Comment Traiter une Hépatite Chronique B en 2009 SEMINAIRE ATELIER 4 Février 2009 Comment Traiter une Hépatite Chronique B en 2009 Hello. I am Albert Min, MD. I am the Director of Hepatitis Research at Beth Israel Medical Center and Professor of Clinical Medicine at Albert Einstein College of Medicine, in New York, New York. I will discuss various treatments and options for the management of chronic hepatitis B virus (HBV) infection. CHABI S., BERKANE S.

Hépatite Chronique Virale B 350 - 400 millions de personnes infectées dans le monde 1,2 Millions décès par an Séroprévalence Ag Hbs en Algérie 2,18% (1998) Histoire naturelle variable Survient chez moins de 5% des cas chez l’adulte et dans 90 à 95% des cas d’infection périnatale Gravité : risque de cirrhose et de cancer du foie Suivi à vie; détecter chez qui et quand introduire le traitement

DÉFINITION Atteinte nécrotico- inflammatoire et fibrosante du foie Liée à la persistance de l’infection par le VHB Ag Hbs + > 6 mois

2 différentes formes d’Hépatite chronique B Ag Hbs + > 6 mois Transaminases > 2N Activité histologique HAI > 4 Sauvage Ag Hbe + DNA VHB > 20 000 IU/m (> 105 copies/mL) Mutant pré-C / C Ag Hbe – DNA VHB > 2000 IU/mL (> 104 copies/mL) Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2:87-106. Chu CJ, et al. Gastroenterology. 2003;125:444-451.

Avantages Inconvénients Biopsie Hépatique Avantages Inconvénients Stade de fibrose Morbidité Activité Coût Lésions associées Reproductibilité Immunomarquage Echantillonnage ADNccc

Hépatites chroniques B: Qui Traiter ? Hello. I am Albert Min, MD. I am the Director of Hepatitis Research at Beth Israel Medical Center and Professor of Clinical Medicine at Albert Einstein College of Medicine, in New York, New York. I will discuss various treatments and options for the management of chronic hepatitis B virus (HBV) infection. 6

4 Phases de l’infection VHB chronique AgHBe Ac Anti-HBe ALT activité DNA VHB Phase Immuno- Tolérance Clairance Immune Etat de portage inactif Réactivation Foie Inflammation et fibrose minimes Inflammation chronique active Hépatite modérée et fibrose minime Inflammation active ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus. However, as seen on the next slide, the current understanding of HBV infection now includes an additional phase. As before, disease progression begins with an immune tolerant phase with minimal liver damage, a high HBV DNA and normal alanine aminotransferase (ALT) levels. Next follows an immune clearance phase, with active inflammation on histology. However, this immune clearance phase may include fluctuating levels of ALT activity as well as fluctuating levels of HBV DNA. This immune clearance phase may potentially be followed by an inactive carrier state, in which patients exhibit mild hepatitis and minimal fibrosis on histology. We now also define a fourth phase, reactivation of HBV, characterized by active inflammation on liver biopsy despite hepatitis B e antigen (HBeAg) negativity and anti-HBeAg positivity. Later in this talk, I will describe the optimal treatment time of both patients in the immune clearance phase and patients in the reactivation phase. Indications optimales du traitement Yim HJ, et al. Hepatology. 2006;43:S173-S181.

Hépatites chroniques B: Quand Traiter ? Hello. I am Albert Min, MD. I am the Director of Hepatitis Research at Beth Israel Medical Center and Professor of Clinical Medicine at Albert Einstein College of Medicine, in New York, New York. I will discuss various treatments and options for the management of chronic hepatitis B virus (HBV) infection. 8

