Hepatitis B-related events in autologous hematopoietic stem cell transplantation recipients

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http://www.wjgnet.com/1007-9327/16/1765.asp

ISSN 1007-9327 CN 14-1219/R World J Gastroenterol 2010 April 14; 16(14):

1765-1771

BRIEF ARTICLE

Hepatitis B-related events in autologous hematopoietic stem cell transplantation

recipients

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Özcan Çeneli, Zübeyde Nur Özkurt, Kadir Acar, Þahika Zeynep Aký, Zeynep Arzu

Yeðin, Münci Yaðcý, Gülsan Türköz Sucak, Department of Hematology, Gazi

University, Faculty of Medicine, Beþevler 06500, Ankara, Turkey

Seyyal Rota, Department of Microbiology, Gazi University, Faculty of Medicine,

Beþevler 06500, Ankara, Turkey

Seren Özenirler, Department of Gastroenterology, Gazi University, Faculty of

Medicine, Beþevler 06500, Ankara, Turkey

Author contributions: Sucak GT, Çeneli Ö, Özkurt ZN, Acar K, Rota S, Aký ÞZ,

Yeðin ZA, Yaðcý M and Özenirler S designed the research; Çeneli Ö and Özkurt ZN

analyzed the data; Çeneli Ö and Sucak GT wrote the paper.

Supported by The Society of Postgraduate Education of Internal Medicine

Correspondence to: Dr. Gülsan Türköz Sucak, Department of Hematology, Gazi

University, Faculty of Medicine, Beþevler 06500, Ankara, Turkey.

aysucak@...

Telephone: +90-312-2026317 Fax: +90-312-2236714

Received: December 24, 2009 Revised: February 12, 2010

Accepted: February 19, 2010

Published online: April 14, 2010

Abstract

AIM: To investigate the frequency of occult hepatitis B, the clinical course of

hepatitis B virus (HBV) reactivation and reverse seroconversion and associated

risk factors in autologous hematopoietic stem cell transplantation (HSCT)

recipients.

METHODS: This study was conducted in 90 patients undergoing autologous HSCT.

Occult HBV infection was investigated by HBV-DNA analysis prior to

transplantation, while HBV serology and liver function tests were screened prior

to and serially after transplantation. HBV-related events including reverse

seroconversion and reactivation were recorded in all patients.

RESULTS: None of the patients had occult HBV prior to transplantation. Six

(6.7%) patients were positive for HBV surface antigen (HBsAg) prior to

transplantation and received lamivudine prophylaxis; they did not develop HBV

reactivation after transplantation. Clinical HBV infection emerged in three

patients after transplantation who had negative HBV-DNA prior to HSCT. Two of

these three patients had HBV reactivation while one patient developed acute

hepatitis B. Three patients had anti-HBc as the sole hepatitis B-related

antibody prior to transplantation, two of whom developed hepatitis B

reactivation while none of the patients with antibody to HBV surface antigen

(anti-HBs) did so. The 14 anti-HBs- and/or anti-HBc-positive patients among the

90 HSCT recipients experienced either persistent (8 patients) or transient (6

patients) disappearance of anti-HBs and/or anti-HBc. HBsAg seroconversion and

clinical hepatitis did not develop in these patients. Female gender and multiple

myeloma emerged as risk factors for loss of antibody in regression analysis (P <

0.05).

CONCLUSION: Anti-HBc as the sole HBV marker seems to be a risk factor for

reactivation after autologous HSCT. Lamivudine prophylaxis in HbsAg-positive

patients continues to be effective.

© 2010 Baishideng. All rights reserved.

Peer reviewer: Dr. Alberto Tommasini, MD, Professor, Laboratory of

Immunopathology, Institute for Maternal and Child Health, IRCCS Burlo Garofolo,

Via dell’Istria 65/1, Trieste 34137, Italy

Çeneli Ö, Özkurt ZN, Acar K, Rota S, Aký ÞZ, Yeðin ZA, Yaðcý M, Özenirler S,

Sucak GT. Hepatitis B-related events in autologous hematopoietic stem cell

transplantation recipients. World J Gastroenterol 2010; 16(14): 1765-1771

Available from: URL: http://www.wjgnet.com/1007-9327/full/v16/i14/1765.htm DOI:

