Comment prendre en charge les patients atteints d h patite B avec les m dicaments disponibles dans mon pays

3. objectifs Données épidémiologiques et profil du patient porteur du virus B au Maroc Présentation d’un cas clinique pour répondre aux questions suivantes : Quels sont les patients à traiter? Comment surveiller les patients non traités ? Quels médicaments et chez quels malades ? Quels sont les résultats du traitement antiviral ? Comment surveiller les malades traités ? * comment adapter le traitement en fonction de la réponse? * comment diagnostiquer et gérer une résistance ?

5. HEPATOPATHIES CHRONIQUESPROFIL SEROLOGIQUE GENERAL (609)

6. Profil du patient marocain porteur de L’Ag HBs cohorte de 342 porteurs d’AgHBS 96.13% étaient AgHBe négatif transaminases normales chez 90.58% 12.58% avaient une charge virale sup à 2000 UI / ml 28 patients ont eu une PBF : 75 % avaient des lésions modérées à sévères 7.60% devraient relever d’un traitement antiviral 4.67% avaient été effectivement traités (problème de prise en charge)

7. En 4 ans 5 centres hospitalo-universitaires 801 Malades traités : 786 HCV dont 23 avec coinfection B : 2.87 / % 15 HVB ( mono-infectés) : 1.87 / % Total patients HVB traités : 4.74% ETUDE NATIONALE( SMMAD)une minorité de patients marocains HVB sonttraités

8. observation Mr E.M , 46 ans,Marocain, commerçant HVB découverte en 2002 Ag Hbe négatif , Anti Hbe positif Anti HVD négatif Anti HCV négatif Anti HIV négatif Transaminases : normales NFS et plaquettes normaux Gamma GT,Albumine,TP,AFP: normaux ADN virus B : 6520 copies /ml. Echographie hépatobiliare normale

9. Que faire ? A- Biopsie du foie B- Surveillance C- Traitement antiviral par interféron D- Traitement antiviral par analogues

10. Hepatite chronique B: Histoire naturelle This slide depicts the different phases of chronic HBV infection Not all patients go through all phases During the Immune tolerant phase patients are HBeAg+, HBV DNA level is high but ALT is normal The Immune clearance phase is characterized by elevated ALT In some patients this is followed by spon HBeAg seroconversion and Patients enter into inactive carrier state with normal ALT and very low HBV DNA In other patients, the immune clearance phase is protracted with recurrent hepatitis flares leading to severe hepatitis and cirrhosis Not all patients who enter the inactive carrier state stay that way Some develop reactivation of HBV replication but remain HBeAg- Many of these patients have precore or core promoter HBV variants that prevent or decrease HBeAg production These patients have e-CHB This slide depicts the different phases of chronic HBV infection Not all patients go through all phases During the Immune tolerant phase patients are HBeAg+, HBV DNA level is high but ALT is normal The Immune clearance phase is characterized by elevated ALT In some patients this is followed by spon HBeAg seroconversion and Patients enter into inactive carrier state with normal ALT and very low HBV DNA In other patients, the immune clearance phase is protracted with recurrent hepatitis flares leading to severe hepatitis and cirrhosis Not all patients who enter the inactive carrier state stay that way Some develop reactivation of HBV replication but remain HBeAg- Many of these patients have precore or core promoter HBV variants that prevent or decrease HBeAg production These patients have e-CHB

11. HVB : indication du traitementrecommandations EASL 2009 ADN VHB > 2000 UI / ml Et /ou transaminases élevées Et activité ou fibrose modérée à sévère Si cirrhose : traitement si ADN + ; même si transaminases normales

12. Au Marocconditions de remboursement Etude dossier patient par médecins conseils Généralement : ADN virus B > 2000 UI / ml transaminases élevées Avec fibrose et activité modérée à sévère Taux de remboursement CNOPS : 100 % Taux de remboursement CNSS : 97 %

13. Suite observation Surveillance : - Clinique - Biologique : Transaminases , ADN /3-6 mois - Echographie hépatobiliaire /12 mois

14. Suite observation En juin 2004 Transaminases : 2.2 fois la normale Gamma GT : normale Albumine normale TP normal ADN VHB : 357 000 UI /ml Echo hépatobiliaire : normale

15. Que faire ? A- Biopsie du foie B- Surveillance C- Traitement antiviral par interféron D- Traitement antiviral par analogues

16. Suite observation Biopsie du foie : F 3 A1

17. Que faire ? A- Traitement antiviral par interféron standard B- Traitement par INF pegylé C- Traitement par INF pegylé + lamivudine D- Traitement par lamivudine N.B : Médicaments disponibles au Maroc en 2004: INF standard et pegylé ,lamivudine

