HVB et risque de réactivation en rhumatologie M Benazzouz Rabat 8ème journée de l’ ARR 01- nov- 2014

objectifs Définition Histoire naturelle Les facteurs de risque Statut HVB Type de médicaments Quelles sont les pratiques Intérêt des analogues Que faire en pratique

objectifs Définition Histoire naturelle Les facteurs de risque Statut HVB Type de médicaments Quelles sont les pratiques Intérêt des analogues Que faire en pratique

Définition de la réactivation Augmentation de l’ADN d’au moins un log ou apparition de l’Ag Hbe ALAT > 3 x Normal Eliminer les autres causes

Définition de la réactivation

objectifs Définition Histoire naturelle Les facteurs de risque Statut HVB Type de médicaments Quelles sont les pratiques Intérêt des analogues Que faire en pratique

Histoire naturelle Biotherapies/immunosuppresseurs

Conséquence de la réactivation Hepatite : 33 % (24 – 88 % ) décompensation : 13 % (5 – 33 % ) décés par décompensation : 5% (0 – 33 % ) Loomba et al. Ann Intern Med 2008

AASLD 2013

objectifs Définition Histoire naturelle Les facteurs de risque Type de médicaments Statut HVB Quelles sont les pratiques Intérêt des analogues Que faire en pratique

Médicaments résponsables Class Agents Corticosteroids Dexamethasone, methylprednisolone, prednisolone Antitumor antibiotics Actinomycin D, bleomycin, daunorubicin, doxorubicin, epirubicin, mitomycin-C Plant alkaloids Vinblastine, vincristine Alkylating agents Carboplatin, chlorambucil, cisplatin, cyclophosphamide, ifosfamide Antimetabolites Azauridine, cytarabine, fluouracil, gemcitabine, mercaptopurine, methotrexate, thioguanine Monoclonal antibodies Alemtuzumab, rituximab Others Colaspase, docetaxel, etoposide, fludarabine, folinic acid, interferon, procarbazine This slide just shows you a long list of agents that have been reported to be associated with hepatitis B reactivation. I don’t want to go through these in detail, but just to show you that a wide range of chemotherapy agents, ranging from steroids all the way through very cytotoxic chemotherapy agents, have been associated with HBV reactivation. You’ll notice that rituximab—I will discuss that in quite a bit more detail later on. Yeo W, et al. Hepatology. 2006;43:209-220.

Autres Agents Anti-TNF (infliximab, adalimumab, etanercept) Other (rituximab, cyclosporine) Antimetabolite (methotrexate) Immunomodulatory Therapy If you look at the agents that have been reported to cause HBV reactivation in the nononcology setting, probably the most number of reports are with anti-TNF agents, infliximab, adalimumab and etanercept. It’s also been reported with antimetabolites like methotrexate, less commonly with purine analogs like azathioprine and 6-MP, with long-term steroid use, prednisone and maybe even budesonide. And then as I’ve mentioned with rituximab, which is now also being used outside of the oncology arena, as well as with cyclosporine. Purine Analogues (azathioprine/6mp) Steroids (prednisone, budesonide) Roche B, et al. Liver Int. 2011;31(suppl 1):104-110.

Risque des médicaments en rhumato  corticoides [ROR 2.3 (95 % confidence interval 1.3-4.0)],  methotrexate [4.9 (3.9-6.0)],  rituximab [7.2 (5.3-9.9)],  tacrolimus [4.2 (1.5-11.9)],  Adalimumab had a lower ROR [0.2 (0.1-0.4)]  Other anti-TNF agents,  leflunomide Oshima Y Mod Rheumatol. 2013 Cobeta Garcia Reumatol Clin. 2011 , Shouval et al Sem Liver Disese 2013

Médicaments en rhumato à risque bas corticoides <7.5 mg / J sulphasalazine Hydroxychloroquine sels d’or acta reumatol port. 2011

Médicaments en rhumato à haut risque corticoides > 7.5 mg /J pour une longue période anti-TNF rituximab Cyclophosphamide methotrexate leflunomide Anti calcineurin mycophenolate mofetil azathioprine acta reumatol port. 2011

prevalence Clin Rheumatol (2014)

