Tratamiento Hepatitis B. Maria Buti

Transcription

1 Tratamiento Hepatitis B Maria Buti Hospital General Universitario Valle de Hebrón Barcelona

2 Advances in HBV Treatment 1957 Discovery interferon 199 Discovery PMEA 1991 Discovery lamivudine (3TC) 1998 Discovery entecavir 21 Discovery telbivudine 25 Peginterferon alfa- 2a Peginterferon alfa- 2b * licensed 28 Tenofovir licensed 1991 Interferon alfa- 2b licensed 1999 Lamivudine (3TC) licensed 23 Adefovir dipivoxil (PMEA prodrug) licensed 26 Entecavir licensed 27 Telbivudine licensed Adapted from: ClinicalCareOptions.com * Specific countries only

3 Hepatitis B: Progresion de la Enfermedad Virus Hepatitis B Infeccion Hepatitis Aguda B Hepatitis Cronica B HBeAg +ve HBeAg -ve Cirrosis HCC Decompensacion Muerte Trasplante Hepático Muerte

4 A quien debemos tratar? Tratamiento Obligatorio Tratamiento recomendable No tratamiento

5 Hepatitis B: Progresion de la Enfermedad Virus Hepatitis B Infeccion Hepatitis Aguda B Hepatitis Cronica B Portador Inactivo HBsAg HBeAg +ve HBeAg -ve Cirrosis HCC Decompensacion Muerte Trasplante Hepático Muerte

6 Tratamiento No Recomendable Hepatitis Aguda B excepto en la Hepatitis Fulminante Fase de Inmunotolerancia ALT normales y altos valores DNA-VHB Portadores Inactivos ALT normales y DNA-VHB < 2. UI/mL

7 Hepatitis B: Progresion de la Enfermedad Virus Hepatitis B Infeccion Hepatitis Aguda B Hepatitis Cronica B HBeAg +ve HBeAg -ve Cirrosis HCC Decompensacion Muerte Trasplante Hepático Muerte

8 Tratamiento Recomendable Hepatitis Cronica B HBeAg positivo HBeAg negativo

9 EASL Guidelines: Indication For 1 st Line Treatment Algorithm HBV DNA >2, IU/mL and/or serum ALT >ULN + biopsy or validated non-invasive markers (A2 or F2 by METAVIR) HBeAg-Positive HBeAg-Negative The most potent drugs with the optimal resistance profile should be used as first-line monotherapies. Indications for treatment must also take into account age, health status, and availability of anti-viral agents in individual countries. EASL guidelines. J Hepatol 29;5:

10 Antivirals approved for hepatitis B Drug Type Nucleoside analogs Nucleotide analogs Approved Lamivudine* Entecavir Telbivudine Adefovir dipivoxil Tenofovir Cytokines Interferon alfa Pegylated Interferon alfa-2a

11 Current Treatment End Points in CHB Treatment end points Undetectable Serum HBV DNA (<1-15 IU/ml) HBeAg seroconversion HBsAg loss with or without anti-hbs EASL, J Hepatol 29

12 Undetectable HBV DNA In HBeAg-Positive and HBeAg-Negative Patients At 1 Year HBeAg-Positive HBeAg-Negative % HBV DNA undetectable % HBV DNA undetectable Adefovir PEG-IFN α Lamivudine Telbivudine Entecavir Tenofovir Adefovir PEG-IFN α Lamivudine Telbivudine Entecavir Tenofovir These trials used different HBV DNA assays and they were not head-to-head comparisons for all the drugs. Adapted from EASL guidelines. J Hepatol 29;5:

13 Overview HBeAg Seroconversion Rates HBeAg seroconversion (%) % 24% 22% 21% Collation of currently available data: not from head-to-head studies using different assays 21% 18% 12% n=271 n=266 n=458 n=176 n=354 n=355 n=171 PEG-IFN α-2a 1 PEG-IFN α-2b 2 Telbivudine 3 Tenofovir 4 Entecavir 5 Lamivudine 5 Adefovir 6 1 Lau, NEJM 25; 2 Janssen, Lancet 25; 3 Lai, AASLD 25; 4 Heathcote, AASLD 27; 5 Chang, NEJM 26; 6 Marcellin, NEJM 23

14 Study 13 - HBeAg-Positive Patients Virological Response: HBV DNA <4 copies/ml at Week Percentage(%) % Percentage(%) % Weeks on Study TDF-TDF ADV-TDF ITT: LTE-TDF Analysis : missing or add emtricitabine = Failure On-Treatment Analysis: Overall 34 patients added FTC and of the 23 on study at Week 192, 19 (or 83%) had HBV DNA <4 at Week % 68% 99% 96% Weeks on Study 14

15 ENTECAVIR IN HBeAg + Efficacy at 5 years % 89% 91% 94% 4 55% 2 N=146 N=14 N=134 N=112 1 Year 2 Years 3 Years 4 Years N=94 5 Years Chang et al. Hepatology 21

16 (%) Comparison of antivirals in HBeAg(-) Patients Percentage of Undetectable HBV DNA * Lamivudine <4 cps/ml(1) Adefovir <1 cps/ml (2,3) Entecavir Telbivudine <3 <3 cps/ml6 cps/ml4, Tenofovir <3 cps/ml > Duration of therapy (Years) *Collation of currently available data not from head-to-head studies 1. Hadziyannis S, et al. Hepatology 2;32: Hadziyannis S, et al. NEJM 25; 352: Hadziyannis S, et al. Hepatology 25; 42 (suppl 1):754A (Abstract LB14). 4. Lai C-L et al. NEJM 26;354: ; 5. Shouval D, et al. EASL 26, Vienna, Austria, Oral abstract Lai CL, AASLD 26