Recommandations thérapeutiques Patients au stade d’hépatite chronique(1) AASLD Guidelines HBeAg Positive HBeAg Negative ALT < 1 x ULN ALT > 2 x ULN ALT < 1 x ULN ALT > 2 x ULN ALAT + DNA 6 / 12 mois HBV DNA > 20,000 IU/mL HBV DNA < 2000 IU/mL HBV DNA ≥ 2,000 IU/mL Traitement indiqué ALAT + DNA 6 / 12 mois Traiter si persistance ALT 1-2 x ULN AASLD, American Association for the Study of the Liver; ALT, alanine aminotransferase; HBeAg, Hepatitis B e antigen; ULN, upper limit of normal. The next slide shows AASLD’s guidelines for chronic hepatitis B treatment initiation. The left half of the slide pertains to patients who are HBeAg positive, and the right side of the slide pertains to patients who are HBeAg negative. According to the AASLD guidelines published in 2007 in Hepatology, the recommendation is to treat patients with persistent elevation of ALT < 2 x ULN and HBV DNA level > 20,000 IU/mL regardless of HBeAg status. Patients with ALT > 1 x ULN should be monitored. For HBeAg-positive patients with ALT 1‑2 x ULN and HBV DNA level < 20,000 IU/mL, the recommendation is to consider biopsy if the patient is older than 40 years of age or if the ALT and HBV DNA remain persistently elevated. Treatment is then based on the results of histological evaluation of the liver biopsy. For HBeAg-negative patients with ALT between 1‑2 times the ULN with a HBV DNA 2000-20,000 IU/mL, the recommendation is to consider biopsy and base treatment on the results of the histology. ALT 1-2 x ULN HBV DNA > 20,000 IU/mL si persistantes et ou âge > 35 ans, ATCD familial de cirrhose ou de CHC, faire PBF et traiter si nécessaire (≥ A2F2) HBV DNA 2000-20,000 IU/mL faire PBF et traiter si nécessaire (≥ A2F2) . Lok ASF & McMahon BJ Hepatology 2007;45:507-39.

Recommandations thérapeutiques Patients au stade d’hépatite chronique (2) EASL Guidelines HBV DNA ALT Recommendation EASL guidelines3 HBeAg(+/-) >2,000 IU/mL ALT >2x ULN Faire la PBF et traiter si atteinte ≥ A2 / F2 KEY TAKEAWAY Current international treatment guidelines differ in their HBV DNA and ALT cut-off points for treatment. For ‘clear-cut’ treatment initiation of CHB-infected patients, international guidelines use serum HBV DNA and ALT levels. Differences in cut-off points vary between guidelines. For treatment initiation of HBeAg(+) patients, the APASL guidelines recommend HBV DNA of at least 20,000 IU/mL (≥105 copies/mL) and serum ALT 2–5 x ULN to be persistent for 3 to 6 months, or if there are concerns for hepatic decompensation. If serum ALT is above 5 x ULN but the HBV DNA level is below 2 x 106 IU/mL, and there are no concerns for hepatic decompensation, the clinician may chose to monitor the patient closely for 3 months for seroconversion. For HBeAg(-) patients, the recommendation for treatment is serum HBV DNA of at least 2,000 IU/mL, a lower cut-off compared to HBeAg(+) patients, and an ALT of more than 2 x ULN to be persistent (3 to 6 months). The AASLD guidelines recommend the same cut-off value of HBV DNA for HBeAg(+) and for HBeAg(-) patients, that is, at least 20,000 IU/mL and ALT more than 2 x ULN. In contrast, the EASL guidelines recommend a much lower HBV DNA cut-off value for both HBeAg(+) and HBeAg(-) patients, that is, greater than 2,000 IU/mL and an ALT level of more than the ULN. A liver biopsy is recommended to assess the extent, if any, of liver disease and to only treat patients that exhibit moderate or severe necroinflammation (at least grade A2) and/or fibrosis (at least stage F2). Recently updated guidelines suggest lowering ‘normal’ ALT cut-off values to 30 IU/L for men and 19 IU/L for women. Lésions histo. < A2F2 METAVIR Trt non requis; suivi EASL guidelines3 ALT <2 x ULN EASL Clinical Practice Guidelines Panel. J Hepatol. 2009;50:227-42. 10

