Anna LOK. Management of Antiviral Resistant Hepatitis B Clinical Case Anna S. F. Lok University of Michigan Ann Arbor, MI, USA.

Slides:



Advertisements
Similar presentations
Hepatitis B & Hepatitis C in HIV
Advertisements

Drug treatment for chronic hepatitis B Implementing NICE guidance NICE technology appraisal guidance 96, 153, 154, 173 Updated 2009.
Egyptian Guidelines For Management of Chronic Hepatitis B
HBV and HIV HIV and HBV VG Naidoo Gastroenterology.
The Hepatitis B&C Past and Present Martin J Spitz MD FACP AGAF Clinical Professor of Medicine UCSF.
Fabien ZOULIM.
Geoffrey DUSHEIKO. Nucleosides for HBeAg-positive chronic hepatitis B G Dusheiko Centre for Hepatology Royal Free and University College School of Medicine.
Professor George KK Lau The University of Hong Kong Hong Kong SAR, China HBeAg-positive chronic hepatitis B: why do I treat my patients with pegylated.
BORDERNETwork Training on HIV and HBV Co-Infections Dr. med. Wolfgang Güthoff / Alexander Leffers, M.A.
Case study: Chronic HBV infection Marion Peters University of California San Francisco 2009.
Hepatitis web study H EPATITIS W EB S TUDY Therapeutic Agents Used to Treat Hepatitis B Presentation Prepared by: Nina Kim, MD and David Spach, MD Last.
How to prevent, diagnose and overcome resistance to nucleoside analogs ? Fabien Zoulim Liver department, Hôtel Dieu Hospital & Hepatitis research laboratory,
Updates in HBV Management CCO Independent Conference Coverage of the 2006 Annual Meeting of the European Association for the Study of the Liver* April.
TELBIVUDINE FOR THE TREATMENT OF CHRONIC HEPATITIS B: A CASE SERIES N.K. Gatselis, K. Zachou, E.I. Rigopoulou, G. Papadamou, K. Galanis G.N. Dalekos Department.
Slide #1 CL Thio, MD. Presented at RWCA Clinical Update, August Optimizing Hepatitis B Virus Treatment in HIV-Infected Individuals Chloe L. Thio,
Coinfection with Hepatitis B and HIV Chia C. Wang Assistant Professor of Medicine AIDS Clinical Conference February 20, 2007.
Robert PERRILLO. 2 nd Paris Hepatitis Conference Why Do I Treat my HBeAg Negative Chronic Hepatitis B Patients with Pegylated Interferon.
Stephanos HADZIYANNIS. Following HBeAg seroconversion a proportion of patients retains or redevelops significant HBV replication associated with persistent.
3 rd Paris Hepatitis Conference January, 20th 2009 How to optimize the management of my HBeAg negative patients? Pietro Lampertico 1st Gastroenterology.
1 FDA Advisory Meeting Clinical Trial Design – Hepatitis B Treatment Anna S.F. Lok, M.D. University of Michigan Ann Arbor, M I.
Rafael ESTEBAN. New Drugs for Chronic Hepatitis B R. Esteban, M.D. Hospital General Universitario Valle de Hebron Barcelona.
1 Hepatitis B Treatment Dr R.V.S.N.Sarma., M.D., Consultant Physician & Chest Specialist.
CHRONIC HEPATITIS B SEROLOGY. Antigens HBsAg -Found on the surface of the intact virus and in serum as unattached particles -Earliest detectable marker.
Can One Pill A Day Keep Hepatitis B Away? Scott K. Fung, MD, FRCPC Toronto General Hospital University of Toronto November 30, 2009 TGH.
Hepatitis B: Chronic Hepatitis and Inactive Carriers - Management
Hepatitis B and Acute Liver Failure Jack Kuritzky, PGY-2 UNC Internal Medicine Morning Report 3/12/10.
1 Roadmap for Management of Patients with Chronic Hepatitis B (CHB) Prof. Xinxin Zhang Rui Jin Hospital Jiao Tong University.
4 th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights.
George LAU. Hepatitis B e antigen positive patients: Why do I treat my patient with pegylated interferon? 2nd Hepatitis Paris conference George KK Lau,
Hepatitis B Patricia D. Jones, M.D. November 13, 2009.
1. Sustained suppression of HBV replication Decrease in serum HBV DNA to
Yves BENHAMOU. Management of Patients with HIV/HBV Co-infection Yves Benhamou Hepatology Department Groupe Hospitalier Pitié Salpétrière Paris, France.