http://dx.doi.org/10.3748/wjg.v16.i14.1765

INTRODUCTION

Hepatitis B virus (HBV) infection is one of the major human health problems in

the world. It is estimated that 350-400 million (approximately 5%) people

worldwide are affected by HBV infection[1,2]. Turkey is one of the endemic areas

for HBV infection. The spectrum of HBV-related disease ranges from asymptomatic

HBV carrier state, chronic hepatitis B, acute hepatitis B, to rarely fulminant

hepatitis. Chronic HBV infection is also associated with cirrhosis and

hepatocellular carcinoma[1]. A new clinical status of persistence of HBV genomes

in the liver tissue and/or serum in HBV surface antigen (HBsAg)-negative

individuals is designated as “occult HBV infection”[3,4]. Though suspected to

exist since the early 1980s, this peculiar form of chronic viral infection has

been better identified during the past 10 years. The availability of highly

sensitive molecular biology techniques made it possible to disclose several of

its virological aspects and to show its worldwide distribution, as well as

revealing its possible implications in various clinical contexts[5,6].

Intensive chemotherapy, radiotherapy, monoclonal antibody treatment and

autologous and allogeneic hematopoietic stem cell transplantation (HSCT) give

rise to immune dysfunction which consequently exposes the patients to the risk

of many infections, including viral hepatitis[7,8]. Exacerbation of hepatitis B

is a serious cause of morbidity and mortality in patients undergoing cytotoxic

or immunosuppressive therapy, particularly in areas where chronic HBV infection

is endemic[9]. Iwai et al[10] reported lethal hepatic failure in an

immunosuppressed patient after allogeneic bone marrow transplantation due to

reactivation of latent HBV. The patient had antibody to HBV surface antigen

(anti-HBs) and no viral DNA detected in the serum prior to transplantation[10].

Carpenter et al[11] described a patient with chronic myelogenous leukemia whose

pretransplantation evaluation revealed normal serum aspartate and alanine

aminotransferase levels, a negative serum for HBsAg, anti-HBs, antibody to HBV

core antigen (anti-HBc), and HBV-DNA assessed by a sensitive real-time

polymerase chain reaction (PCR). The donor was seropositive for anti-HBc, but

serum HBV-DNA was negative by PCR. This case went on to develop acute HBV

infection 7 mo after transplantation[11].

To date, there have been several reports of reverse seroconversion/HBV

reactivation in patients previously positive for anti-HBs after allogeneic or

autologous HSCT[12-19]. There is also growing evidence regarding increased

frequency of occult HBV infection in areas where hepatitis B is

endemic[5,20-22]. However, information pertaining to prevalence of occult

hepatitis B prior to HSCT and frequency of reverse seroconversion/HBV

reactivation after HSCT has been scant.

This study aimed to determine: (1) prevalence of occult HBV infection in

patients with various hematologic malignancies who are candidates for autologous

HSCT; (2) frequency, course and results of HBV reactivation and reverse

seroconversion after autologous HSCT; and (3) risk factors for HBV reactivation

and reverse seroconversion in patients undergoing autologous HSCT for various

malignancies.

MATERIALS AND METHODS

Study population

Ninety consecutive patients who underwent autologous HSCT at the Stem Cell

Transplantation Unit of Gazi University with the diagnosis of various

hematological malignancies from September 2003 through July 2008 were included

in the study.

Detection of hepatitis markers and HBV-DNA

HBV serology and liver function tests were screened before transplantation, at

day +30 and every 3 mo thereafter. HBV-DNA was tested in all patients prior to

transplantation, and after transplantation in the patients who had reverse

seroconversion/reactivation of HBV or acute HBV infection. HBV serology (HBsAg,

anti-HBs, anti-HBc, HBeAg, anti-HBe) was tested by ELISA. HBV-DNA was extracted

using the MagAttract Virus Mini M48 kit (Qiagen, Hamburg, Germany) on the

BioRobot M48 workstation (Qiagen, Hamburg, Germany) following the manufacturer’s

instructions. Besides HBV markers, all patients were screened for antibody to

hepatitis C virus (anti-HCV) and anti-human immunodeficiency virus antibodies

prior to transplantation.

Definitions of HBV-related events

Hepatitis was defined as a serum alanine aminotransferase level greater than 100

IU/mL on two consecutive determinations more than 5 d apart[23].

Occult hepatitis B was defined as the presence of HBV-DNA and the absence of

HBsAg in plasma[3].