Recommandations thérapeutiques Patients au stade de cirrhose Cirrhose Compensée Qui traiter? Ag HBe positif ou négatif DNA VHB > 2000 UI/mL; ALT non spécifiées DNA VHB < 2000 UI/mL; considérer traitement si ALT élevées DNA VHB négatif; observer Cirrhose Décompensée Qui traiter? AgHbe positif ou négatif Quelque soit le taux de DNA VHB ALT, alanine aminotransferase. Treatment recommendations for cirrhotic patients differ from those for noncirrhotic patients. HBeAg-positive or HBeAg-negative patients with HBV DNA > 2000 IU/mL and any ALT level are candidates for treatment if they have compensated cirrhosis. A patient with HBV DNA < 2000 IU/mL can be considered for treatment if his or her ALT is elevated. However, HBV DNA-negative patients with compensated cirrhosis should simply be observed because those patients are not likely to benefit from therapy. Interferon is not a treatment option for compensated cirrhotic patients because of the risk of flare with interferon therapy. Therefore, the preferred drugs for the treatment of a compensated cirrhotic patient are adefovir and entecavir. An HBeAg-positive or HBeAg-negative decompensated cirrhotic patient with any detectable HBV DNA should be treated. The preferred drugs are lamivudine and telbivudine plus adefovir or entecavir. Combination therapy is preferred in decompensated cirrhotic patients because minimizing the risk of resistance or flare is particularly important in this group of patients. Long-term therapy is indicated for these patients to maintain viral suppression, and referral for transplantation should be considered. Lok AS, et al. Hepatology. 2007;45:507-539. EASL 2009 11

Objectifs du traitement Ag HBe + ADN VHB – Séroconversion HBe Normalisation ALAT Séroconversion HBs Ag HBe – ADN VHB – Normalisation ALAT Séroconversion HBs Diminution de l’ADN super enroulé (cccDNA) Diminution des complications de la cirrhose (HTP ou CHC ?) Amélioration de la survie

Traitements disponibles

Hépatite chronique B Immuno-modulateurs IFNa IFNpeg Antiviraux autres cytokines vaccinothérapie Antiviraux Lamivudine Adefovir Entecavir Telbivudine Tenofovir Emtricitabine Clevudine Valtorcitabine Elvucitabine Pradefovir CD8+ HBV

posologie INF PEG 180 ng / semaien, / 48 semianes Lamivudine 100 mg / J > 1 an Adefovir 10mg /J > 1 an Entecavit 0,5 mg / J > 1 an Telbuvidune 300mg/j > 1 an

Choix du traitement initial (1) PEG interféron Analogues nucléos(t)idiques Avantages -Durée de traitement définie -Administration orale, bien tolérés, -Réponse au traitement durable -Effets secondaires négligeables -Pas de résistance -Pas de CID en cas de cirrhose décompensée -Taux élevés de séroconversion et après transplantation hépatique AgHBe et AgHBs Inconvénients -Administration sous cutanée -Durée de traitement indéfinie -Effets secondaires fréquents -Risque de résistance antivirale -Contre indiqué si cirrhose avancée -Faible taux de séroconversion Ag Hbs

Facteurs prédictifs de réponse à l’interféron pégylé Patients Ag Hbe positf Sujet jeune < 60 ans et sans comorbidité DNA VHB basal ≤109 copies/mL ALAT basales > 2-3 x ULN Génotype A ou B Activité nécrotico-inflammatoire à l’histologie en l’absence de cirrhose Option attractive chez la femme en âge de procréer qui préfère suivre un trt de durée définie

Facteurs prédictifs de réponse aux analogues nucléos(t)ides Adulte quelque soit l’âge DNA VHB basal ≥ 2 x 108 IU/mL ALAT basale > 5 x ULN Tout Génotype HBV Cirrhose avec ou sans décompensation

