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Keywords:

  • Clinical observations;
  • interventions;
  • therapeutic trials

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Use of hepatitis B surface antigen (HBsAg) positive donors for allogeneic hematopoietic stem cell transplantation (HSCT) causes serious hepatitis B virus (HBV)-related liver morbidity and mortality in the recipient. We compared the effectiveness of anti-HBV therapy in 29 recipients who underwent HSCT using HBsAg positive marrow (group I) against a historical control group of 25 patients who received HBsAg positive marrow without pre-HSCT prophylaxis (group II). Anti-HBV therapy consisted of lamivudine for HBsAg-positive donors and all recipients (n = 29) as well as HBV vaccination to all HBsAg-negative recipients (n = 10) before HSCT. After transplantation, HBV-related hepatitis was significantly higher in group II than group I recipients [12 of 25 recipients (48%) vs. 2 of 29 recipients (6.9%), p = 0.002] and in recipients whose donors had detectable serum HBV DNA by Digene Hybrid Capture II assay [8 of 14 recipients (57.1%) vs. 6 of 40 recipients (15.0%), p = 0.02]. Six recipients in group II and none in group I died of HBV-related hepatic failure (24.0% vs. 0%, p = 0.01). By multivariate Cox analysis, anti-HBV therapy effectively reduces post-HSCT HBV-related hepatitis (p = 0.01, adjusted hazards ratio 7.27, 95%CI 1.62–32.58). Our data support the use of prophylactic therapy in preventing HBV-related hepatitis after allogeneic HSCT from HBsAg-positive donor.


Abbreviations: 
HBV

hepatitis B virus;

HBsAg

hepatitis B surface antigen;

HBeAg

hepatitis B e antigen;

Anti-HBe

hepatitis B e antibody;

Anti-HBs

hepatitis B surface antibody;

Anti-HCV Ab

anti-hepatitis C antibody;

GVHD

graft-versus-host-disease;

VOD

veno-occlusive disease;

HSCT

hematopoietic stem cell transplantation;

ALT

alanine aminotransaminase;

HLA

human leucocyte antigen;

TBI

total body irradiation

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Hematopoietic stem cell transplantation (HSCT) is performed annually in over 30 000 patients worldwide for a wide range of hematological disorders (1). Hepatic complications in HSCT recipients are well-recognized causes of transplantation-related morbidity and mortality. In addition to veno-occlusive disease (VOD) and graft-versus-host disease (GVHD), viral hepatitis, especially hepatitis B virus (HBV) infection in endemic areas, can lead to a wide spectrum of hepatic complications after HSCT (2–4).

Previously, we and others have reported a high incidence of HBV-related hepatitis after the transplantation of hematopoietic stem cell (HSC) from hepatitis B surface antigen (HBsAg) positive donors to recipients, with up to one-sixth of patients dying from HBV-related hepatic failure after HSCT (5–8). Despite the intensive myeloablation and immuno-suppressive effects of allogeneic HSCT, the protective effect of anti-HBV immunity seems to be preserved in some of the hepatitis B surface antibody (anti-HBs) positive recipients (5,9). The persistence of anti-HBV activity in these recipients after transplantation may be due to residual recipient lymphocytes that have survived the intensive preconditioning regime. This is in keeping with the long-term persistence of hematopoietic chimerism following allogeneic HSCT (10). Further analyses have shown that a high donor viral load appeared to predispose recipients to the development of HBV-related hepatitis post-HSCT (5).