Les corticoides augmente le risque de réactivation 50 patients LMNH HBsAg positive traités par epirubicin, cyclophosphamid etoposide (ACE) ± prednisolone (P) 100 ACE PACE 80 73* 68 60 *P < .05 44* 46 HBsAg Patients (%) 38 35 36 40 28* * 20 13 So if we look specifically at steroids, you see in this study that was published in 2003, 50 patients with non-Hodgkin’s lymphoma who were HBsAg positive were randomized to receive epirubicin, cyclophosphamide, and etoposide, so called ACE therapy, or ACE therapy combined with prednisolone, so-called PACE therapy. And what you see here are the rates of reactivation in those patients randomized to the different strategies. Now remember, all of these patients were HBsAg positive at baseline, and you can see that the addition of prednisolone increased the reactivation rate from 38% to 73%, and also generally made the reactivation rates more significant.   So you see higher or more patients with very high elevations of their ALT, more patients with jaundice, but importantly, a slight increase in the number of patients who went into complete remission. If you look overall, at overall survival at 4 years, you see that the prednisolone did improve the cancer outcomes. So although prednisolone increased the risk in severity of HBV reactivation, this led to a trend towards improved lymphoma outcome. So that means that just getting rid of prednisolone is not really a good strategy for avoiding hepatitis B reactivation. 4 Reactivation Remission complète ALT > 10 x ULN ictère Survie à 4 ans Prednisolone augmente le risque et la severité de la reactivation Mais effet positif sur le LMNH Cheng AL, et al. Hepatology. 2003;37:1320-1328.

Reactivation avec Rituximab chez patients AgHBs Négatif Patients avec lymphome AgHBs-negative, anti-HBc–positive traités par CHOP ou CHOP-R 40 CHOP (n = 25) CHOP-R (n = 21) 30 24 Anti-HBc Positive, HBsAg-Negative Patients (%) 20 This study published by Yeo and colleagues in the Journal of Clinical Oncology in 2009 showed that this is not a trivial risk, so they looked at patients with diffuse large B cell lymphoma who were all HBsAg negative but anti-HBc positive at baseline, and were randomized to receive CHOP or CHOP with rituximab, so-called CHOP-R. And what you see, importantly in the patients randomized to CHOP, there were no cases of reverse seroconversion. So none of these people became HBsAg positive and that’s certainly reassuring.   However, when you look in the population who received rituximab, almost a quarter of these patients went on to become HBsAg positive, and one of these patients went on to die from a severe HBV reactivation. So when you start thinking about these numbers in terms of the total number of people with anti-HBc positive in the population, this becomes a fairly daunting figure and an important issue. 10 5 HBV Reverse Seroconversion HBV-Related Death Risk de reactivation avec rituximab significatif si anti-HBc positive Yeo W, et al. J Clin Oncol. 2009;27:605-611.

Ritixumab Niitsu et al J Clin Oncol 2010

Mise à jour de la notice anti TNF

Réactivation chez les patients avec PR traitée par biotherapie International Journal of Rheumatology 2014

Meta-analysis on HBV reactivation among patients treated with etanercept. International Journal of Rheumatology 2014

Meta-analysis on HBV reactivation among patients treated with adalimumab.

objectifs Définition Histoire naturelle Les facteurs de risque Type de médicaments Statut HVB Quelles sont les pratiques Intérêt des analogues Que faire en pratique

Niveau du Risque

Niveau du risque

Niveau du risque vs traitement

objectifs Définition Histoire naturelle Les facteurs de risque Statut HVB Type de médicaments Quelles sont les pratiques Intérêt des analogues Que faire en pratique

Quelles sont les pratiques ? 131 Oncologistes1] Etude monocentrique (208 Pts) [2] 100 80 62 60 HBV Screening (%) 40 24 14 So here I’ve shown data from a couple of studies and the first study is self-reported hepatitis B screening among 131 American oncologists. And what you see is that 62% of them do no screening, 24% screen only high-risk, and a very small percentage, just 14% of oncologists, screen all patients prior to starting chemotherapy. Similarly, in a chart review of actual screening done at an urban hospital in Toronto, only 14% of patients were actually screened prior to starting chemotherapy. So the point is that few oncologists are routinely screening all patients prior to initiating chemotherapy.   20 14 aucun Si risque elevé Dépistés tous les patients Patient dépistés 1. Khokhar OS, et al. Chemotherapy. 2009;55:69-75. 2. Lee R, et al. Curr Oncol. 2010;17:32-38.