Résultats thérapeutiques Sujet Ag Hbe +

Patients With Undetectable Réponses virologique (DNA VHB indétectable*) à 48-52 semaines; patients Ag Hbe + Essais non comparatifs; populations et design des essais différents 100 80 76 67 60 60 Patients With Undetectable HBV DNA (%) 40-44 40 25 21 20 0-16 ADV, adefovir; ETV, entecavir; HBeAg, hepatitis B e antigen; LAM, lamivudine; LdT, telbivudine; LLD, lower level of detection; PLB, placebo; TDF, tenofovir disoproxil fumarate; PegIFN, peginterferon; PCR, polymerase chain reaction. The graph on this slide shows virologic response rates of HBeAg‑positive patients in response to various antiviral therapies. Of note is that these are not head‑to‑head clinical trials and that they contain different patient populations and trial designs. The Y axis is the percentage of patients achieving undetectable HBV DNA in response to 1 year of treatment with the different agents listed on the X axis. A baseline 0% to 16% of patients receiving placebo achieved undetectable HBV DNA. However, 67% of patients on the potent agent entecavir achieved undetectable HBV DNA. Sixty percent of patients receiving telbivudine achieved undetectable HBV DNA, and 76% of patients receiving tenofovir achieved undetectable HBV DNA. Even though these are not head‑to‑head clinical trials, it is promising that some treatments can achieve between two thirds to three quarter of patients with undetectable level of virus after 1 year of treatment. For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Boston%202007/Tracks/HBV%20Treatment/Capsules/LB6.aspx PLB LAM ADV ETV LdT TDF Peg- IFN *PCR based assay (LLD ~ 50 IU/mL) except pour certaines études LAM. Adapted from Lok AS, et al. Hepatology. 2007;45:507-539. Heathcote EJ, et al. AASLD 2007. Abstract LB6. 20

Séroconversion AgHbe, Perte de l’Ag Hbs, après 1 an de traitement Données à partir des études individuelles, pas de comparaisons directes (différentes populations, différentes valeurs basales) 40 Séroconversion Hbe Perte de l’Ag Hbs 30 22-27 23 21 HBeAg Seroconversion (%) HBsAg loss (%) 20 17 12 10 10 3-5 2 1 PegIFN TBV ETV LAM ADV Untreated Lau G, et al. N Engl J Med. 2005;352:2682-2695. Janssen H, et al. Lancet . 2005;365:123-129. Dienstag J, et al. N Engl J Med. 1999;341:1256-1263. Baraclude [package insert]. Tyzeka [package insert]. Hepsera [package insert]. Chang TT, et al. N Engl J Med. 2006;354:1001-1010. Perrillo RP, et al. N Engl J Med. 1990;323:295-301. Lok AS, et al. Gastroenterology. 1987; 92: 1839-1843.

Séroconversion AgHbe en fonction de la durée du traitement Essais non comparatifs; populations et design des essais différents 100 100 LAM ADV 80 80 60 60 Patients (%) 47 50 Patients (%) 48 40 40 40 29 22 20 20 12 100 100 ETV LdT 80 80 60 60 Patients (%) 47* Patients (%) ADV, adefovir; ETV, entecavir; HBeAg, hepatitis B e antigen; LAM, lamivudine; LdT, telbivudine. However, this next slide shows that prolonged treatment of more than 1 year with nucleos(t)ide analogues like lamivudine, adefovir, entecavir, or telbivudine can achieve increasing HBeAg seroconversion rates. Up to 50% of patients on lamivudine or adefovir for 5 years can achieve seroconversion. On a shorter time scale, 30% of patients on entecavir or telbivudine can achieve seroconversion within 2 years. For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Boston%202007/Tracks/HBV%20Treatment/Capsules/938.aspx 40 37 31 40 29 21 23 20 20 1 2 3 4 5 1 2 3 4 5 Années de traitement Années de traitement *(ETV-022 + ETV-901) 16% additional to 31% HBeAg seroconversion in ETV-022 (Year 2). Chang TT, et al. J Gastro Hepatol. 2004;19:1276-1282. Lok AS et al. Gastroenterol. 2003;125:1714-1722. Chang TT, et al. N Engl J Med. 2006;354:1001-1010. Chang TT, et al. Hepatology. 2006;44(suppl 1):229A. Marcellin P, et al. N Engl J Med. 2003;348:808-816. Marcellin P, et al. Hepatology. 2006;44(suppl 1):548A. Lai CL, et al, Hepatology. 2005;42(suppl 1):748A. Lai CL, et al. Hepatology. 2006;44(suppl 1):222A. Han S, et al. AASLD 2007. A938. 22