In HBV endemic areas, the exclusion of HBsAg positive donors will greatly limit the application of allogeneic HSCT. Therefore, we have developed a specific prophylactic anti-HBV therapy to minimize the risk from using HBsAg positive HSCT donor when there are no other alternatives (11). First, the HBV viral load in the donor's marrow is reduced before harvest with lamivudine (5). Second, anti-HBV immunity in HBsAg negative recipients is induced or enhanced by HBV vaccination. Third, as the majority (about two-thirds) of anti-HBs negative recipients of HBsAg positive marrow will become infected with HBV, they are also given lamivudine after allogeneic HSCT in order to reduce HBV replication (5). In this report, we describe the results of this prophylactic anti-HBV strategy and compare them with those of a historical group of patients who received HBsAg positive HSC without specific pre-HSCT treatment.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Patient studied

From May 1990 to July 2004, 854 consecutive patients underwent allogeneic HSCT at the Bone Marrow Transplantation Unit, Queen Mary Hospital, Hong Kong SAR. In accordance with standard protocols, all donors and recipients were screened for HBsAg and anti-HBs (Abbott Laboratories, North Chicago, IL). For HBsAg-positive donors and recipients, further assays for hepatitis B e antigen (HBeAg), hepatitis B e antibody (anti-HBe) (Abbott Laboratories, North Chicago, IL) and serum HBV DNA were performed. HBsAg positive donors and recipients from May 1990 to January 2000 were all tested for HBV DNA by Digene Hybrid Capture assay II, with a lower detection limit of 0.142 × 106 copies/mL (Digene Diagnostics Inc., Beltsville, MD) on stored serum samples (12). Those after January 2000 were prospectively tested with Digene Hybrid Capture assay II (Digene Diagnostics Inc., Beltsville, MD). The Digene Hybrid Capture II assay was used in this study because we have previously demonstrated that a serum HBV DNA of more than 105 copies/mL was an independent factor associated with an increased risk of HBV-related hepatitis after HSCT (13).

From November 1998 to July 2004, 29 consecutive recipients who received HBsAg positive marrow in the absence of concomitant hepatitis C virus (HCV) infection (anti-HCV negative) were prospectively recruited to receive prophylactic anti-HBV therapy prior to HSCT (group I). All HBsAg positive donors and recipients were prospectively treated with lamivudine before marrow harvest and HSCT, and continued for 52 weeks after HSCT (Figure 1). Marrow harvesting and HSCT was performed when both donor's and recipient's serum HBV DNA became undetectable by Digene Hybrid Capture assay II (Digene Diagnostics Inc., Beltsville, MD) (Figure 1). All HBsAg and anti-HBs negative recipients at recruitment were prospectively given 1–3 doses of HBV vaccine monthly before HSCT (Engerix-B, GlaxoSmithKline, Research Triangle Park, NC) and anti-HBs positive recipients at recruitment were given a booster dose of HBV vaccine (Engerix-B, GlaxoSmithKline, Research Triangle Park, NC) before HSCT (Figure 1). Lamivudine was then prospectively started at least one week prior to HSCT for HBsAg positive recipients and on the day of marrow infusion for HBsAg negative recipients and continued for 52 weeks after HSCT in all recipients.

image

Figure 1. Management of patients undergoing hematopoietic stem cell transplantation. Proportion of HBsAg positive marrow and HBsAg positive or negative recipients with and without prophylactic anti-HBV therapy before marrow harvest and transplant. HSCT—hematopoietic stem cell transplantation.

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Twenty-five consecutive recipients of HBsAg positive marrow from May 1990 to October 1998 without concomitant HCV infection (anti-HCV negative) were transplanted and they served as historical control (group II). None of the donors and recipients had been treated with nucleoside analogues, interferon-α, intravenous immunoglobulin or HBV vaccination before or after HSCT.

All donors' and recipients' had their HBsAg, HBeAg, anti-HBs and HBV DNA repeated before the day of HSCT (pre-HSCT).

In both groups, the preconditioning regimen for HSCT was chosen according to the underlying diseases. Busulfan and cyclophosphamide for chronic myeloid leukemia, acute myeloid leukemia and myelodysplastic syndrome; total body irradiation (TBI) and cyclophosphamide for acute lymphoblastic leukemia; cyclophosphamide, carmustine and etoposide for non-Hodgkin's lymphoma; and fludarabine and TBI for multiple myeloma (14–16).

