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Recommendations for the management of acute hepatitis B: position paper of the Italian Society for the Study of Infectious and Tropical Diseases (SIMIT) R. Bruno, G. Carosi, N. Coppola, G. B. Gaeta, M. Puoti, T. Santantonio, G. Taliani, O. Armignacco, E. Sagnelli, M. Andreoni, et al. Infection A Journal of Infectious Disease ISSN 0300-8126 Infection DOI 10.1007/s15010-014-0642-0 1 23 Your article is protected by copyright and all rights are held exclusively by SpringerVerlag Berlin Heidelberg. This e-offprint is for personal use only and shall not be selfarchived in electronic repositories. If you wish to self-archive your article, please use the accepted manuscript version for posting on your own website. You may further deposit the accepted manuscript version in any repository, provided it is only made publicly available 12 months after official publication or later and provided acknowledgement is given to the original source of publication and a link is inserted to the published article on Springer's website. The link must be accompanied by the following text: "The final publication is available at link.springer.com”. 1 23 Author's personal copy Infection DOI 10.1007/s15010-014-0642-0 REVIEW Recommendations for the management of acute hepatitis B: position paper of the Italian Society for the Study of Infectious and Tropical Diseases (SIMIT) R. Bruno • G. Carosi • N. Coppola • G. B. Gaeta • M. Puoti • T. Santantonio G. Taliani • O. Armignacco • E. Sagnelli • M. Andreoni • G. Angarano • G. Di Perri • G. D’Offizi • M. Galli • G. Rizzardini • Received: 25 March 2014 / Accepted: 27 May 2014 Ó Springer-Verlag Berlin Heidelberg 2014 Abstract Purpose To develop recommendations for the management of acute hepatitis B by the Italian Society for the Study of Infectious and Tropical Diseases. Methods Development of the recommendations divided into three levels of evidence according to the GRADE system: A (high), B (medium) and C (low experts opinion), together with three recommendation levels: 1 (strong), 2 (medium), 3 (weak). Results The treatment with antivirals is in selected cases the mainstay of management of severe acute hepatitis, and should be started as a matter of urgency in order to prevent death. Contributors: R. Bruno, G. Carosi, N. Coppola, G. B. Gaeta, M. Puoti, T.Santantonio,G. Taliani, O. Armignacco, E. Sagnelli, M. Andreoni Counsulting Committee: G. Angarano, G. Di Perri, G. D’Offizi, M. Galli, G. Rizzardini. R. Bruno (&) Department of Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Via Taramelli, 5, 27100 Pavia, Italy e-mail: [email protected] G. Carosi Malattie Infettive e Tropicali-Università degli Studi di Brescia, Brescia, Italy N. Coppola G. B. Gaeta E. Sagnelli Malattie Infettive-Seconda Università degli studi di Napoli, Naples, Italy M. Puoti Malattie infettive-Ospedale Niguarda Ca’Granda, Milan, Italy T. Santantonio Malattie Infettive-Università degli Studi di Foggia, Foggia, Italy G. Taliani Malattie Infettive-Sapienza Università di Roma, Rome, Italy Conclusions These recommendations are meant to provide the rationale and practical indications for the management of acute hepatitis B (AHB). Keywords HBV Acute hepatitis Introduction Viral hepatitis is recognized by WHO as an important public health priority. The transmission of hepatitis B virus has not been halted, despite the availability of effective tools for prevention (the vaccine) and treatment, including medical [nucleos(t)idic, NA drugs] and surgical (liver transplantation) options. There are several reasons for that: O. Armignacco Malattie Infettive-Ospedale Belcolle di Viterbo, Viterbo, Italy M. Andreoni Malattie Infettive-Policlinico Tor Vergata Roma and President of SIMIT, Rome, Italy G. Angarano Malattie Infettive-Università degli Studi di Bari, Bari, Italy G. Di Perri Malattie Infettive-Università degli Studi di Torino, Turin, Italy G. D’Offizi Malattie Infettive-Istituto Lazzaro Spallanzani, Rome, Italy M. Galli Malattie Infettive-Università di Milano, Milan, Italy G. Rizzardini Malattie Infettive-Ospedale Luigi Sacco, Milan, Italy 123 Author's personal copy R. Bruno et al. 1. 