Résultats thérapeutiques Sujet Ag Hbe - HBeAg, hepatitis B e antigen. The next session will focus on the treatment of HBeAg-negative patients. 23

Patients With Undetectable Réponse virologique (DNA VHB indétectable*) à 48-52 semaines; patients Ag Hbe - Essais non comparatifs; populations et design des essais différents 100 93 90 88 87 80 ~ 70 63 60 51 Patients With Undetectable HBV DNA (%) 40 ADV, adefovir; ETV, entecavir; HBeAg, hepatitis B e antigen; LAM, lamivudine; LdT, telbivudine; LLD, lower level of detection TDF, tenofovir disoproxil fumarate; PegIFN, peginterferon; PCR, polymerase chain reaction; PLB, placebo. The next slide shows data on virologic response in HBeAg‑negative patients with chronic hepatitis B in response to various treatments. The Y axis shows the percentage of patients with undetectable HBV DNA after 1 year of treatment with the different agents listed on the X axis. In comparison to the data on HBeAg‑positive patients, the achievement of undetectable HBV DNA is very high, approximately 90% or higher. The most significant factor underlying this increased HBV DNA clearance is that HBeAg‑negative patients normally exhibit a pretreatment HBV DNA approximately 2 logs lower than HBeAg‑positive patients. Therefore, since the baseline HBV DNA is lower, it is easier to achieve undetectable HBV DNA in HBeAg‑negative patients. For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Boston%202007/Tracks/HBV%20Treatment/Capsules/LB2.aspx 20 LAM ADV ETV LdT TDF Peg- IFN Peg- IFN + LAM *By PCR based assay (LLD ~ 50 IU/mL) except for some LAM studies. Adapted from Lok AS, et al. Hepatology 2007;45:507-539. Marcellin P, et al. AASLD 2007. Abstract LB2. 24

Suivi du traitement par interféron pégylé FNS à 2s puis toutes les 4 semaines, ALAT / mois et TSH / 3 mois DNA VHB sérique / 12 à 24 semaines durant le traitement si réduction à 6 mois < 3Log, changez de traitement Après arrêt du traitement Hbe +: Ag/Ac Hbe / 6 mois Hbe -: Ag/Ac Hbs / 12 mois 1. Lok AS, et al. Hepatology. 2007;45:507-539. 2007 AASLD guidelines[1]

Les 2 piliers du traitement oral de l’infection VHB Suivi du traitement par les analogues: Les 2 piliers du traitement oral de l’infection VHB Suppression virale Eviter la résistance HBV, hepatitis B virus.   The goal of HBV therapy is the attainment of profound long-term viral suppression with a minimum risk of resistance. Clinical studies have demonstrated that long-term viral suppression is associated with improvement in clinical outcomes. Furthermore, the emergence of resistance has been shown to impair the improvement and outcomes otherwise conferred by successful suppression of HBV replication. As shown in this slide, viral suppression and resistance are intricately related to each other because resistance is much more likely to occur when viral suppression is incomplete. Conversely, the emergence of resistant mutations leads subsequently to viral breakthrough in patients whose virus had previously been effectively suppressed. 26