All recipients were followed-up weekly for the first 12 weeks and then every 2- to 12-weekly until the time of analysis, November 2004. During each follow-up, the recipients had a complete physical examination, testing of liver biochemistry and HBV serology (HBsAg, HBeAg, anti-HBe and anti-HBs). For HBsAg positive recipients, their serum was tested for HBV DNA by Digene Hybrid Capture II assay. The occurrence of hepatic events (acute hepatitis, chronic hepatitis, anicteric and icteric hepatitis, hepatic failure, VOD and hepatic GVHD) and death were recorded. Liver biopsies were not performed in either the recipients or donors. Group I patients would be tested for lamivudine resistant mutants by determination of HBV polymerase gene by direct PCR sequencing if they developed HBV-related hepatitis during the period of this study (17).

The pre-HSCT serum HBV DNA of donors with undetectable HBV DNA by the Digene Hybrid Capture II assay (Digene Diagnostics Inc., Beltsville, MD) whose recipients still developed HBV-related hepatitis after HSCT were retrospectively retested with the Cobas Amplicor HBV Monitor version 2 (Roche Molecular Systems Inc., Branchburg, NJ).

The Institutional Review Board at the Queen Mary Hospital approved the study and informed consent was obtained from all patients from groups I and II.

Definition of hepatic events

Clinical hepatitis was defined as more than a three-fold elevation of serum alanine aminotransaminase (ALT) on two consecutive tests 5 days apart, in the absence of clinical features suggestive of VOD, GVHD or superinfection with cytomegalovirus or herpes simplex virus. Icteric hepatitis was defined as hepatitis associated with clinical jaundice and a serum bilirubin level more of than 30 μmol/L (normal range 7–19 μmol/L). Hepatitis was defined as HBV-related if it was preceded by an elevation of serum HBV DNA to more than 10 times that of the pre-exacerbation baseline in a patient who remained HBV DNA positive, if the serum HBV DNA turned from negative to positive, or if the HBsAg became positive and remained so for 2 consecutive tests 5 days apart. Hepatic failure was defined as the presence of hepatic encephalopathy and abnormal blood coagulation (prothrombin time exceeding 10 s of control). VOD was defined and graded as described by McDonald et al. (18). Acute GVHD of the liver was defined and graded in accordance with the Glucksberg criteria (19).

Statistical analysis

The sample size was computed on the basis of the primary comparison of survival free from HBV-related hepatitis between the two groups. Based on previous reports, approximately half of the recipients of HBsAg positive marrow would develop HBV-related hepatitis after allogeneic HSCT in the absence of effective prophylactic anti-HBV therapy (5,6). A high viral load was found to be a good predictor of HBV-related hepatitis after HSCT in these studies. We anticipated that our prophylactic anti-HBV protocol would reduce the frequency of HBV-related hepatitis to 10%. Thus, 23 patients would be required in each group by a log-rank test of 80% power and a maximum 5% chance of false positive error rate. In order to account for 10% of patients lost to follow-up, 25 patients would be required in each group.

All statistical analyses were performed using the Statistical Program for Social Sciences (SPSS 10.0 for windows; SPSS Inc., Chicago, IL). The Mann-Whitney U-test was used for continuous variables with skewed distribution and the chi-square with Yates' correction for continuity or Fischer's exact test for categorical variables. Cumulative mortality was analyzed by using Kaplan–Meier curves. Possible factors associated with the rate of occurrence of HBV-related hepatitis were studied using a multivariate Cox proportional hazards model, and hazard ratios adjusted for other model factors were obtained together with their 95% confidence interval (CI). Continuous variables are expressed as median (range). All statistical analyses were performed on an intention-to-treat population. Statistical significance was defined as p<0.05 (2 tailed).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Patients demographic

The demographic characteristics of both groups before HSCT are shown in Table 1. After prophylactic anti-HBV therapy, group I had more donors and recipients with undetectable HBV DNA compared to group II before HSCT (p < 0.001 and p < 0.001, respectively).

Table 1.  Demographic data of recipients with and without prophylactic anti-HBV therapy before hematopoietic stem cell transplantation
 Group I (n = 29)Group II (n = 25) p-Value
  1. 1On Digene Hybrid Capture II assay.

  2. 2Results were repeated 1 day before HSCT was performed.

