Resolved hepatitis B and immunosuppressive and biological therapies. Rene Gerolami, CHU Conception Marseille. France. 26 March 2010 Title: Resolved hepatitis B and immunosuppressive and biological therapies. Philippe Colson 1, Sandrine Guis 2, Patrick Borentain3, Caroline Charpin2, Jean Pierre Mattei2, Rene Gerolami3 1. Laboratoire de Virologie, Fédération Hospitalière de Microbiologie Clinique, Centre Hospitalo-Universitaire Timone, Marseille, France 2. Service de Rhumatologie, Centre Hospitalier Universitaire Conception, Marseille, France. 3. Service d'Hépato-gastroentérologie, Centre Hospitalier Universitaire Conception, Marseille, France To the Editor: We would like to thank Dr Jansen for his interesting editorial on our article recently published in this journal (1). This author points out the evolution of therapies in rheumatology and the concerns related to their administration to patients with on-going and resolved hepatitis B virus (HBV) infection (2). Nevertheless, we would like to clearly distinguish between patients with resolved HBV infection, who were those targeted in our work, and HBV carriers, to avoid bringing misunderstanding to the aim and interpretation of our study. Chronic HBV carriers are HBV-infected individuals positive for hepatitis B surface antigen (HBsAg) for more than six months. Their serological pattern associates positive testing for HBsAg and anti-HB core (HBc) antibodies. Among them, inactive HBsAg carriers are defined by very low or undetectable serum HBV DNA levels (<2,000 IU/ml), persistently normal ALT/AST levels, and absence of significant hepatitis (3). By contrast to HBV carriers, people in whom hepatitis B resolved spontaneously are HBsAg-negative but still harbor anti-HBc antibodies, which are promoted by a very robust and persistent immune response against HBc antigen (4); concurrently, anti-HBs antibodies can be present or absent. HBV DNA in serum, when tested, is classically negative. Nevertheless, to add pitfalls to define clearly the status of HBV infection, recent dramatic decrease of the detection threshold of PCR assays (from 20,000 to about 10 IU/ml) revealed that a very low HBV DNA level (< 200 IU/ml) might be present occasionally in the absence of detectable HBsAg, defining one of the two categories of so-called occult hepatitis B (5). As stated by Jansen, HBV infection, regardless its outcome, results in the production of covalently-closed circular HBV DNA (HBV cccDNA), an episomal resistant HBV genomic form that serves as template for transcription of viral messenger RNA and pre-genomic RNA, and which might persist beyond hepatitis B resolution (6). Thus, HBV cccDNA could be found in the nucleus of hepatocytes from individuals with resolved HBV infection (7). As a matter of fact, HBV reactivation depicts two different events. It can correspond to the re-occurence of active necroinflammatory disease of the liver, concurrently to re-appearance or increase of HBV DNA in serum, in patients known to have the inactive HBsAg carrier state (3). In these HBsAg positive patients, HBV reactivation has been documented following immunosuppressive or immunomodulatory treatments including anti-TNF, and the prophylactic use of antiviral agents has been proposed (8,9). Alternatively, HBV reactivation can consist in reappearance of HBV DNA and HBsAg seroreversion in individuals previously negative for HBsAg, i.e. with a serology indicating resolved HBV infection. In such a setting, HBV reactivation has been observed following immunosuppressive or biological therapies, although much less frequently than in HBsAg-positive patients. Nonetheless, rates of 9-25% HBV reactivation have been recently described in patients with a serology indicating resolved HBV infection and who received polychemotherapy for lymphoma, especially in case of rituximab use (10,11). The risk of anti TNF-alpha -induced HBV reactivation is therefore a concern not only in chronic HBsAg carriers but also in HBsAg-negative patients presenting with resolved HBV infection. In our work, we focused on 21 rheumatic patients presenting with such a serological pattern indicating