Suivi du traitement par les analogues: Résistance Réponse au traitement Durée prolongée

Incidence cumulée de la résistance aux Analogues N. Essais non comparatifs; populations et design des essais différents LAM LdT, all patients TDF 100 ADV, HBeAg negative LdT, HBeAg positive ETV LdT, HBeAg negative 80 71 65 60 55 46 Patients (%) 40 30 23 25 19 20 11 5 3 <1 <1 1.2 11 ? ? ? 1.2 ? ? 1.2 ? ? 1 2 3 4 5 Year Lai CL, et al. Clin Infect Dis. 2003;36:687-696. Lok AS, et al. Gastroenterology. 2003;125:1714-1722. Adefovir [package insert]. Colonno R, et al. EASL 2007. Abstract 781. Lai CL, et al. Gastroenterology. 2005;129:528-536. Zeuzem S, et al. AASLD 2007. Abstract 994. Marcellin P, et al. AASLD 2007. Abstract LB2. Heathcote EJ, et al. AASLD 2007. Abstract LB6. Tenney DJ, et al. APASL 2008. Abstract PL02

Prise en charge de la résistance anti-virale VHB Définition de la résistance ? Comment évaluer la résistance ? Que faire en cas de résistance ? HBV, hepatitis B virus.   We will examine 3 important questions. First, how is resistance measured clinically? Second, how should patients be monitored to reduce the risk of resistance prospectively? And third, what should be done when evidence of resistance is present? 29

Chronologie des évènements de survenue de la résistance Lamivudine 2. Rebond de charge virale 3. Montée des ALAT 600 8 500 7 200 6 HBV DNA log copies/mL ALT (U/L) 150 5 100 4 50 3 This slide shows what I like to think of as the chronology of HBV resistance, or its evolution. Initially, early in the chronology of resistance, one sees the emergence of the variants that confer genotypic resistance, as we defined it earlier. After a period, as the resistant variants come to comprise an increasing proportion of the viral population, virologic breakthrough, another term we defined earlier, from whatever native viral level all the way down to undetectable that had been developed during drug-treatment, might occur. Once this happens, that is once virologic breakthrough occurs, patients are at risk of renewal of the necroinflammatory activity associated with biochemical breakthrough and worsening histology on liver biopsy, with progression of liver disease. Consistent with the chronology just outlined, viral levels are lowest when genotypic resistance just begins to emerge, higher when virologic breakthrough occurs and higher still when biochemical breakthrough occurs. 6 12 18 24 30 36 42 Mois Codon 180 L L L/M M M M M M Codon 204 M M M M M/V M/V V V Codon 207 V V V V V V V V 1. Résistance génotypique Si Ahmed et al. Hepatology. 2000;32:1078-1088; Zoulim Antivir Chem Chemother 2001;12: 131-142; Yuen et al Hepatology 2001; 34:784-791; Locarnini et al Antiviral Therapy 2004;9:679-693

Non réponse, Réponse suboptimale, et échappement virologique 1.0 Ananalogue Oral Non réponse primaire Virologic breakthrough -1.0 Change in HBV DNA (log10 IU/mL) Réponse suboptimale -2.0 This figure is a simple demonstration of what one might see utilizing these different definitions. In a primary nonresponse, as shown in the yellow line, you can see that there is less than a 1 log reduction at the end of 6-12 months. Shown in the green line is a suboptimal response and where there is a reduction in the HBV DNA, but it does not go to low levels or to undetectability. The blue line is an example of an individual who has virologic breakthrough. First of all, there is a substantial reduction in serum HBV DNA to very low or undetectable levels, but then over time—for example at Month 12—there is breakthrough, defined as a 1 log increase, that becomes apparent very quickly and this represents failure of therapy after it has initially been begun—what we call “virologic breakthrough.” We want to recognize this early so we can intervene with therapy, as we will see later. We do not want to wait until there is biochemical breakthrough because there then could be clinical deterioration associated with this virologic breakthrough. -3.0 1 log Nadir -4.0 6 12 18 Months Lok AS, et al. Hepatology. 2007;45:507-539.