18. Résultats des traitements siAg HBe négatif: ADN HVB négative (48 s)

19. Durabilité de la réponse +++ Type Ag HBe + Ag HBe – INF 80-90 % 10- 20 % INF peg na 20 % LVD 50-80 % inf 10 % ADF 90 % inf 5 % ETV 69 % na LdT 80 % na

20. Résultats des traitements disponibles:négativation de l’Ag HBs Taux d’Ag HBs Négatif à 3 ans si INFpeg Si Ag HBe positif : 11 % Si Ag HBe négatif : 8 % ( 10 % à 4 ans) Si taux d’Ag HBS est < à 10 ui/ml à 48 S le taux de patients Ag HBs négatif à 3 ans est de 52 % Si analogues : 0 à 5 %

21. Facteurs prédictifs de bonne réponse si traitement par INF pegylé + HBV DNA faible + ALAT elevé + Au cours du traitement : si HBVDNA est < 20,000 IU/ml à S12 : 50% de chance de seroconversion HBe si AgHBe positive et 50% de chance de RVP si AgHBe negative

22. La réponse à 4 ans et à 6 mois est sup si Ag HBs à S12 est = 1500 IU/mL vs > 1500 IU/mL Taux d’Ag HBS est un facteurprédictif de réponse durable si traitement par INFpeg Figures used with permission from Patrick Marcellin, MD. HBsAg, hepatitis B surface antigen; PegIFN, peginterferon. The researchers also examined HBsAg level as a predictor of the durability of response to peginterferon by looking at patients who had HBsAg clearance. This slide illustrates patients who had HBsAg levels < 1500 IU/mL (in the bar chart on the left) or HBsAg levels > 1500 IU/mL (in the bar chart on the right) at Week 12 of treatment. The HBsAg clearance rates at 6 months and 4 years posttreatment were much higher among patients who had HBsAg levels < 1500 IU/mL than those with HBsAg levels > 1500 IU/mL. In fact, at 4 years, a substantial 23% HBsAg clearance was seen in the population of patients who had the lower level of HBsAg at Week 12 of treatment compared with only 4% HBsAg clearance in patients who had HBsAg levels > 1500 IU/mL at 12 weeks of therapy. Figures used with permission from Patrick Marcellin, MD. HBsAg, hepatitis B surface antigen; PegIFN, peginterferon. The researchers also examined HBsAg level as a predictor of the durability of response to peginterferon by looking at patients who had HBsAg clearance. This slide illustrates patients who had HBsAg levels < 1500 IU/mL (in the bar chart on the left) or HBsAg levels > 1500 IU/mL (in the bar chart on the right) at Week 12 of treatment. The HBsAg clearance rates at 6 months and 4 years posttreatment were much higher among patients who had HBsAg levels < 1500 IU/mL than those with HBsAg levels > 1500 IU/mL. In fact, at 4 years, a substantial 23% HBsAg clearance was seen in the population of patients who had the lower level of HBsAg at Week 12 of treatment compared with only 4% HBsAg clearance in patients who had HBsAg levels > 1500 IU/mL at 12 weeks of therapy.

23. Suite observation * Après 12 mois de traitement par INF peg ADN VHB négative Transaminases normales

24. Suite observation * À 6 mois de l’arrêt du traitement : Transaminases normales ADN VHB : 5780 UI / ml

25. Que faire ? A- Pas de traitement et surveillance B- Traitement antiviral par interféron standard C- Retraitement par INF pegylé D- Traitement par lamivudine N.B : Médicaments disponibles au Maroc en 2005: INF standard et pegylé , lamivudine

26. Suite Observation Zeffix 100mg : 1 cp / J Evolution : ADN VHB à 3 mois : 1800 UI /ml ADN VHB à 6 mois : 845 UI/ml ADN VHB à 12 mois : négative ADN VHB à 18 et 24 mois de traitement par zeffix : ADN VHB toujours négative

27. Que faire ? A- Arrêter le traitement à 2 ans B- Continuer pour 2 ans supplémentaires C- Continuer le traitement à vie D- Continuer jusqu’à négativation de l’Ag HBs

28. Quand arrêter le traitement ? Si interferon pegylé : traitement pour 48s Si pas de diminution de l’ ADN > 1 log /ml à S12 : arrêt ( EASL 2009) Si analogues : * Patients AgHBe + : continuer 6 à 12 mois après séroconversion Ag HBe et négativation de l’ADN Sinon ou si cirrhose continuer * Patients Ag HBe - : traitement au long cours objectif : Ag HBS négatif

29. Suite observation Debut 2008 : Transaminases normales ADN VHB : négative (nov 2007) Entécavir et Adefovir : disponibles au Maroc