HBV reactivation was defined as seroconversion from HBsAg-negative to positive

for HBsAg with an increase in HBV-DNA levels compared with baseline HBV-DNA

levels, in the absence of clinical and laboratory features of acute infection

with hepatitis A, hepatitis C, or other systemic infection[24].

Reverse seroconversion was defined as appearance of HBsAg and disappearance of

anti-HBs after HSCT in patients who had no HBsAg but did have anti-HBs or

anti-HBc before transplantation [14,19].

Loss of antibody was defined as disappearance of anti-HBs and/or anti-HBc after

transplantation.

Lamivudine prophylaxis

All patients with a positive HBsAg received 100 mg/d lamivudine prophylaxis

before the transplantation conditioning regimen. Lamivudine prophylaxis was

maintained for at least 1 year after transplantation. Liver function tests were

within normal limits in all patients before starting the conditioning regimen.

This study was approved by the Institutional Board of Gazi University Medical

School.

Statistical analysis

Statistical analysis was performed using the program of SPSS for Windows,

version 11.5. Relative risks for reactivation of HBV and loss of antibodies were

calculated by logistic regression analysis. P < 0.05 was considered to be

statistically significant.

RESULTS

Patient characteristics

Among the ninety (59 male and 31 female) patients included in the study,

forty-six had multiple myeloma (MM), 23 Hodgkin’s lymphoma (HL), 15 non-HL

(NHL), 4 acute myeloblastic leukemia, 1 acute lymphoblastic leukemia, 1

primitive neuroectodermal tumor (PNET). The median age at transplantation was 48

years (range: 16-71 years). The median follow-up after autologous HSCT was 15 mo

(range: 6-36 mo). Patients with MM comprised the most common subgroup (46

patients, 51.1%) as shown in Table 1.

Changes in HBV serologic markers

Pre-transplantation surveillance of HBV infection showed that 6 patients (6.7%)

were HbsAg-positive; three of these patients were HBV-DNA-positive. None of the

patients in our cohort had occult hepatitis B. Total numbers of patients with

anti-HBs and anti-HBc were 30 (33.3%) and 23 (25.6%), respectively. Forty-nine

patients (54.4%) had neither anti-HBs nor anti-HBc; 12 patients (13.3%) had both

(Table 2).

Clinical hepatitis B infection was detected in three patients. Two of these

infections were HBV reactivation while one patient developed acute hepatitis B.

While none of the patients with positive HBsAg reactivated after autologous

HSCT, 2 of the 3 patients with negative HBsAg and positive anti-HBc had

hepatitis B reactivation. On the other hand, none of the patients with negative

HBsAg and positive anti-HBs reactivated.

Six patients with pretransplantation HBsAg received prophylactic lamivudine.

Autologous HSCT was performed under lamivudine prophylaxis in those 6 patients;

none of whom had HBV reactivation in the post-transplantation period.

Reactivation case 1: A 55-year-old male patient with MM had anti-HBc antibody as

the sole HBV-related marker at pretransplantation screening. HBsAg, anti-HBs,

HBeAg, anti-Hbe and HBV-DNA were all negative. The patient had received four

cycles of VAD (vincristine, adriamycin, dexamethasone) as first line treatment,

and four cycles of thal-dex (thalidomide-dexamethasone) as second line

treatment. Cyclophosphamide-etoposide and melphalan were administered as

mobilization and conditioning regimens, respectively. At day 110 after

autologous HSCT, HBsAg and HBV-DNA became positive. He was in partial remission

at the time of hepatitis B reactivation. Lamivudine treatment was started on the

same day. Although ALT was within normal limits initially, it increased to 590

U/L (0-49 U/L, reference value) at day 225 post-transplantation. Subsequently

ALT levels decreased gradually and normalized within 2 wk. Anti-HBc was still

positive at the time of HBV reactivation and it remained positive during

follow-up period. Anti-HBe and anti-HBs have not become positive during the

follow-up. HBsAg and HBV-DNA disappeared in the first year after autologous

HSCT. HBV-DNA titer was 1.1 × 106 copies/mL at day +110, 1.9 × 106 copies/mL at

day +183, 0.9 × 106 copies/mL at day +225, 1100 copies/mL at day +256 and

negative at day 365 after autologous HSCT.