Relation entre la détection de la résistance et la sensibilité des tests (PCR en temps réel) Drogue anti virale 1.0 Echappement viral -1.0 Change HBV DNA (log10 IU/mL) 1 log10 -2.0 Assay LOD -3.0 1 log10 Nadir -4.0 6 12 16 18 Mois Reproduced with permission from Locarnini S, et al. Management of antiviral resistance in patients with chronic hepatitis B. Antiviral Ther 2004; 9:679-693. ©2004 International Medical Press. All rights reserved.

Tests de quantification du DNA VHB Weiss J, et al Tests de quantification du DNA VHB Weiss J, et al. J Clin Virol 2004; 30:86-93. HBV Digene HybridCapture I Digene Corp. HBV Digene HybridCapture II Ultra-SensitiveDigene HybridCapture II Bayer Versant HBV DNA 1.0 Healthcare Versant HBV DNA 3.0 Roche Amplicor HBV Monitor Molecular Cobas Amplicor HBV Monitor System Cobas Taqman 48 HBV Diagen/Artus HBV PCR Kit Abbott Abbott RealTime HBV Molecular inc. 1 10 102 103 104 105 106 107 108 109 1010 ADN du VHB UI/mL

Quand tester la résistance durant un traitement par analogues ? Evaluation régulière du DNA VHB sérique ++ 2007 AASLD guidelines[1] Tous les 3 à 6 mois 2007 HBV Drug Resistance Working Group[2] DNA VHB avant traitement puis tous les 3 mois sous trt EASL 2009 : tous les 3 mois 1. Lok AS, et al. Hepatology. 2007;45:507-539. 2. Lok, AS, et al. Hepatology. 2007;46:254-265.

Que faire en cas de survenue de la résistance virale ? 1) Confirmer la résistance (2 prélèvements à 1 mois d’intervalle) éliminer une mauvaise compliance +++, non nécessaire si ALAT élevées 2) Adaptation précoce avant l’élévation des ALAT Au moment du rebond virologique 3) Adaptation en fonction des données de résistance croisée Changer de famille anti-virale +++

Recommandations AASLD en cas de résistance aux analogues Traitements de secours Lamivudine Add adefovir (meilleur que switcher) Switch à l’entecavir (augmente le risque de résistance à l’ETV) Add tenofovir* ou switch to emtricitabine/tenofovir* Adefovir Add lamivudine (meilleur que switcher) Switcher ou add entecavir (si pas de résistance à la lamivudine) Switch to emtricitabine/tenofovir* Entecavir Add ou switcher adefovir or tenofovir* Telbivudine Add adefovir (superior to adefovir switch) Switch to entecavir (increased risk of entecavir-R development) Add tenofovir* or switch to emtricitabine/tenofovir* AASLD, American Association for the Study of Liver Diseases; R, resistant. Here is a summary of the AASLD recommendations for managing virologic breakthrough with resistance. Let’s look at lamivudine first. The preferences are shown in the bright orange color, so we now feel that adefovir should be added and this is superior to switching. Why is this? If we switch to adefovir, there is a higher rate of subsequent adefovir resistance that approaches 20% over 2 years. We do not see this with add‑on therapy. One can also switch to entecavir, but there is this increased risk of entecavir‑resistant mutations that might develop. Finally, although it is off label, one could add tenofovir or switch to the combination of emtricitabine and tenofovir. In the case of adefovir, we go in the opposite direction. We can add lamivudine, although one might also add telbivudine as well—although not shown here—or you could switch or add to entecavir, and finally, one could also switch to emtricitabine plus tenofovir. For entecavir resistance, there are less data, but once again we go in the opposite direction: We would go to the nucleotide analogues and switch to or add adefovir or tenofovir. Telbivudine is much like lamivudine. One can add adefovir, which is superior to switch; switch to entecavir, although there is a risk of subsequent entecavir resistance; or go in the direction of tenofovir or emtricitabine plus tenofovir. *Off label. Lok A, et al. Hepatology. 2007;45:507-539. 36