resolved HBV infection and undergoing anti-TNF-alpha therapy. Thus, none of them was HBsAg-positive at the time of treatment initiation. All patients remained HBsAg-negative and were HBV DNA negative after a mean duration of 27 months of therapy. Further studies including a larger number of patients and a longer follow-up are however necessary. Finally, it should be pointed out, from an epidemiological perspective, that a serological pattern indicating resolved HBV infection is harbored by a non negligible proportion of people, including those who have to face cancer and auto-immune diseases and will receive immunosuppressive therapies. In France, in line with reports in other developed countries, an estimated 7.3% of adults have serological markers indicating resolved HBV infection, and this proportion increases with age (12). As an illustration, in our study, resolved HBV infection had been diagnosed in 58 (13%) of 504 rheumatic patients. Taken together, these data prompt to be cautious about the HBV status of any patient who will undergo an immunosuppressive therapy and to perform surveys on large cohorts to determine the appropriate monitoring in case of resolved HBV infection. Concomitantly, the propensity of each immunosuppressive treatment to promote HBV reactivation in patients presenting HBsAg-positivity as well as serology indicating resolved hepatitis B should be studied. References 1. Charpin C, Guis S, Colson P, Borentain P, Mattéi JP, Alcaraz P, Balandraud N, Thomachot B, Roudier J, Gérolami R: Safety of TNF-blocking agents in rheumatic patients with serology suggesting past hepatitis B state: results from a cohort of 21 patients. Arthritis Res Ther 2009, 11(6):R179. 2. Jansen TL: When rheumatology meets hepatology: are anti-TNFs safe in hepatitis B virus carriers? Arthritis Res Ther 2010, 12(1):103. 3. Lok AS, McMahon BJ: Chronic hepatitis B. Hepatology 2007, 45(2):507-39. 4. Liaw YF, Chu CM: Hepatitis B virus infection. Lancet 2009, 373(9663):582-92. 5. Raimondo G, Allain JP, Brunetto MR, Buendia MA, Chen DS, Colombo M, Craxì A, Donato F, Ferrari C, Gaeta GB, Gerlich WH, Levrero M, Locarnini S, Michalak T, Mondelli MU, Pawlotsky JM, Pollicino T, Prati D, Puoti M, Samuel D, Shouval D, Smedile A, Squadrito G, Trépo C, Villa E, Will H, Zanetti AR, Zoulim F: Statements from the Taormina expert meeting on occult hepatitis B virus infection. J Hepatol 2008, 49(4):652-7. 6. Zoulim F: New insight on hepatitis B virus persistence from the study of intrahepatic viral cccDNA. J Hepatol 2005, 42(3):302-8. 7. Nassal M: Hepatitis B viruses: reverse transcription a different way. Virus Res 2008, 134(1-2):235-49. 8. Chung SJ, Kim JK, Park MC, Park YB, Lee SK: Reactivation of hepatitis B viral infection in inactive HBsAg carriers following anti-tumor necrosis factor-alpha therapy. J Rheumatol 2009, 36(11):2416-20. 9. Esteve M, Saro C, González-Huix F, Suarez F, Forné M, Viver JM: Chronic hepatitis B reactivation following infliximab therapy in Crohn's disease patients: need for primary prophylaxis. Gut 2004, 53(9):1363-5. 10. Borentain P, Colson P, Coso D, Bories E, Charbonnier A, Stoppa AM, Auran T, Loundou A, Motte A, Ressiot E, Norguet E, Chabannon C, Bouabdallah R, Tamalet C, Gérolami R: Clinical and virological factors associated with hepatitis B virus reactivation in HBsAg-negative and anti-HBc antibodies-positive patients undergoing chemotherapy and/or autologous stem cell transplantation for cancer. J Viral Hepat. [Epub ahead of print] 11. Yeo W, Chan TC, Leung NW, Lam WY, Mo FK, Chu MT, Chan HL, Hui EP, Lei KI, Mok TS, Chan PK: Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab. J Clin Oncol 2009, 27(4):605-11. 12. Meffre C, Le Strat Y, Delarocque-Astagneau E, Dubois F, Antona D, Lemasson JM, Warszawski J, Steinmetz J, Coste D, Meyer JF, Leiser S, Giordanella JP, Gueguen R, Desenclos JC : Prevalence of hepatitis B and hepatitis C virus infections in France in 2004: Social factors are important predictors after adjusting for known risk factors. J Med Virol 2010, 82(4):546-55. Competing interests There is no competing interest for all the authors of this comment.