HBV related complications in HIV positive patients during HAART therapy Irina Magdalena Dumitru*, E. Dumitru*, S. Rugina*, Roxana Carmen Cernat**, Simona.
Gui-Qiang Wang Department of Infectious Diseases
Treating HBV Infection: Sustained Remission with Immune control Joseph Sung MD, PhD Department of Medicine and Therapeutics Institute of Digestive Diseases.
Management of Resistance: Implications for Treatment Choices
On-treatment management for chronic hepatitis B (CHB) in patients receiving oral antiviral therapy Byung-Ho Kim Kyung Hee University School of Medicine.
내과스텝강의 국내 만성B형간염의 현황과 치료 전략.
Maria Buti, MD Professor of Medicine Hospital Universitario Vall d'Hebron Barcelona, Spain Clinical Focus: Impact of HBV Therapy on Liver Fibrosis and.
Choosing First-Line Therapy in Chronic Hepatitis B This program is supported by an unrestricted educational grant from.
Clinicaloptions.com/hepatitis Using Virologic and Serologic Tests in the Management of Hepatitis B Diagnose chronic HBV infection When in slideshow mode,
Copyright 2007 The ACT-HBV Korea & UMT. All Rights Reserved 강동 경희대병원 소화기내과 이 정일 만성 B 형 간염의 치료.
Entecavir Superior to Lamivudine for Treatment of Nucleoside-Naive, HBeAg- Negative Patients Slideset on: Lai CL, Shouval D, Lok AS, et al. Entecavir versus.
Understanding and Implementing the AASLD’s HBV Practice Guidelines* and Other Recent Guidelines and Recommendations on the Diagnosis, Management, and Treatment.
Jung Min Lee, Sang Hoon Ahn, Hyon Suk Kim, Hana Park, Hye Young Chang, Do Young Kim, Seong Gyu Hwang, Kyu Sung Rim, Chae Yoon Chon, Kwang-Hyub Han, and.
Debate: What Is the Best Rescue Strategy for the Management of Primary Nonresponse: Switch or Add? Jointly sponsored by Postgraduate Institute for Medicine.
بنام خداوند مهربان. دکتر نرگس نجفی دانشیار دانشگاه.
Kenneth E. Sherman, MD, PhD Gould Professor of Medicine Director, Division of Digestive Diseases University of Cincinnati College of Medicine Cincinnati,
A randomized study of tenofovir containing HAART compared to lamivudine containing HAART in antiretroviral naïve HIV/HBV coinfected patients in Thailand:
Adefovir Suppresses HBV DNA Levels in Lamivudine-Resistant HIV/HBV Patients Slideset on: Benhamou Y, Thibault V, Vig P, et al. Safety and efficacy of adefovir.
Hepatitis B virus infection in renal transplant recipients
Telbivudine Versus Lamivudine in Chinese Patients with Chronic Hepatitis B: Results at 1 Year of a Randomized, Double-Blind Trial HEPATOLOGY 2008;47:
Early Hepatitis B Virus DNA Reduction in Hepatitis B e Antigen–Positive Patients with Chronic Hepatitis B : A Randomized International Study of Entecavir.
Efficacy, Resistance, and Durability Supported by an unrestricted educational grant from.
PI project: Hepatitis B prophylaxis in patients with malignancies
Evidence-based Treatment for Hepatitis B Infection
Jointly sponsored by Postgraduate Institute for Medicine and Clinical Care Options, LLC Treatment Selection for HBV-Infected Patients With Decompensated.
Clinical Focus: Impact of HBV Therapy on Liver Fibrosis and Cirrhosis
HBV Management in 2012… Where Are We Heading?
Volume 67, Issue 2, Pages (August 2017)
How to optimize the management of my HBeAg negative patients?
Hepatitis B Virus Resistance to Nucleos(t)ide Analogues
A comparison of telbivudine and entecavir in the treatment of hepatitis B e antigen- positive patients: a prospective cohort study in China  Y. Zhang,
Ming-Ling Chang, Yun-Fan Liaw  Journal of Hepatology 
Clinicaloptions.com/hepatitis Using Virologic and Serologic Tests in the Management of Hepatitis B Diagnose chronic HBV infection When in slideshow mode,
Volume 44, Issue 2, Pages (February 2006)
EASL Clinical Practice Guidelines: Management of chronic hepatitis B
Ten-year follow-up of hepatitis B relapse after cessation of lamivudine or telbivudine treatment in chronic hepatitis B patients  H.-Y. Pan, H.-Y. Pan,
HEPATITIS B VIRUS ; WHAT`S NEW
Emmet B. Keeffe, Douglas T
Presentation transcript:

Anna LOK

Management of Antiviral Resistant Hepatitis B Clinical Case Anna S. F. Lok University of Michigan Ann Arbor, MI, USA

Clinical Case M/25, born in Taiwan, moved to USA 3 yr ago, single, attending graduate school 3/02 – incidental mild increase in ALT No past history of acute hepatitis or jaundice Denied risk factors for hepatitis B FH: uncle diagnosed liver cancer at age 55, mother and 1 brother HBV+ PE: Normal

M/25, asymptomatic LFT normal except for ALT 46 IU/L (N <40), AST 34 (N <35) CBC, PT, AFP – normal HBsAg+, HBeAg+ HBV DNA 8.7 log 10 c/mL US: normal liver size and texture, spleen not enlarged

M/25, perinatal infection, HBeAg+ Repeat labs 1 month later: ALT 42 IU/L (N <40), HBV DNA 9.4 log 10 c/mL Gastroenterologist concerned, HBV DNA doubled!!, ALT still increase, particularly by “new” standard Liver biopsy recommended but patient declined Treatment recommended: HBeAg+, high HBV DNA, abnormal ALT, family history of HCC Only approved therapies then: standard IFN and lamivudine

M/25, HBeAg+, ALT mild increase 6/02 - Lamivudine started, HBV DNA 9.4 log 9/02 - HBV DNA 5.8 log 12/02 – HBV DNA 4.5 log, ALT 29, HBeAg+ 7/03 – ALT 31, AFP 7.1, HBV DNA not tested Patient graduated and relocated

M/25, Lamivudine breakthrough after 20 months 2/04 – severe fatigue ALT 237 IU/L, bil 0.9 mg/dL, INR 1.0 HBeAg+, HBV DNA 8.7 log10 c/mL

M/25, HBeAg+, HBV DNA 9 log, ALT mild increase, lamivudine breakthrough after 20 months. What would you do at this time? A)Stop lamivudine and observe B)Continue lamivudine and observe C)Stop lamivudine and switch to adefovir D)Continue lamivudine and add adefovir E)Stop lamivudine and switch to entecavir

Lamivudine breakthrough, switched to Adefovir monotherapy in 3/04 3/04 – Patient advised to stop lamivudine and switch to adefovir 9/04 – HBV DNA decreased from 8.7 to 6.4 log10 c/mL 4/05 – HBV DNA 5.2 log10 c/mL

Lamivudine breakthrough, switched to Adefovir monotherapy, HBV DNA 5 log after 13 months What would you now do? A)Increase dose of adefovir to 20 mg B)Add lamivudine C)Add entecavir D)Add interferon E)Switch to tenofovir