Suivi du traitement par les analogues: Concept du HBV Roadmap Initiaton du traitement oral A 12 semaines Evaluer la non réponse primaire Réponse primaire Chute du DNA VHB  1 log10 IU/mL Echec primaire au traitement Chute du DNA VHB NA < 1 log10 IU/mL Si adhérant, Ajouter une drogue plus puissante Si non adhérant, Corriger A 24 semaines Evaluer les Facteurs prédictifs précoces de l’efficacité Keeffe E, et al. Clin Gastroenterol Hepatol. 2007;5:890-897.

Suivi du traitement par les analogues: Concept du HBV Roadmap A 24 semaines Evaluer les F. prédictifs précoces de l’efficacité Réponse partielle DNA VHB 60 à < 2000 IU/mL Réponse inadéquate DNA VHB ≥ 2000 IU/mL Réponse complète DNA VHB négative en PCR Poursuivre le traitement; Contrôle / 6 mois Ajouter une drogue plus puissante; Contrôle / 3 mois Antiviral: faible barrière génétique Ajouter une seconde drogue sans résistance croisée Antiviral: barrière génétique élevée Contrôle / 3 mois; continuer à ≥ 48 semaines Antiviral: activité antiviral sous optimale Contrôler / 3 mois; continuer à 48 semaines* Keeffe E, et al. Clin Gastroenterol Hepatol. 2007;5:890-897.

Durée du traitement par Analogues nucléos(t)idiques : Ag HBeAg positif 6-12 mois après séroconversion AgHbe; réduire le taux de récidive AgHBe négatif Récidive fréquente à l’arrêt du traitement Un traitement à long terme est recommandé Cirrhose Traitement à long terme +++ Traitement combiné fréquemment utilisé Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962. 39

Décision thérapeutique QUELLE MOLECULE UTILISER EN 1ère INTENTION ? Risque Bénéfice Décision thérapeutique Forme de HVB Stade

Hépatite chronique B active, 1ère ligne thérapeutique AgHBe positif 1) Interferon pégylé Si critères favorables de réponse 2) Analogues nucléos(t)ides Entecavir et Tenofovir: puissance antivirale et faible taux de résistance Lamivudine: A éviter +++ Adefovir: efficacité lente

1ère ligne thérapeutique 1) Interféron pégylé Pas de critères de réponse pré-thérapeutique Incompatible avec une longue durée de traitement Ag Hbe négatif 2) Analogues de nucléosides Entecavir ou Tenofovir : puissance antivirale faible taux de résistance Lamivudine: A éviter +++ Adefovir: efficacité à 5 ans (contrôle virologique et histologique)

Patient au stade de cirrhose décompensée Interféron CI (aggrave IHC + infection) Combainaison TRT Liste d’attente pour TH Effet antiviral Amélioration de la maladie Retirer de la liste Transplantation Poursuivre la bithérapie + Ig anti HBs

Le meilleur Traitement La prévention vaccination +++ 44

Conclusions Suivi régulier des hépatites chroniques B (ALAT, DNA VHB, PBF) Savoir: -qui traiter ? (bonne indication) -comment traiter ? (le bon choix) INF: durée de traitement définie, pas de résistance Antiviraux: risque de résistance, une adaptation précoce des traitements évite la progression de la maladie Majorité des patients maintenus en rémission par un traitement mérite une surveillance optimale Problèmes du coût, de la tolérance, et de la résistance à long terme des antiviraux Ne pas oublier la vaccination !!!