Preemptive Use of Lamivudine Reduces Hepatitis B Exacerbation After Allogeneic Hematopoietic Cell Transplantation George K. K. Lau,1 Ming-Liang He,2 Daniel Y. T. Fong,3 Angeline Bartholomeusz,4 Wing-yan Au,5 Albert K. W. Lie,5 Stephen Locarnini,4 and Raymond Liang5 Exacerbation of hepatitis B virus (HBV) is a serious cause of morbidity and mortality in hepatitis B surface antigen (HBsAg)-positive patients undergoing transplantation. Our aim was to evaluate the effectiveness of lamivudine to prevent hepatitis due to exacerbation of HBV in HBsAg-positive patients treated with allogeneic hematopoietic cell transplantation. We studied 20 consecutive HBsAg-positive recipients of allogeneic hematopoietic cell transplantation who received lamivudine 100 mg daily starting one week before transplantation until week 52 after transplantation (group 1). Serial serum alanine aminotransferase and HBV DNA levels were measured before and after transplantation at 4- to 8-week intervals for the first year and then 4- to 12-week intervals. Their virologic and clinical outcomes were compared with 20 case-matched recipients who did not receive any antiviral therapy to HBV (anti-HBV) before and after hematopoietic cell transplantation (group 2). After transplantation, 9 patients (45%) in group 2 and one patient (5%) in group 1 had hepatitis due to exacerbation of HBV (P < .008), with 3 hepatic failures in group 2 and none in group 1. The one-year actuarial probability of survival without hepatitis due to exacerbation of HBV was higher in group 1 than group 2 (94.1% vs. 54.3%, P ⴝ .002). By multivariate Cox analysis, preemptive use of lamivudine effectively reduced hepatitis due to exacerbation of HBV (adjusted hazards ratio, 0.09; P ⴝ .021). In conclusion, preemptive lamivudine reduced HBV exacerbation. The use of lamivudine with other immunosuppressive regimens to prevent exacerbation of HBV should be further explored. (HEPATOLOGY 2002;36:702-709.)
I
n an endemic area for chronic hepatitis B infection, exacerbation of this virus is a serious cause of morbidity and mortality in patients undergoing cytotoxic or immunosuppressive therapy.1,2 Careful prospective serologic testing has shown that liver damage due to exacer-
Abbreviations: HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; anti-HBV, antibody to hepatitis B virus; PCR, polymerase chain reaction; GVHD, graft-versus-host disease. From the 1Division of Gastroenterology and Hepatology, 5Division of Hematology, Department of Medicine, 2Institute of Molecular Biology, and 3Clinical Trials Centre, University of Hong Kong, Hong Kong Special Administrative Region, China; and 4Victorian Infectious Diseases Reference Laboratory, Fairfield, Victoria, Australia. Received February 27, 2002; accepted June 2, 2002. Supported by 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.L.), and a grant from the Kadoori Charitable Foundation (to R.L.). Address reprint requests to: George K. K. Lau, M.D., University Department of Medicine, Queen Mary Hospital, 102 Pokfulum Rd., Hong Kong SAR, China. E-mail:
[email protected]; fax: (852) 28190694. Copyright © 2002 by the American Association for the Study of Liver Diseases. 0270-9139/02/3603-0023$35.00/0 doi:10.1053/jhep.2002.35068 702
bation of hepatitis B virus (HBV) is a 2-stage process. The initial stage occurs during intense cytotoxic or immunosuppressive therapy and is characterized by enhanced viral replication, as reflected by increases in serum levels of HBV DNA, hepatitis B e antigen, and HBV DNA polymerase, which presumably results in widespread infection of hepatocytes. The second stage is related to restoration of immune function following withdrawal of cytotoxic or immunosuppressive therapy, which causes rapid immune-mediated destruction of infected hepatocytes. Clinically, this may lead to hepatitis, hepatic failure, and even death.3-5 In keeping with these observations, our recent data suggest that a high pretreatment level of serum HBV DNA is the single most important factor for exacerbation of HBV after intense immunosuppression.6 In the past few decades, hematopoietic cell transplantation has been established as the standard treatment of various hematologic and oncologic problems.7 In areas such as Southeast Asia, where HBV infection is prevalent, hematopoietic cell transplantation might be complicated by HBV-related morbidity and mortality.8 The pre– he-