Lamivudine breakthrough, switched to Adefovir monotherapy in 3/04 11/05 – HBV DNA 5.9 log10 c/mL, ALT 27 2/06 – HBV DNA 6.5 log10 c/mL, ALT 39 IU/mL, no symptoms –rtN236T mutation detected

Lamivudine breakthrough in 2/04 Adefovir breakthrough in 2/06 What to do now? A)Stop treatment and observe B)Add lamivudine C)Add entecavir D)Switch to Truvada: combination of emtricitabine + tenofovir E)Add interferon

Figure 1. Sequential monotherapy leading to sequential antiviral resistance HBV DNA (Log 10 copies/ml) ALT (IU/L) LAMIVUDINE ADEFOVIR ALT HBV DNA

Management of Antiviral-Resistant HBV How often should patients be monitored during antiviral therapy? Should all patients with breakthrough infection be tested for resistance mutation? When should rescue therapy be implemented? Which is the most appropriate rescue therapy?

How often should patients be monitored during nucleos/tide analogue therapy? Quantitative HBV DNA by PCR assay and ALT (LFT) –Q 3 months – ideally –Q 1 month – initially, in patients with severe flare or decompensation –Q 6 months – minimum frequency HBeAg in those initially positive –Month 12, then every 6-12 months HBsAg in those HBeAg negative –Month 12, then yearly

Why is it necessary to monitor patients so frequently? To enable early detection of treatment failure –Primary treatment failure (primary nonresponse) –Secondary treatment failure (breakthrough) To enable timely adjustment of treatment –To prevent death and liver failure due to hepatitis flares associated with emergence of drug resistance –To ensure better response through early institution of rescue therapy in patients with drug resistance –To decrease the risk of drug resistance by adjusting treatment in patients with primary nonresponse

Primary Treatment Failure or Primary Non Response Definition: Serum HBV DNA decrease by 4 log 10 IU/mL after 6 months of treatment Estimated frequency (using >4 log 10 copies/mL at week 24) –Adefovir ~30-50%Lamivudine 10-35% –Telbivudine 8-30%Entecavir 5-10% Consequences: –Lower rates of response at year 1 and 2 –Higher rates of drug resistance

Entecavir vs. Lamivudine Treatment of Nucleoside-Naϊve Patients HBeAg+ patients Lai CL, NEJM 2006; 354: HBeAg- patients Chang T, NEJM 2006; 354:

Week 24 HBV DNA Level is Predictive of Response to Telbivudine or Lamivudine at 2 years % of patients HBeAg seroconversionALT normalization PCR negative PCR neg 4 HBV DNA at wk 24 (log 10 copies /ml) Di Bisceglie A, AASLD 2006, Abstract 112 HBeAg+HBeAg-

Better viral suppression reduces the risk of genotypic resistance Lamivudine Resistance (median 29 mos) vs. wk 24 HBV DNA Adefovir Resistance at wk 144 vs. wk 48 HBV DNA % Resistance 8 % 13 % 32 % 64 % 4 % 26 % 67 % Wk 24 HBV DNA (log10 c/ml) N = 159 HBeAg+ patients Yuen M, Hepatology 2001; 34:785 < ND 3-6>6< ND> 4< 4< 3 Wk 48 HBV DNA (log10 c/ml) N = 114, primarily HBeAg- patients Locarnini S, J Hepatol 2005; 42(Suppli 2):17

Should All Patients with Breakthrough Infection be Tested for Antiviral Resistant Mutations? Not all patients with breakthrough infection are confirmed to have resistant mutations –~70% in clinical trials, likely less in practice Rescue therapy can be tailored to pattern of resistant mutations –More important in patients who had been exposed to sequential monotherapy

When Should Rescue Therapy be Initiated? Detection of resistant mutations through surveillance program –Impractical in practice –Overall benefit not established, may consider for patients with decompensated cirrhosis or immunosuppressed patients Virologic breakthrough – HBV DNA increase by >1 log10 from nadir –More effective Viral rebound – HBV DNA increase to >5 log10 –Not as effective Biochemical breakthrough – ALT increase –Not as effective Hepatitis flare or hepatic decompensation –May not reverse outcome

