Download Recommendations for the management of acute hepatitis B

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. J Hepatol. 2012;57:167–85.
5. Ito K, Yotsuyanagi H, Yatsuhashi H, Karino Y, Takikawa Y,
Saito T, Arase Y, Imazeki F, Kurosaki M, Umemura T, Ichida T,
Toyoda H, Yoneda M, Mita E, Yamamoto K, Michitaka K,
Maeshiro T, Tanuma J, Tanaka Y, Sugiyama M, Murata K,
Masaki N, Mizokami M; Japanese AHB Study Group. Risk
factors for long-term persistence of serum hepatitis B surface
antigen following acute hepatitis B virus infection in Japanese
adults. Hepatology. 2014;59(1):89–97. doi:10.1002/hep.26635.
6. Chulanov VP, Shipulin GA, Schaefer S, Gerlich WH. Kinetics of
HBV DNA and HBsAg in acute hepatitis B patients with and
without coinfection by other hepatitis viruses. J Med Virol.
2003;69:313–23.
Author's personal copy
Recommendations for the management of acute hepatitis B
7. Baxa DM, Thekdi AD, Golembieski A, Krishnan PV, Sharif O,
Kizy A, Shetron-Rama L, Jovanovich J, Chappell BJ, Snow-Lampart A, Borroto-Esoda K, Gordon SC. Evaluation of anti-HBV drug
resistant mutations among patients with acute symptomatic hepatitis B in the United States. J Hepatol. 2013;58:212–6.
8. Coppola N, Tonziello G, Colombatto P, Pisaturo M, Messina V,
Moriconi F, Alessio L, Sagnelli C, Cavallone D, Brunetto M,
Sagnelli E. Lamivudine-resistant HBV strain rtM204V/I in acute
hepatitis B. J Infect. 2013;67:322–8.
9. European Association for the Study of the Liver. EASL clinical
practice guidelines: management of chronic hepatitis B. J Hepatol. 2009;50:227–42.
10. Tillmann HL, Zachou K, Dalekos GN. Management of severe
acute to fulminant hepatitis B: to treat or not to treat or when to
treat? Liver Int. 2012;32:544–53.
11. Rapicetta M, Ferrari C, Levrero M. Viral determinants and host
immune responses in the pathogenesis of HBV infection. J Med
Virol. 2002;67:454–7.
12. Garg H, Sarin SK, Kumar M, Garg V, Sharma BC, Kumar A.
Tenofovir improve the outcome in patients with spontaneous
reactivation of hepatitis B presenting as acute-on-chronic liver
failure. Hepatology. 2011;53:774–80.
13. Galli M, Crocchiolo P, Negri C, et al. Attempt to treat acute type B
hepatitis with an orally administered thymic extract (thymomodulin): preliminary results. Drugs Exp Clin Res. 1985;11:665–9.
14. Galský J, Bansky G, Holubová T, Kõnig J. Effect of ursodeoxycholic acid in acute viral hepatitis. J Clin Gastroenterol
1999;28:249–53.
15. Fabris P, Tositti G, Mazzella G, Zanetti AR, Nicolin R, Pellizzer
G, Benedetti P, de Lalla F. Effect of ursodeoxycholic acid
administration in patients with acute viral hepatitis: a pilot study.
Aliment Pharmacol Ther. 1999;13:1187–93.
16. Weiss L, Hildt E, Hofschneider PH. Anti-hepatitis B virus
activity of N-acetyl-L-cysteine (NAC): new aspects of a wellestablished drug. Antivir Res. 1996;32:43–53.
17. Gunduz H, Karabay O, Tamer A, et al. N-acetyl cysteine therapy
in acute viral hepatitis. World J Gastroenterol. 2003;9:2698–700.
18. Evans TW. Review article: albumin as a drug—biological effects
of albumin unrelated to oncotic pressure. Aliment Pharmacol
Ther. 2002;16:6–11.
19. Laleman W, Wilmer A, Evenepoel P, et al. Effect of the
molecular adsorbent recirculating system and Prometheus devices
on systemic haemodynamics and vasoactive agents in patients
with acute-on-chronic alcoholic liver failure. Crit Care
2006;10(4):R108.
20. Schmidt LE, Wang LP, Hansen BA, et al. Systemic hemodynamic effects of treatment with the molecular adsorbents recirculating system in patients with hyperacute liver failure: a
prospective controlled trial. Liver Transpl. 2003;9:290–7.
21. Saliba F, Camus C, Durand F, et al. Randomized controlled
multicentre trial evaluating the efficacy and safety of albumin
dialysis with MARS in patients with fulminant and subfulminant
hepatic failure. Hepatology 2008;48:LB1.
123