  3. HBsAg = hepatitis B surface antigen, anti-HBe = hepatitis B e antibody, HBeAg = hepatitis B e antigen, Anti-HBs = hepatitis B surface antibody, CML = chronic myeloid leukemia, AML = acute myeloid leukemia, MDS = myelodysplastic syndrome, ALL = acute lymphocytic leukemia, CSP = cyclosporine, MTx = methotrexate, BCNU = carmustine, VP-16 = etoposide.

Age (years)39 (23–58)27 (20–46)0.08
Sex (M:F)16:1320:50.08
Number of HSCT33281.00
Donor HBeAg status0.97
 HBeAg positive87 
 anti-HBe positive2118 
Donor HBV DNA at recruitment10.95
 Detectable1614 
 Undetectable1311 
Donor HBV DNA pre-HSCT1,2<0.001
 Detectable014 
 Undetectable2911 
Recipient HBsAg status at recruitment0.47
 Positive1914 
 Negative1011 
Recipient HBV DNA at recruitment10.71
 Detectable119 
 Undetectable85 
Recipient HBV DNA pre-HSCT1,2<0.001
 Detectable29 
 Undetectable175 
Recipient HBeAg status0.29
 HBeAg-positive13 
 Anti-HBe-positive1811 
 Anti-HBs positive at recruitment560.84
 Anti-HBs positive pre-HSCT2860.36
 Anti-HBs titer in HBsAg negative, anti-HBs positive recipients at recruitment (IU/mL)21 (14–54)24 (12–38)0.42
 Anti-HBs titer in HBsAg negative, anti-HBs positive recipients pre-HSCT (IU/mL)296 (52–137)24 (12–38)0.03
 Anti-HBs titer in HBsAg negative, anti-HBs negative recipientsat recruitment (IU/mL)<10<101.00
 Anti-HBs titer in HBsAg negative, anti-HBs negative recipients pre-HSCT (IU/mL)272 (<10–120)<100.01
 Bilirubin (μmol/L)9 (5–47)11 (4–28)0.39
 Alkaline phosphatase (U/L)64 (37–159)69 (54–167)0.18
 Alanine aminotransaminase (U/L)17 (11–411)26 (8–109)0.19
Hematological disease0.16
 CML910 
 AML37 
 MDS34 
 ALL42 
 Multiple myeloma21 
 Non-Hodgkin's lymphoma81 
GVHD prophylaxis0.36
 CSP + MTx/MMF2524 
 CSP41 
Conditioning regimen0.08
 Busulfan and cyclophosphamide1521 
 Total body irradiation and cyclophosphamide42 
 Cyclophosphamide/BCNU/VP-1681 
 Fludarabine and total body irradiation21 

Group I patients who were HBsAg negative, anti-HBs positive at recruitment had a higher anti-HBs titer pre-HSCT when compared with group II patients who were HBsAg negative, anti-HBs positive (p = 0.03; Table 1). Three of the 5 (60%) group I HBsAg negative, anti-HBs negative recipients at the time of recruitment completed the three courses of HBV vaccination before HSCT, while the remaining 2 of these 5 recipients (40%) received 2 doses of HBV vaccination before HSCT. The pre-HSCT median anti-HBs titer in these 5 recipients from group I was higher than the HBsAg negative, anti-HBs negative recipients in group II (p = 0.01; Table 1).

Four of the 29 recipients (14.0%) in group I required a second allogeneic HSCT (3 due to disease relapse and 1 due to graft failure) while 3 of the 25 recipients (12.0%) in group II required a second allogeneic HSCT (2 due to graft failure and 1 due to disease relapse) [p = NS (not significant)].

Hepatic events following HSCT

The median follow-up was 13.1 (range 0.1–67.1) months in group I and 12.0 (range 1.1–152.7) months in group II (p = 0.23). The clinical events in both groups are shown in Table 2. Two of the 29 recipients in group I and 12 of the 25 recipients in group II developed HBV-related hepatitis after HSCT (6.9% vs. 48.0%, p = 0.002 on log-rank; Figure 2A; Table 2). The clinical features of these 14 recipients and their outcome are shown in Table 3.

