrome, acute encephalitis, ataxia and cognitive decline. Purcell and Emerson J Hepatol 2008 Donnelly et al,. Aliment Pharmacol Ther. 2017; 1-6. Davern et al., Gastro 2011

36 Hepatitis E (HEV) diagnosis and therapy Consider HEV infection in Possible DILI, ACLF or seronegative acute / chronic hepatitis Reliable testing available DVH laboratory at CDC contact Amanda Poe APoe@cdc.gov ; phone: If anti-hev IgM reactive, check HEV RNA by PCR in serum or stool Therapy RBV mg alone for 3 months PegInterferon alfa2b SVR 66-75%

37 Thank You!