30. Que faire ? A- Ajouter l’adefovir B- Suitcher à l’adefovir C- Suitcher à l’entecavir D- Ne rien changer et garder le zeffix seul

31. Le risque de mutation est dépendant de la puissance de l’agent antiviral utilisé

32. GLOBE: le risque de resistance à S104 est fonction de l’ADN VHB à S24 ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; LdT, telbivudine; PCR, polymerase chain reaction; ULN, upper limit of normal.   The size of the GLOBE trial made it possible to break out resistance rates at Week 104 by level of viral suppression attained at Week 24 into 4 different ranges as we saw a moment ago in the analysis of viral suppression and e-antigen seroconversion. What is clear from this slide is that there is an inverse relationship between the magnitude of viral suppression at Week 24 and the risk of resistance later at Week 104. Clearly patients who attained PCR negativity for HBV DNA at Week 24 had by far the lowest rates of resistance at Week 104, 6% in e-positive patients and 5% in e-negative patients, respectively.   For more information on this study, go online to: clinicaloptions.com/Hepatitis/Conference%20Coverage/Boston%202007/Tracks/HBV%20Treatment/Capsules/994.aspx ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; LdT, telbivudine; PCR, polymerase chain reaction; ULN, upper limit of normal.   The size of the GLOBE trial made it possible to break out resistance rates at Week 104 by level of viral suppression attained at Week 24 into 4 different ranges as we saw a moment ago in the analysis of viral suppression and e-antigen seroconversion. What is clear from this slide is that there is an inverse relationship between the magnitude of viral suppression at Week 24 and the risk of resistance later at Week 104. Clearly patients who attained PCR negativity for HBV DNA at Week 24 had by far the lowest rates of resistance at Week 104, 6% in e-positive patients and 5% in e-negative patients, respectively.   For more information on this study, go online to: clinicaloptions.com/Hepatitis/Conference%20Coverage/Boston%202007/Tracks/HBV%20Treatment/Capsules/994.aspx

33. Suite observation Fin Mars 2008 : patient toujours sous zeffix Transaminases normales Gamma GT : normale Albumine normale TP normal ADN VHB : 4.7 log Echo hépatobiliaire normale

34. Surveillance des patients traitésdiagnostic de résistance In patients with an initial response to treatment, the detection of genotypic resistance often precedes any increase in HBV DNA or ALT. According to AASLD 2007 guidelines viral breakthrough is said to have occurred when the level of HBV DNA increases by 1 log10 copies/mL above the on-treatment nadir. Increases in ALT can follow, resulting in biochemical breakthrough, defined as an increase in ALT to above the upper limit of normal (ULN). If HBV DNA levels continue to rise to above 105 copies/mL virologic rebound is said to have occurred. In patients with an initial response to treatment, the detection of genotypic resistance often precedes any increase in HBV DNA or ALT. According to AASLD 2007 guidelines viral breakthrough is said to have occurred when the level of HBV DNA increases by 1 log10 copies/mL above the on-treatment nadir. Increases in ALT can follow, resulting in biochemical breakthrough, defined as an increase in ALT to above the upper limit of normal (ULN). If HBV DNA levels continue to rise to above 105 copies/mL virologic rebound is said to have occurred.

35. Incidence de la résistance chez les patients naïfs aux analogues sous monothérapie antivirale Resistance is a key consideration when choosing the appropriate regimen. Lamivudine has the highest rate of resistance among HBV therapies: approximately 23% of treatment-naive patients receiving lamivudine develop resistance after 1 year of therapy, and that number increases to 71% by Year 4. Therefore, although lamivudine is a potent agent, it is not a preferred drug for the treatment of HBV infection. Adefovir leads to relatively low resistance rates at Years 1 and 2, but these increase to 30% by Year 5. Entecavir has the lowest rates of viral resistance among HBV therapies, at 1.2% by Years 3-5. Telbivudine, like lamivudine, results in resistance rates of 5% at 1 year of therapy, increasing to 25% in HBeAg-positive patients and 11% in HBeAg-negative patients at Year 2. Finally, early data on tenofovir show 0% resistance at Year 1, but longer-term data are not yet available. Resistance is a key consideration when choosing the appropriate regimen. Lamivudine has the highest rate of resistance among HBV therapies: approximately 23% of treatment-naive patients receiving lamivudine develop resistance after 1 year of therapy, and that number increases to 71% by Year 4. Therefore, although lamivudine is a potent agent, it is not a preferred drug for the treatment of HBV infection. Adefovir leads to relatively low resistance rates at Years 1 and 2, but these increase to 30% by Year 5. Entecavir has the lowest rates of viral resistance among HBV therapies, at 1.2% by Years 3-5. Telbivudine, like lamivudine, results in resistance rates of 5% at 1 year of therapy, increasing to 25% in HBeAg-positive patients and 11% in HBeAg-negative patients at Year 2. Finally, early data on tenofovir show 0% resistance at Year 1, but longer-term data are not yet available.