2. The weakness of screening programs targeting highrisk populations, limiting access to vaccination of many susceptible individuals. The HBV persistence within the hepatocyte (as cccDNA) following HBsAg clearance (either spontaneous or drug-induced) is the basis for the development of occult hepatitis B virus infection, alternatively defined as OBI, a challenging clinical entity, which may reactivate as immune depression develops. Approximately 90–95 % of all acute hepatitis B (AHB) infections recover spontaneously, while about 1 % manifest as fulminant hepatitis, which is characterized by very high fatality rate largely relying on organ liver transplantation (OLT) as life-saving intervention. Unfortunately, access to liver transplantation is significantly limited by the shortage of organs and by the high costs of the procedure. NA drugs are not routinely recommended for the management of AHB cases; however, treatment with such drugs is the mainstay of management of cases of severe acute or reactivation hepatitis, and should be started as a matter of urgency in order to prevent death. For these reasons the Italian Society for the Study of Infectious and Tropical Diseases promoted the present ‘‘Recommendations for the management of acute hepatitis B: position paper of the Italian Society for the Study of Infectious and Tropical Diseases’’. These recommendations are meant to provide the rationale and practical indications for the management of AHB. The recommendations are divided into three levels of evidence according to the GRADE system: A (high), B (medium) and C (low experts opinion), together with three recommendation levels: 1 (strong), 2 (medium), 3 (weak). A writing commission of experts indicated by the President of the Society and a consulting committee have contributed to the document. The final draft was then submitted to the evaluation of external experts and the text modified according to their suggestion and comments. illness and to prevent the progression to chronic HBV infection. The usefulness of antiviral treatment has been questioned because shortening the duration of HBV replication might induce a less efficient presentation of viral antigens to the immune system, inhibit the production of neutralizing antibodies and delay the seroconversion to either HBeAb and HBsAb. However, the reported results are still controversial and have been obtained by employing lamivudine (LAM) treatment [1, 2]. Patients to be treated Because of the widespread vaccination against hepatitis B in Italian younger population, AHB occurs more frequently among immigrants or non-vaccinated older people who often have comorbid conditions, such as diabetes, which are associated with higher probability of severe presentation and higher mortality [3]. Recommendation Severe AHB is defined based on the presence of at least two of the following criteria: bilirubin levels higher than 10 mg/dl, international normalized ratio (INR) of 1.6 or higher, hepatic encephalopathy. In such patients, prompt and timely antiviral administration is warranted because it can shorten the duration of disease, promote recovery and improve survival (Grade C, level 1) [4]. Antiviral treatment is also indicated in acutely infected patients who progress to chronic disease, the early recognition of whom is critical to avoid overtreatment of those who will recover [5, 6] (Grade C, level 2). To this end, evaluation of HBsAg and HBV–DNA kinetics and of HBV genotype may prove extremely useful to recognize patients who will benefit of antiviral treatment as soon as at week 2 of acute disease onset [5, 6]. How to treat The treatment with antivirals in acute hepatitis Rationale Although 95 % of adults with AHB will recover spontaneously, the 0.4–8.9 % death rates reported in recent years favour treatment of some AHB patients, namely of those with fulminant or severe acute hepatitis B, in order to prevent death or the need of OLT. In addition, treatment seems warranted in patients with extrahepatic manifestations and in those with prolonged disease course and impaired immune system in order to shorten the duration of 123 Published studies mainly refer to lamivudine therapy, whereas adefovir has not been used because of its weak antiviral activity and potential nephrotoxicity. In a small case series with severe acute or fulminant hepatitis B (17 patients) LAM administered until HBsAg clearance improved survival when compared to historical untreated controls (82.4 vs 20 %, p \ 0.001) [3]. In a randomized controlled trial of LAM vs placebo, 31 patients (22 with severe AHB) received LAM 100 mg/day for 3 months and 40 patients (25 with severe AHB) were untreated. No significant difference in the clinical course and outcome between LAM-treated and placebo groups was observed. Author's personal copy Recommendations for the management of acute hepatitis B Likewise there was no difference in the rate of HBsAg