17 Study 12 - HBeAg-Negative Patients Virological Response: HBV DNA <4 copies/ml at Week Percentage(%) % Percentage(%) % Weeks on Study TDF-TDF ADV-TDF ITT: LTE-TDF Analysis : missing or add emtricitabine = Failure On-Treatment Analysis: Of the 12 who were eligible to add FTC, 4 added. 8 did not and 6/8 <4 at Week % 84% 1% 99% Weeks on Study

18 % of patients with HBV resistance Cumulative Incidence Of HBV Resistance In Published Pivotal Trials In NUC-Naïve Naïve Patients Year 1 Year 2 Year 3 Year 4 Year ,2,51,2 1,2 1,2 Lamivudine Adefovir Telbivudine Entecavir Tenofovir These trials used different populations, exclusion criteria, follow-up end points, and they were not head-to-head comparisons for all the drugs. Adapted from EASL guidelines. J Hepatol 29;5:

19 Dynamics of Lamividine Resistance Lamivudine ALT (U/L) PCR assay Virologic breakthrough HBV DNA log copies/ml Months Codon 18 Codon 24 Codon 27 L M V L M V L/M M V M M V M M/V V M M/V V M VV M V V Genotypic resistance Biochemical breakthrough Adapted from Si Ahmed et al. Hepatology 2;32:178 88

20 Guidelines for the Management of Antiviral-Resistant HBV Resistance LAM Recommendations Add ADV or TDF Switch to TDF/FTC* Switch to ETV (preexisting( LAM-R R predisposes to ETV-R) ADV Add LAM Switch to TDF/FTC* Switch to or add ETV ETV Telbivudine Switch to or add ADV or TDF Add ADV or TDF Switch to TDF/FTC* Switch to ETV (preexisting( LdT-R R predisposes to ETV-R)

21 Tratamiento Obligatorio Cirrosis Hepática y Complicaciones Sujetos HBsAg positivo que deben recibir inmunosupresion Hepatitis Fulminante

22 High Baseline HBV DNA Associated With Increased Risk Of Cirrhosis And HCC 5 Cumulative incidence of cirrhosis at year 11 follow-up [1] N=3,582 5 Cumulative incidence of HCC at year 13 follow-up [2] N=3, ,2 4 % of patients ,5 5,9 < ,8 23,5 1-1, ,999 million % of patients ,3 1,4 <3 3-9,999 3,6 12,2 14,9 1,-1,- 1 99, ,999 million Baseline HBV DNA (copies/ml) 1. Iloeje UH, et al. Gastroenterology 26;13: Adapted from: Chen C, et al. JAMA 26;295:65 73.

23 Decrease In Disease Progression With Effective Antiviral therapy 25 % with disease progression Placebo = 17.7% P=.1 Lamivudine = 7.8% Time after randomisation (Months) Placebo Baseline, N=215 Month 36, N=43 Lamivudine Baseline, N=436 Month 36, N=122 Adapted from: Liaw YF et al. N Engl J Med. 24;351:

24 1 Tenofovir Patients with Cirrhosis Proportion of HBV DNA <4 c/ml 9 8 Percentage (%) % vs. 85% p= Weeks on Study Cirrhotic N= Non-Cirrhotic N= Buti M et al. EASL 29

25 25 Long term Histological efficacy of ETV in patients with advanced fibrosis or cirrhosis at baseline Patients (n) 1 Liaw Y-F, et al. Hepatology Baseline Week 48 Long-term Ishak fibrosis score n=1

26 Tenofovir vs. Entecavir vs. Truvada in Decompensated Chronic Hepatitis B Liver Disease. HBV DNA < 4 Copies/mL (69 IU/mL): ITT Liaw YF et al Hepatology 21 Percentage % Week 12 Week 24 Week TDF TVD ETV TDF (N=45) TVD (N=45) ETV (N=22) Median CPT score (Q1, Q3) Baseline Mean Change week 48 7 (6-8) -1 7 (6-9) -1 7 (6-8) -1

27 Lange CM Hepatology 29 Severe Lactic Acidosis during Treatment of CHB with ETV in Patients with Impaired Liver Function 13 treatment-naïve patients received entecavir at a dose of.5 mg daily. Three patients with lamivudine-refractory hepatitis B were treated with 1 mg entecavir daily. Mean Age 5.25) years (24-8) including 13 Caucasians (81.3%) and three Asians (62% male). All patients had liver cirrhosis with MELD scores between 6 and 38. Lactate Creatinine-Clearance ph Creatinine-Clearance ETV BE Day of ETV treatment ph Creatinine-Clearance ETV Day of ETV treatment ph

28 Sujetos HBsAg positivo que deben recibir inmunosupresion Reactivaciones graves de la infección por VHB Hepatitis Aguda Elevada Mortalidad Riesgo de reactivacion depende Presencia de DNA-VHB Tratamiento inmunosupresor Ac Monoclonales>Citostaticos y Corticoides Iniciar Profilaxis con un antiviral oral desde antes de la IS hasta meses despues de terminar

29 HBV Reactivation during chemotherapy Prophylaxis vs. deferred treatment Prophylaxis (n=16): Start LAM when start chemo Deferred treatment (n=19): Start LAM only when ALT > 5xULN 5% 4% 3% 37% Deferred LAM p<.2 LAM prophylaxis 27% p=.5 2% Lim, 22 1% % Acute hepatitis % % Death following reactivation

30 Tratamiento de Hepatitis B Resumen No todos los pacientes deben tratarse Antivirales Potentes Alta Barrera Genética evitar resistencias Monoterapia como primer tratamiento Tratamiento debe individualizarse