Reactivation case 2: A 55-year-old male patient with MM had anti-HBc antibody as

the sole HBV-related marker at pretransplantation screening. HBsAg, anti-HBs,

HBeAg, anti-Hbe and HBV-DNA were all negative in this patient as well. At day

148 after autologous HSCT, HBsAg and HBV-DNA became positive. Lamivudine

treatment was started the same day. ALT level was normal initially, but it was

measured as 1157 U/L at day +198. Subsequently, ALT level decreased gradually

and returned to normal limits within 2 wk. HBV-DNA titer was 1000 copies/mL at

the time of reactivation, then decreased gradually and it became negative at day

+225. HBsAg also disappeared in patient’s serum on day 365 after autologous

HSCT. Anti-HBc was still positive at the time of HBV reactivation and it

remained positive during follow-up. Anti-HBe and anti-HBs became positive at day

+198 and day +457 after autologous HSCT, respectively. He was in complete

remission at the time of hepatitis B reactivation.

Acute HBV infection case 1: A 48-year-old female patient with MM received

methylprednisolone for autologous graft-versus-host disease (GVHD) treatment at

day 18 post-transplantation. HBsAg, anti-HBs, anti-HBc, HBeAg, anti-Hbe and

HBV-DNA were all negative prior to transplantation in this patient. On day +210

post-transplantation, HBsAg, HBeAg and HBV-DNA became positive. Lamivudine

treatment was started. ALT level, which initially was normal, gradually

increased to 534 U/L at day 287 post-transplantation. She remained on steroid

treatment for the treatment of grade IV chronic dermal GVHD. HBV-DNA titer was

5.3 × 107 copies/mL on the day of reactivation, 1 × 106 copies/mL at day +287,

3.3 × 104 copies/mL at day +365, and 2000 copies/mL at day 580 after autologous

HSCT. On day 580 post-transplantation when the data of this study were analyzed,

she was positive for HBsAg, HBeAg and HBV-DNA (gradually decreasing titer, YMDD

mutation negative).

Loss of antibody

The 14 anti-HBs- and/or anti-HBc-positive patients who underwent autologous HSCT

experienced persistent (8 patients) or transient (6 patients) disappearance of

anti-HBs and/or anti-HBc. Interestingly, neither seroconversion for HBsAg nor

clinical hepatitis developed in these patients. Eleven of these 14 patients had

MM, 1 had NHL, 1 had HL, and 1 had PNET. Anti-HBs or anti-HBc reappeared in 5 of

these patients within 6 to 8 mo. Characteristics of these patients and details

of the changes in serologic markers are shown in Table 3.

Possible risk factors for reactivation and loss of antibodies, including age,

gender, underlying disease, the number of pre-transplant chemotherapy cycles and

the mobilization and conditioning regimens, were tested both in univariate and

multivariate logistic regression analysis. No specific risk factors were found

for reactivation of HBV. Female gender (P = 0.04, OR = 3.4, CI: 1.17-9.81) and

MM (P = 0.035, OR = 4.29, CI: 1.29-16.2) emerged as risk factors for loss of

antibody in univariate analysis; whereas only MM was an independent risk factor

in multivariate analysis (P = 0.043, OR = 3.6, CI: 1.1-14.4).

DISCUSSION

HBV carriers have increased liver-related morbidity and mortality during

chemotherapy of hematological disorders[25]. Reactivation in patients supposedly

immune to hepatitis B has also became an emerging problem during the treatment

of various hematologic disorders with chemotherapeutic agents, monoclonal

antibodies, immunosuppressive agents and HSCT[26]. HBV is a latent virus which

may persist for a long time despite the presence of anti-HBs and/or anti-HBc

antibodies. Reverse seroconversion/reactivation may occur which results in

increased liver-related morbidity and mortality[25], particularly in areas with

high hepatitis B prevalence. Turkey is among the middle-endemic regions for

hepatitis B with a mean seroprevalence for hepatitis B among healthy blood

donors reported as 4.19% (3.9%-12.9%)[2,27].

Occult HBV infections are defined as the presence of HBV-DNA and the absence of

HBsAg in liver tissue, plasma or serum of HBV-infected patients[3-5]. The risk

of reactivation and fulminant course is particularly high in this group of

patients. We investigated the prevalence of occult HBV infection in patients

with various hematologic malignancies who were candidates for autologous HSCT.

We also investigated the frequency and the risk factors associated with HBV

reactivation/reverse seroconversion after autologous HSCT.