loss (93.5 vs 96.7 %) [7]. More recently, another randomized controlled trial of LAM in severe AHB showed that liver failure and mortality rates were significantly lower in treated patients compared to the control group when LAM was administered within a week from disease onset. However, HBsAg and HBeAg seroconversion rates of the LAM-group were significantly lower than those of the control group [2]. Currently, few data exist on treatment with newer nucleos(t)ide analogues (NA), entecavir or tenofovir, showing encouraging results in patients with acute, severe hepatitis B [5]. In particular, the concern regarding impaired seroconversion seems not to be confirmed [5]. Finally, some recent reports describe the emergence of spontaneous resistance mutations to antiviral drugs in patients with acute HBV infection [7, 8]. The clinical importance of this finding remains to be clarified, but it discourages the use of drugs such as lamivudine with a low genetic barrier and suggests to use, rather, a drug with high genetic barrier such as tenofovir or entecavir if resistance mutations cannot be evaluated promptly. Recommendation The few published data indicate entecavir and tenofovir as the NA of choice (Grade C, level 2), but it should be confirmed in large randomized trial. Time to start and treatment duration It has been demonstrated that the earlier NUC administration is started, the better the outcome of the disease. A recent study showed that the period of HBsAg positivity in patients starting NUC treatment (entecavir or lamivudine) within 8 weeks from acute hepatitis onset was significantly shorter than that of patients beginning NUC treatment after more than 8 weeks from acute hepatitis onset [1]. No data exist to establish the appropriate duration of antiviral treatment in patients with acute HBV hepatitis. Recommendation No data are available concerning the proper duration of antiviral treatment in AHB. However, it seems reasonable that in patients with AHB, similar to the rule in chronic patients, the NUC treatment should be continued until HBsAg clearance [1, 2] (Grade C, level 2) or, better, until seroconversion to HBsAb, both of which would mark the transition to recovery and may allow to discontinue treatment safely. Antiviral treatment of fulminant hepatitis Rationale for antiviral treatment in fulminant hepatitis In the setting of fulminant hepatitis, liver transplantation remains the most relevant therapeutic option [9]. Even if most reports did not refer to an established definition of fulminant hepatitis and did not exclude cases of non fulminant severe hepatitis and possible reactivations of chronic diseases, they clearly support the benefit of antiviral use in fulminant hepatitis [10]. Recommendation Liver transplantation is the main treatment option in patients with fulminant hepatitis (Grade A, level 1). Anti-HBV antiviral treatment is a component of pre-transplant management which has been associated with improved survival independently from liver transplantation (Grade B, level 2). Who to treat Most of the patients with acute hepatitis clear HBV infection spontaneously and most severe forms are the expression of an uncontrolled and vigorous immune response with low level viremia at presentation [11]. Analyzing published series it appears that an early initiation of antiviral is also related to improvement in survival [10]. So antiviral treatment should be started in acute severe hepatitis B without waiting for the full blown development of fulminant hepatitis. The definition of acute severe infections used in most of the studies demonstrating an improved survival with antiviral treatment in acute HBV infection was the following: bilirubin levels more or equal to 10 mg/dl, INR more or equal to 1.6 and the presence of hepatic encephalopathy. Recommendation An antiviral treatment should be considered in all cases of AHB with HBeAg reactivity or detectable HBV–DNA, bilirubin levels more or equal to 10 mg/dl, INR more or equal to 1.6 and the presence of hepatic encephalopathy (Grade B, level 2). If HBV–DNA results will not be available in 48 h. Antiviral treatment should be started without waiting for HBV–DNA results (Grade C, level 3). How to treat Interferon has been used anecdotally in fulminant hepatitis B with poor efficacy and safety [10]. Lamivudine has been used in most of the published cases of acute severe hepatitis and was not associated with evidence of toxicity [10]. 