36. Que faire ? A- Suitcher à l’adefovir B- Suitcher à l’entecavir C- Ajouter l’adefovir D- Ajouter l’entecavir

37. ADV plus LAM si resistance à la lamivudine 145 patients avec resistance à la LAM (73% cirrhotiques, 86% AgHBe negative, 92% genotype D) Après un suivi de 42 mois 80% : HBV DNA negative 100% : pas de rebond virologique ou clinique 9 patients ont développé une mutation à ADV * HBV DNA a diminué au cours du taitement, * 7/9 : négativation HBV DNA

39. Que faire si résistance?Adapté au contexte marocain Si résistance à la lamivudine : addition Adéfovir Si résistance à l’adéfovir : addition lamivudine ou entécavir Si résistance à entécavir : addition Adéfovir Si résistance à un traitement séquentiel par Lam et Adéfovir: ajouter Entécavir

40. Suite observation CAT : zeffix + adefovir 10 mg /jour Evolution : ADN VHB à 3 mois : 3. 9 log /ml ADN VHB à 6 mois : 3.7 log/ml ADN VHB à 9 mois : 3.4 log/ ml ( dec 2008)

41. Que faire ? A- Continuer zeffix + adefovir B- Suitcher à l’entecavir C- Associer entecavir à adefovir D- Chercher génotype de mutation aux antiviraux

42. Que faire si réponse partielle If a patient is taking a drug with a low genetic barrier to resistance, like lamivudine or telbivudine, the risk of subsequent resistance, as we saw earlier, is unacceptably high, in the presence of any viremia at this time point, so a second drug from another class, without cross-resistance, should be added. If the patient is taking a drug with a high genetic barrier to resistance, then the risk of resistance at 1 year is extremely low, so it is acceptable to continue the initial drug. A special scenario, shown on the right, is one in which a partial response is obtained with a drug that has a high genetic barrier to resistance but suboptimal potency, and here we are referring to adefovir. Here, one can argue that if the residual HBV DNA is toward the high end of the range shown here, that is toward 2000 IU/mL, the chance of complete suppression at 48 weeks is relatively low, as suggested in a recent paper that we will elaborate on in the next couple of slides one might consider a change at 24 weeks, even if the risk of resistance at 1 year of adefovir is very low. In this regard, it is worth noting that several publications have indicated very high rates of complete response, when suboptimal responders to adefovir are switched to tenofovir which is still off-label for HBV.   For more information, go online to: clinicaloptions.com/roadmap If a patient is taking a drug with a low genetic barrier to resistance, like lamivudine or telbivudine, the risk of subsequent resistance, as we saw earlier, is unacceptably high, in the presence of any viremia at this time point, so a second drug from another class, without cross-resistance, should be added. If the patient is taking a drug with a high genetic barrier to resistance, then the risk of resistance at 1 year is extremely low, so it is acceptable to continue the initial drug. A special scenario, shown on the right, is one in which a partial response is obtained with a drug that has a high genetic barrier to resistance but suboptimal potency, and here we are referring to adefovir. Here, one can argue that if the residual HBV DNA is toward the high end of the range shown here, that is toward 2000 IU/mL, the chance of complete suppression at 48 weeks is relatively low, as suggested in a recent paper that we will elaborate on in the next couple of slides one might consider a change at 24 weeks, even if the risk of resistance at 1 year of adefovir is very low. In this regard, it is worth noting that several publications have indicated very high rates of complete response, when suboptimal responders to adefovir are switched to tenofovir which is still off-label for HBV.   For more information, go online to: clinicaloptions.com/roadmap

43. Que faire si réponse partielle ? Si lamivudine,adéfovir,ou télbuvidine : à 24S * suitcher : entecavir ou tenofovir * ou ajouter une molécule sans résistance croisée Si entecavir ou tenofovir : à 48 S associer les deux molécules ?

44. CONCLUSIONS + bien poser l’indication thérapeutique ++++++ + choix du traitement doit être adapté : patient et virus + si analogue choisi : action rapide et puissante avec bonne barrière génétique + surveillance ADN et transaminases à intervalle régulier ( 3à 6 mois ) + résistance : augmentation de l’ADN d’un log / nadir + démarrer une autre molécule sans arrêter la première + ne pas ajouter une molécule avec résistance croisée