Pre-transplantation surveillance of HBV infection showed that six patients

(6.7%) were HbsAg-positive, three of whom were also HBV-DNA-positive. The 6.7%

HBsAg seropositivity among patients with hematologic malignancies in the

presented study seems to be similar to the frequency in the normal population.

There are several reports describing effective lamivudine prophylaxis in

HbsAg-positive patients receiving chemotherapy or HSCT[9,28-30]. None of our

patients with HBsAg, with or without positive HBV-DNA, had hepatitis

reactivation under lamivudine prophylaxis. Our study results might suggest an

efficacy of lamivudine prophylaxis in HbsAg-positive patients undergoing

autologous HSCT, although lamivudine resistance has also been reported in other

series[23,31,32].

Reactivation of HBV in patients previously positive for anti-HBs and/or

anti-HBc, so called “reverse seroconversion”, has been reported in

immunosuppressed patients including patients with acquired immunodeficiency and

recipients of organ transplantation or HSCT[14,33,34]. In particular, patients

with lymphoma receiving rituximab with or without chemotherapy have an increased

risk of reactivation[26]. The precise frequency of reactivation in the setting

of HSCT in anti-HBs- and/or anti-HBc-positive and HbsAg-negative patients is not

known, though previous reports mention a frequency of 7% to 12%[18,35,36]. Two

among the 3 patients (66.7%), who had anti-HBc as the “only” hepatitis B-related

marker prior to transplantation developed HBV reactivation after autologous

HSCT. The cause of the hepatitis in the two patients presented above seems to be

reactivation of a previous infection. Similarly, Matsue et al[37] found an

increased risk of reactivation in their patients who had anti-HBc antibodies,

while none of the patients in their series with anti-HBs developed a reverse

seroconversion. In the absence of HBV-DNA prior to transplantation, patients

with anti-HBc as the sole HBV-related marker might be a variant or subgroup of

patients with occult hepatitis where the infection is limited to the liver. Our

results suggest that patients with anti-HBc in the absence of anti-HBs seem to

be a high risk group requiring monitoring and even prophylaxis, though these

data warrant verification with further prospective randomized studies. In

contrast to the patients presented by Matsue et al[37], whose HBV reactivation

was after corticosteroid therapy for chronic GVHD, our patients who had HBV

reactivation were not receiving corticosteroids and were in remission from their

underlying diseases. The immunosuppressive effect of autologous HSCT per se

might be responsible from the reverse seroconversion in our cases.

At present, HBV serological markers including HBsAg, anti-HBs and anti-HBc may

not be adequate to perceive the existence of HBV. Recent studies have

demonstrated that improvement of PCR methods have favored the recognition of

occult HBV infections in an increasing number of clinical settings and

geographical areas. To date, documentation of occult HBV prevalence rates has

been limited to blood or organ donors and selected patient populations such as

hemodialysis patients with HCV[38-40], AIDS patients and hemophiliacs. The

prevalence of HBV viremia in adult hemodialysis patients is 3.8%-15%, or 4-20

times higher than what standard monoclonal antibody-based HBsAg testing would

have suggested. It is possible that host immune mechanisms and viral

interactions can maintain HBV infection in a latent state until more profound

immunosuppression ensues[38-40]. Recently, occult HBV prevalence has also been

investigated in community-based populations[21]. The prevalence of occult

hepatitis was found to be 15.3% in a cohort of 124 consecutive HbsAg-negative

stem cell donors in Hong Kong, which suggests occult hepatitis is a matter of

concern in endemic areas[13].

None of the patients presented in this study with various hematological

malignancies had occult hepatitis B prior to transplantation. Uhm et al[7]

similarly have not detected occult HBV infection in their patients with

hematologic malignancies in Korea, which is also an endemic area for HBV

infection. Absence of occult hepatitis in a relatively high risk group of

patients requires further elucidation. On the other hand, patients with anti-HBc

as the only HBV marker might be a variant subgroup with occult hepatitis. More

sensitive methods such as detection of covalently closed circular DNA - the key

intermediate of replication of the virus - in liver biopsy specimens may be

required in patients with immunosuppression, in order to exclude occult

infection.