Enquête faite par AASLD

Enquête faite AASLD

Quelles sont les pratiques

Enquête Française chez les internistes Faite vous un depistge HVB : ( N 290) si Corticosteroids : 44% si Immunosuppresseur : 67% Biotherapy (Rituximab, antiTNFalpha...) : 76% Terrier et al. Rev Med Interne 2012

objectifs Définition Histoire naturelle Les facteurs de risque Statut HVB Type de médicaments Quelles sont les pratiques Intérêt des analogues Que faire en pratique

Patients avec PR et risque de réactivation si anti TNF avec ou sans traitement préemptif

Reduction du risque de réactivation avec Lamivudine HBsAg-positive patients with NHL treated with CHOP randomized to “preemptive” vs “on-demand” lamivudine 100 On-demand group: start LAM if ALT > 1.5 x ULN Preemptive group: start LAM on Day 1 of CHOP 80 60 HBsAg Patients (%) 48 40 36 The best data on this come from a study by Hsu et al published in Hepatology in 2008, and in this study it was similar to the Lau study in that HBsAg positive patients with non-Hodgkin’s lymphoma who were treated with CHOP chemotherapy were randomized again to either preemptive or on-demand lamivudine. And what you see is, again, the preemptive group started lamivudine on Day 1 of CHOP chemotherapy, whereas the on-demand group started lamivudine only if the ALT rose above 1 and a half times the upper limit of normal.   So the first thing you see is similar to the Lau study. They did see that preemptive therapy prevented, on or during chemotherapy, HBV reactivation. So in the first panel you see lower rates of reactivation and hepatitis flares, no reactivations that led to ALT elevations above 10 times the upper limit of normal, and no episode of jaundice, so it looks very promising. However, what you see highlighted in the red box is that in the blue arm, in those patients who received preemptive lamivudine, you see that there were actually a couple of deaths in this study. And why was that? Well, all of these deaths occurred after chemotherapy, and they occurred because of severe withdrawal flares. In the protocol in this study, the lamivudine was continued for 2 months after the end of chemotherapy, and this was associated with this risk of withdrawal flare and really emphasizes the point that these patients need to be followed carefully after stopping therapy. But based on this data, most guidelines and most experts recommend continuing therapy for at least 6 months, and the absolute stopping rules and the absolute optimal duration are really unknown. 20 20 8 8 HBV Reactivation and Hepatitis Flare HBV Reactivation and ALT >10 x ULN HBV Reactivation and Jaundice Death (After ChemoTx) Preemptive antivirals decrease HBV reactivation Hsu C, et al. Hepatology. 2008;47:844-853.

Intérêt du traitement préemptif

objectifs Définition Histoire naturelle Les facteurs de risque Statut HVB Type de médicaments Quelles sont les pratiques Intérêt des analogues Que faire en pratique

Les recommendations

RA guidelines on safety of anti-TNF therapies Recommendation 12: close monitoring of serum amino- transaminases and HBV DNA load during therapy should be considered in patients with HBV treated with anti-TNF therapy and concomitant anti-viral treatment would be recommended. (Level IV evidence, Grade of recommen- dation C.)

RA guidelines on safety of anti-TNF therapies Recommendation 13: patients with serological evidence of cleared past infection [HBsAg negative/core antibody (anti-HBcAb) positive] should have their HBV serology monitored during therapy and may require concomitant anti-viral treatment if detrimental changes develop. (Level IV evidence, Grade of recommendation C.)

Traitement préemptif Si Ag HBS positif et ADN VHB + ou - Traitement par analogues EASL 2012

Traitement préemptif indications Si AgHBs négatif Anti HBc postif Anti Hbs +/- ADN VHB négative Si rituximab Greffe de moelle ou de cellules souches Greffe hépatique et donneur anti HBc + surveillance Traitement par analogue EASL 2012

Traitement préemptif comment traiter ? Traitement par analogues lamivudine si ADN < 2000 ui/ml Si ADN elevée ou traitement pour longue durée traitement avec tenofovir ou entecavir Arrêt un an après la fin du traitement si pas d’atteinte hépatique nécessitant un traitement EASL 2012

CAT Nat. Rev. Rheumatol 2012.