Table 2.  Frequency of hepatic event and mortality after hematopoietic stem cell transplantation.
Clinical events Group I Group II p-Value1
  1. 1By log-rank.

  2. VOD = veno-occlusive disease, GVHD = graft-versus-host-disease.

HBV-related hepatitis2120.002
Causes of non HBV-related hepatic event0.50
 VOD011 
 GVHD liver (Grade)9 (1/5/3)8 (2/3/3) 
 Sepsis24 
 Drug related20 
 Unknown21 
 Mortality10150.06
HBV-related
 Hepatic failure060.01
Other causes1.00
 Relapse/disease progression65 
 Infection22 
 Intracranial hemorrhage20 
 GVHD02 
imageimageimageimage

Figure 2. (A) Graph showing the cumulative probability of HBV-related hepatitis after hematopoietic stem cell transplantation in groups I and II. (B) Graph showing the cumulative probability of HBV-related hepatitis after hematopoietic stem cell transplantation in donor with and without detectable serum HBV DNA. (C) Graph showing cumulative probability of mortality in groups I and II. (D) Graph showing the cumulative probability of mortality from hepatic failure in groups I and II.

Table 3.  Clinical features of recipients with hepatitis B virus-related clinical hepatitis after hematopoietic stem cell transplantation
Recipient Prophylactic therapyRecipient HBsAg pre-HSCTRecipient HBeAg pre-HSCTRecipient Anti-HBe pre-HSCT Recipient anti-HBsDonor HBeAg statusTime of HBV-related clinical hepatitis after HSCT (months)HBsAg status at the time of analysisHBeAg at the time of analysisAnti-HBe at the time of analysisAnti-HBs at the time of analysisFulminant hepatic failure Outcome
  1. HBsAg = hepatitis B surface antigen, anti-HBe = hepatitis B e antibody, HBeAg = hepatitis B e antigen, anti-HBs = hepatitis B surface antibody, HSCT = hematopoietic stem cell transplantation.

1No0.9++ NoDied
2No1.0++ NoDied
3No++0.5 +NoAlive
4No0.4 +NoAlive
5No1.1++ NoDied
6Yes++ 4.4 +NoAlive
7Yes++ 8.8++ NoAlive
8No++ 1.8++ YesDied
9No++ 8.5++ YesDied
10No++ 14.9++ YesDied
11No++ 18.8++ NoAlive
12No++ +6.1++ YesDied
13No++ 7.6++ YesDied
14No++ +6.1++ YesDied

The 2 recipients from group I recovered spontaneously with normalization of serum ALT levels. Lamivudine resistant mutant was detected in the recipient who developed HBV-related hepatitis at 8.8 months after HSCT (recipient 7 in Table 3). This patient was not started on adefovir dipivoxil as it was not available at the time. None of the HBsAg negative recipients pre-HSCT developed HBV-related hepatitis regardless of the number of HBV vaccination received before HSCT (Table 3). In group II, 6 recipients spontaneously recovered with normalization of serum ALT level. Six of the 25 recipients in group II and none of the 29 recipients in group I developed hepatic failure (24.0% vs. 0%, p = 0.01 by log-rank). None of the patients from group II received lamivudine as it was not available at the time.

Among all of the 54 recipients, HBV-related hepatitis occurred more frequently in those whose donor had detectable serum HBV DNA than in recipients whose donor had undetectable serum HBV DNA, by Digene Hybrid Capture assay II [8 of 14 recipients (57.1%) vs. 6 of 40 recipients (15.0%), p = 0.02 by log-rank; Figure 2B]. The pre-HSCT serum HBV DNA of the 6 donors with undetectable HBV DNA by the Digene Hybrid Capture II assay (Digene Diagnostics Inc., Beltsville, MD) whose recipients developed HBV-related hepatitis was retested with the Cobas Amplicor version 2 (Roche Molecular Systems Inc., Branchburg, NJ) The median HBV DNA of these 6 donors was 112 000 (range 86 000–128 000) copies/mL.