Manifestations of Antiviral Resistance HBV DNA (Log 10 IU/ml) Biochemical Breakthrough ULN Viral Breakthrough Years Antiviral Treatment Hepatitis Flare Viral Rebound Genotypic Resistance

Early Addition of Adefovir is More Effective in Patients with Lamivudine Resistance Lampertico P, Hepatology 2005;42:1414 Months % Patients with undetectable HBV-DNA Virologic BT <6 log HBV-DNA Virologic BT 6-8 log HBV-DNA Biochemical BT >8 log HBV DNA p< Patients still at risk

Choice of Rescue Therapy Depends on knowledge of Prior therapy Pattern of resistant mutations In vitro data on susceptibility of mutants to other antiviral therapies and any cross- resistance

Location of Primary Antiviral-Resistant HBV Mutations in the HBV Polymerase/RT Domain LAM Resistance rtA181TrtM204V/I/S ADV ResistancertA181T/VrtN236T ETV Resistance*rtI169TrtT184S/A/I/LrtS202G/IrtM250I/V L-dT ResistancertM204I * In association with LAM-resistant mutations 845 a.a. Terminal Protein Spacer POL/RT RNaseH ABCED (rt1)692 (rt 344) YMDD F__V__LLAQ__ I(G) II(F)

Selection of lamivudine-resistant mutations limits future treatment options L180M A181V/T T184G/S/A/C S202G M204V/1 N236T M250V LAM FTC LdT ADV ETV

In Vitro Cross-Resistance LAMLdTETVADVTDF M 204 I┼┼┼┼┼┼┼?┼┼ L 180M+ M 204 V ┼┼┼┼┼┼┼┼┼ A 181 T/V┼┼ ┼ ? N 236 T┼┼┼┼┼ I 169+ M 250V* ┼┼┼┼ ┼┼ T 184G+ S202 I* ┼┼┼┼ ┼┼ * (+ L180M + M 204 V/I)

Management of Lamivudine- or Telbivudine- Resistant HBV Add Adefovir Add Tenofovir or Switch to Truvada (FTC+Tenofovir) –Not yet approved for HBV Switch to Entecavir –Response not as good as wild type HBV, increase risk of ETV resistance Switch to Adefovir –Response not as good as add-on therapy (some studies), increase risk of ADV resistance Switch to Interferon –Limited data

Lamivudine resistant HBV: Add-on Adefovir is less likely to be associated with subsequent resistance to Adefovir 5/5 (100%) 9/29 (31%) % patients switched to ADV Fung et al, J Hepatol 2006; 44: p= ADV-RNo ADV-R 5/5 5/5100% 9/2931%

Management of Adefovir-Resistant HBV Lamivudine-naïve patients –Add Lamivudine: long-term efficacy unknown –Switch to Truvada: limited data –Add or switch to Entecavir: limited data –Switch to IFN: no data –Switch to Tenofovir: partial response

Management of Adefovir-Resistant HBV Lamivudine-experienced patients –Add Lamivudine: long-term efficacy unknown Rapid re-emergence of LAM-resistant mutations reported –Switch to Truvada: limited data –Add or switch to Entecavir: limited data Possibility of subsequent ETV-resistance unknown –Switch to IFN: no data –Switch to Tenofovir: partial response

Management of Entecavir-Resistant HBV Add or switch to Adefovir Add or switch to Tenofovir Switch to IFN Little or no data on all options

Prevention of Antiviral-resistant HBV Judicious use of antiviral treatment Initiate treatment with combination therapy – what agents to combine? Use most potent agent with highest genetic barrier to resistance Monitor viral response – switch therapy if response suboptimal Counsel on medication compliance Avoid sequential monotherapy Avoid cross-resistant drugs