The rates of disappearance of anti-HBs, anti-HBc, and both (loss of antibody)

were 40% (12/30 patients), 6.7% (2/30 patients), and 6.7% (2/30 patients),

respectively, in our series. Total rate of disappearance of anti-HBs and/or

anti-HBc was 46.7% (14/30 patients). Loss of antibody was transient in 6 of

these patients. Anti-HBs reappeared after 8-18 mo (median 15 mo) in 4 patients

and anti-HBc reappeared after 6 mo in 2 patients (Table 3). The most common

underlying disease among the patients who had loss of antibody (11/14 patients)

was MM. MM was discovered to be an independent risk factor for loss of antibody

in multivariate analysis (P = 0.043, OR = 0.27). The reason why the loss of

antibody emerges more in MM patients who have undergone autologous HSCT remains

to be elucidated.

None of the patients who lost their hepatitis B antibodies developed HBsAg

seroconversion or clinical hepatitis during the median 15 mo follow up period.

The actual risk of disappearance of anti-HBs and reverse seroconversion was

estimated to be 75% and 39.8% at 2 years, and 100% and 70% at 5 years,

respectively, in allogeneic HSCT recipients in the study of Onozawa et al[19].

Lower rates of disappearance of antibody and reverse seroconversion in our study

could be explained by the fact that our study population consisted of patients

who had undergone autologous HSCT which is less immunosuppressive than

allogeneic HSCT.

In conclusion, HBV-related events such as reactivation, acute hepatitis and loss

of antibody can develop in patients undergoing autologous HSCT. Patients with

anti-HBc antibody as the only HBV-related serologic marker might be a special

risk group where antiviral prophylaxis should be considered. Loss of anti-HBs

and/or anti-HBc after transplantation is not a rare complication of autologous

HSCT, especially in MM patients, and does not necessarily progress to reverse

seroconversion and clinical hepatitis. Further prospective and randomized

studies are required to validate the prognostic significance and treatment of

anti-HBc-positive patients.

COMMENTS

Background

Hepatitis B virus (HBV) infection is one of the major human health problems in

the world. Turkey is one of the endemic areas for HBV infection. Intensive

chemotherapy, radiotherapy, monoclonal antibody treatment, and autologous and

allogeneic hematopoietic stem cell transplantation (HSCT) give rise to immune

dysfunction which consequently expose the patients to the risk of many

infections, including viral hepatitis. Exacerbation of hepatitis B is a serious

cause of morbidity and mortality in patients undergoing cytotoxic or

immunosuppressive therapy, particularly in areas where chronic HBV infection is

endemic.

Research frontiers

This study aimed to determine the prevalence of occult HBV infection in patients

with various hematologic malignancies who are candidates for autologous HSCT.

Frequency, course of disease, results of HBV reactivation and reverse

seroconversion after autologous HSCT, and the risk factors for HBV reactivation

and reverse seroconversion in patients undergoing autologous HSCT for various

malignancies were also determined.

Innovations and breakthroughs

HBV-related events such as reactivation, acute hepatitis and loss of antibody

can develop in patients undergoing autologous HSCT. Patients with anti-HBc

antibody as the only HBV-related serologic marker might be a special risk group

where antiviral prophylaxis should be considered. Loss of antibody to HBV

surface antigen (anti-HBs) and/or anti-HBc after transplantation is not a rare

complication of autologous HSCT, especially in multiple myeloma patients, and

does not necessarily mean progression to reverse seroconversion and clinical

hepatitis. Further prospective and randomized studies are required to validate

the prognostic significance and treatment of anti-HBc-positive patients.

Applications

Presence of anti-HBc as the sole HBV-related marker seems to be a risk factor

for reactivation. Loss of anti-HBs and anti-HBc are frequently seen after

autologous HSCT, not necessarily having a poor prognostic significance.

Lamivudine prophylaxis in HBV surface antigen (HBsAg)-positive patients, and

treatment in patients with HBV reactivation, continues to be effective.

Terminology

HBV reactivation was defined as seroconversion from HBsAg-negative to positive

for HBsAg with an increase in HBV-DNA levels compared with baseline HBV-DNA

levels, in the absence of clinical and laboratory features of acute infection

with hepatitis A, hepatitis C, or other systemic infection. Reverse

seroconversion was defined as appearance of HBsAg and disappearance of anti-HBs

after HSCT in patients who had no HBsAg but did have anti-HBs or anti-HBc before

transplantation. Loss of antibody was defined as disappearance of anti-HBs

and/or anti-HBc after transplantation.

Peer review

In this paper, the authors provide consistent data which may help better

understanding of the yet unsolved topic of HBV reactivation after

immunosuppression, even if they do not change significantly current practices in

this field.

REFERENCES <CUT>