Prophylactic anti-HBV therapy was the only significant and independent factor associated with a reduction in HBV-related hepatitis after HSCT on multivariate Cox regression analysis (p = 0.01, adjusted hazards ratio 7.27, 95%CI 1.62–32.58).

At the time of analysis, 10 of the 29 recipients in group I and 15 of the 25 recipients in group II had died (34.5% vs. 60.0%, p = 0.06 by log-rank; Figure 2C). The causes of death are shown in Table 2. Six of the 25 recipients in group II and none of the 29 recipients in group I died from hepatic failure (24.0% vs. 0%, p = 0.01 by log-rank; Figure 2D). None of the recipients in group I developed HBV-related hepatitis after lamivudine was discontinued.

HBV serological changes after HSCT

Five of the 11 HBsAg negative recipients in group II but none of the 10 HBsAg-negative recipients in group I had HBV-related hepatitis (45.5% vs. 0%, p = 0.03). All 5 HBsAg negative recipients in group II became HBsAg positive after receiving the HBsAg positive marrow (3 sustained and 2 transient; Table 3).

For the HBsAg positive recipients, 1 recipient (5.3%) in group I had HBsAg clearance at 6 months after HSCT. He remained HBsAg negative and anti-HBs positive at a follow-up time of 61.8 months after HSCT.

Of the 6 recipients in the group II with positive anti-HBs, 3 (50%) remained anti-HBs positive after HSCT, whereas those in group I, 6 (75.0%) remained anti-HBs positive at a follow-up time of 61.8 months after HSCT.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Most transplantation units have traditionally regarded HBV infection as a relative contraindication for organ donation (20,21). The use of HBsAg positive donors for HSCT has been shown to be associated with an increased incidence of HBV-related hepatitis and fatal hepatic failure, when compared with the use of HBsAg negative marrow (5,6). However, in places endemic of HBV infection like the Asia-Pacific region, where the prevalence of HBV is more than 10%, a donor with HBsAg positivity is often the only available option (22). Therefore, there is a need to develop a strategy to minimize the risk of using HBsAg positive donors for HSCT in the event that an alternative donor is not available.

In our current study, we have adopted a three-level approach, which consists of pre-HSCT reduction of HBV viral replication in donors by lamivudine, and pre-HSCT enhancement of the recipient's anti-HBV immunity by HBV vaccination, and finally, post-HSCT suppression of HBV viral replication in recipients with lamviudine. Lamivudine was administered to the HBsAg positive donor as their marrow may infect HBsAg negative recipients' hepatocytes and lead to HBV-related hepatitis (23). Indeed, as observed in our historical control group, 48.0% of the recipients developed HBV-related hepatitis after the infusion of HBV infected marrow. With the use of such approach, the incidence of HBV-related hepatitis has been reduced to 6.8% after allogeneic HSCT. This reduction in HBV-related hepatitis is unlikely to be related to the preconditioning HSCT regimen employed as the preconditioning regimen used in our Centre has been standardized according to the primary disease of the recipients.

Despite the suppression of serum HBV DNA in both the donor and recipient to an undetectable level by Digene Hybrid Capture assay II, 2 recipients still developed HBV-related hepatitis post-HSCT. This is likely to be related to the relatively low sensitivity of the Digene Hybrid Capture assay II that has a detection limit of 0.142 × 106 copies/mL. Indeed, by retesting the serum HBV DNA with the Cobas Amplicor HBV Monitor version 2 (Roche Molecular Systems Inc., Branchburg, NJ), the donors' serum of both of these recipients was positive with a level of 108 000 and 86 000 copies/mL, respectively. In the 6 recipients who still developed HBV-related hepatitis despite their donors' having an undetectable HBV DNA by the Digene Hybrid Capture assay II, their donors' serum HBV DNA pre-HSCT was more than 104 copies/mL by Cobas Amplicor version 2. Hence, a more sensitive assay for quantifying serum HBV DNA might be needed for pre-HSCT assessment.