123 Author's personal copy R. Bruno et al. However, the risk of Lamivudine resistance development is relevant if lamivudine treatment is prolonged for more than 6 months and after liver transplantation [9]. Tenofovir and entecavir are indicated as the first line treatment for severe reactivation of hepatitis B in immunosuppressed patient by international guidelines [9, 12] and have been used in this setting without toxic adverse effects. In chronic hepatitis the combination of entecavir and tenofovir has induced a significantly more rapid decline of HBV–DNA than entecavir monotherapy in patients with baseline HBV–DNA levels [108 IU/ml. Recommendation Lamivudine 100 mg/d (Grade B, level 2), Tenofovir 245 mg/ d or entecavir 0.5 mg/d (Grade C, level 2) can be used as antivirals in patients with fulminant hepatitis. Patients, if not transplanted, should be treated until 6 months after anti HBs seroconversion (Grade B, level 2). Lamivudine should be switched to tenofovir in case of lack of virological response or breakthrough and if there is no anti HBs seroconversion after 3 months (Grade C, level 3). In patients with HBV–DNA levels [8 log at baseline a combination of entecavir ? tenofovir could be used in order to accelerate HBV–DNA suppression (Grade C, level 3). Interferon must not be used in acute fulminant hepatitis (Grade B, level 1). Other treatment for acute and fulminant hepatitis Thymosin: in a placebo controlled study, showed any impact in the HBsAg clearance but improved ALT normalization [13]. Ursodeoxycholic acid (UDCA): only one randomized study evaluated the role of UDCA in AHB and found some benefit on ALT normalization and persistence of HBsAg at 12 months was seen in only 1/33 UDCA-treated patients vs 5/26 placebo treated patients (p = 0.02). However, the reported frequency of chronicity in the placebo group is rather unusual and despite randomization the two groups differed in some characteristics [14]. In addition, another study in 43 HBV patients did not find a difference on the clinical outcome in relation with UDCA use [15]. Of interest, however, none of the patients developed persistent HBsAg [15]. N-Acetylcysteine (NAC): NAC was found to inhibit HBV replication in a cell culture model [16], but no significant benefit was found in acute viral hepatitis [17]. Extracorporeal liver support systems Multisystem organ failure, hepatic encephalopathy, and intracranial hypertension in the setting of Acute Liver 123 failure are exacerbated by impaired metabolism of proteinbound toxins, including ammonia, inflammatory cytokines, protein breakdown products, conjugated bilirubin, and nitric oxide/prostanoids [18]. Potential goals of extra-corporeal albumin dialysis in acute liver failure include improvement in hemodynamics and reversal of hepatic encephalopathy and intracranial hypertension by reduction in glutamine production [19]. Molecular adsorbent recycling system (MARS) is the most studied of the available liver support systems in acute liver failure. In a 13-patient pilot study compared with continuous renal replacement therapy, Schmidt and colleagues [20] demonstrated improvements in hemodynamics after one 6-h MARS run but no mortality benefit. In a prospective randomized study of 102 patients with acute liver failure (FULMAR study) performed by Saliba and colleagues [21] there was no significant difference in 6-month survival, but there was a trend toward increased transplant-free survival in the MARS group for acetaminophen hepatotoxicity. A definitive recommendation on MARS in acute liver failure cannot be made at this time. Despite extensive research, there is little evidence showing a mortality benefit with an artificial support system in fulminant viral hepatitis/acute liver failure. Acknowledgments We would like to thank Dr.ssa Serena Cima for her excellent editing of the manuscript. Conflict of interest of interest. The authors declare that there are no conflicts References 1. Kumar M, Satapathy S, Monga R, et al. A randomized controlled trial of lamivudine to treat acute hepatitis B. Hepatology. 2007;45:96–101. 2. Yu JW, Sun LJ, Zhao YH, et al. The study of efficacy of lamivudine in patients with severe acute hepatitis B. Dig Dis Sci. 2010;56:775–83. 3. Tillmann HL, Hadem J, Leifeld L, Zachou K, Canby A, Eisenbach C, et al. Safety and efficacy of lamivudine in patients with severe acute fulminant hepatitis B, a multicenter experience. J Viral Hepat 2006;13:256–63. 4. European Association for the Study of the Liver. EASL clinical practice guidelines: management of chronic hepatitis B virus infection. 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