The enhancement of anti-HBV immunity in HBsAg negative recipients is important as anti-HBs positivity has been shown to confer protection against HBV after receiving HBsAg positive marrow (5,8,9). The use of this prophylactic anti-HBV therapy decreased the frequency of HBV-related hepatitis in HBsAg negative recipients from 45.5% to 0%. Whether this is the effect of lamivudine or the vaccine, or both acting synergistically, cannot be determined. We postulate that both the vaccine and lamivudine are important. The anti-HBs positivity and increased anti-HBs titer induced by the vaccine can protect the recipients from being infected by the HBV in the donor's marrow. Continuing lamivudine in these recipients can suppress the replication of HBV in the donor's marrow even after its infusion into the recipient and in the recipients' hepatocytes once it get infected.

A major concern of HBV vaccination is that the efficacy of conventional HBV vaccines in transplantation recipients is unpredictable because of the primary disease of the patients and the heavy immunosuppression. Vaccination with conventional HBV vaccine pre-HSCT only induced anti-HBs positivity in 60% of the recipients in this study. The use of third generation pre-S1/S2 recombinant HBV vaccine, which has been shown to be efficacious even in solid organ transplantation recipients, may enhance the response rate even in this select group of patients (24,25).

As the optimum timing or urgency of HSCT is an important consideration, some of the HBsAg negative, anti-HBs negative recipients received less than 3 doses of the HBV vaccine. However, since none of the HBsAg negative recipients who were vaccinated developed HBV-related hepatitis after HSCT, it is unlikely that the inability to complete the full course of vaccination had an impact on the frequency of HBV-related hepatitis after HSCT.

In our current study, the use of a historical control group is justified as previous observations had shown an unacceptably high incidence of morbidity and mortality associated with the use of HBsAg positive donors. In addition, there were emerging data on the safety and effectiveness of “early” rather than “deferred” pre-emptive lamivudine in decreasing HBV-related hepatitis after HSCT or cytotoxic therapy at the conception of this treatment strategy (26). Furthermore, as mortality can still occur when lamivudine is only started after the occurrence of cytotoxic chemotherapy induced HBV-related hepatitis, we decided to start lamivudine pre-emptively before HSCT (27).

The drawback of this is the cost and prolonged course of lamivudine therapy. As prolonged lamivudine therapy is associated with the development of lamivudine resistance, as seen in one of our recipients, newer antiviral with better resistance profile, such as adefovir dipivoxil or entecavir may be advantageous in this setting. A recent study of adefovir dipivoxil on patients with chronic HBV related liver cirrhosis and lamivudine resistance in the liver transplantation setting demonstrated a decrease in serum HBV DNA levels by 4 log10 copies/mL by week 48 of therapy. This reduction in HBV DNA is maintained to week 96 (28). Therefore, further clinical trials with these agents or combination regimens with at least additivity or preferably synergistic effects are warranted in the HSCT setting (29).

Finally, the use of this prophylactic anti-HBV therapy on living donor transplantation of the kidney or the liver may help to overcome the shortage of solid organ availability in HBV endemic areas. Nucleoside analogues are used to suppress the HBV viral load in the donor before living donor transplantation is performed while HBV vaccination is used to increase the recipient's anti-HBV immunity. However, nucleoside analogues may have to be continued indefinitely in recipients of HBsAg positive liver since the liver is the largest reservoir of HBV. Further clinical trials on the use of prophylactic anti-HBV therapy should be carried out in living solid organ transplantation in order to determine the effectiveness of such therapy in this setting.

In conclusion, prophylactic anti-HBV therapy with lamivudine therapy and HBV vaccination can reduce HBV-related clinical hepatitis and mortality in recipients receiving HBsAg-positive marrow. Using this approach, a more favorable clinical outcome is achievable when HBsAg positive marrow is being used for HSCT when an alternative donor is not available.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Wing-sze Yuen, Crosby Lu. This project was supported with a grant from the Cheng Si-yuan (China-International) Hepatitis Research Foundation (to the University of Hong Kong), China National 973 research grant (G 1999 054105 to G.K.K. Lau).

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References
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