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matopoietic cell transplantation median prevalence of hepatitis B surface antigen (HBsAg)-positive patients has been reported as 1% in American recipients,9 3.5% in European recipients,10 9% in Turkish recipients,11 and 16% in Asian Chinese recipients.6 Hepatic complications related to HBV infection after hematopoietic cell transplantation are mainly related to exacerbation of HBV.12-16 Before the availability of nucleoside analogue therapy for HBV infection, various agents such as interferon,16 prostaglandin E2,14 corticosteroids,15,17-18 and cyclosporine16 were used to treat hepatitis due to exacerbation of HBV after immunosuppression, with largely disappointing results. With the recent introduction of effective antiviral therapy to HBV (anti-HBV) such as lamivudine19,20 and famciclovir,21-23 new treatment options are available for these patients. Both lamivudine24-27 and famciclovir28 have been used to treat hepatitis due to exacerbation of HBV. Despite the use of these antiviral agents, some HBsAg-positive patients still developed hepatic failure and died.24,29 This is probably related to the late institution of the nucleoside analogues when the immune-mediated liver damage has already been established.24 In view of this, a better approach might be to use these nucleoside analogues preemptively, that is, start the nucleoside analogues before the institution of immunosuppression and hence prevent the enhancement of HBV replication in the early immunosuppressive phase.24,30 In this study, we examine the effectiveness of preemptive use of lamivudine in preventing hepatitis due to exacerbation of HBV in HBsAg-positive patients undergoing allogeneic hematopoietic cell transplantation.
Patients and Methods Patients Studied. We studied 2 groups of HBsAgpositive patients who received allogeneic hematopoietic cell transplantation at Queen Mary Hospital (Hong Kong Special Administrative Region, China). Group 1 included 20 consecutive HBsAg-positive patients who received allogeneic hematopoietic cell transplantation from March 1998 to January 2001, and they all received lamivudine 100 mg daily at least one week before allogeneic hematopoietic cell transplantation and continued for 52 weeks after hematopoietic cell transplantation or until their death. Group 2 included 20 HBsAg-positive patients who received allogeneic hematopoietic cell transplantation from August 1991 to February 1998. Because effective anti-HBV nucleoside analogues were not available at that time and interferon therapy is potentially myelotoxic, none of these patients received any specific anti-HBV treatment before and after their allogeneic hematopoietic
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cell transplantation. From our previous study, pretransplant serum alanine aminotransferase level, HBV serology, HBV genotype, and serum HBV DNA level were the variables that might affect posttransplant exacerbation of HBV in HBsAg-positive patients undergoing hematopoietic cell transplantation.6 Hence, in our present study, the patients in group 2 were case matched to those in group 1 in terms of pretransplant serum alanine aminotransferase level, HBV serology, HBV genotype, and serum HBV DNA level. In addition, all patients in our transplant center received a high-dose conditioning regimen (Table 1). This investigation was approved by the Ethics Committee of The University of Hong Kong (Hong Kong Special Administrative Region, China). In accordance with our standard protocols, all donors and recipients for hematopoietic cell transplantation were screened for HBsAg, hepatitis B surface antibody, and human immunodeficiency virus antibody. In addition, all donors and recipients were also screened for hepatitis C virus antibody after July 1993. Pretransplant serum of both donors and recipients collected before July 1993 was retrospectively tested for hepatitis C virus antibody. For all HBsAg-positive donors and recipients, further serologic testing for hepatitis B e antigen, hepatitis B e antibody, and serum HBV DNA by polymerase chain reaction (PCR) was performed within 4 to 8 weeks of marrow harvest or hematopoietic cell transplantation. In addition, all HBsAg-positive pretransplant serum of both donors and recipients collected after December 1995 was tested for HBV DNA by Digene Hybrid Capture II assay (Murex Diagnostics Ltd., Dartford, United Kingdom) within 4 to 8 weeks of marrow harvest or hematopoietic cell transplantation. All HBsAg-positive pretransplant serum of both donors and recipients collected before December 1995 was tested retrospectively for HBV DNA by Digene Hybrid Capture II assay. The precore and core promoter HBV DNA sequences for all HBsAg-positive marrow donors and recipients were also determined by direct DNA sequencing. The hematopoietic cell transplantation recipients of both groups underwent liver function tests (including serum alanine aminotransferase, serum albumin, and bilirubin) and hepatitis B serology (HBsAg, hepatitis B e antigen, hepatitis B e antibody, and HBV DNA by Digene Hybrid Capture II assay) at the following intervals: once a week for the first 12 weeks immediately after transplantation, every 4 to 8 weeks until 52 weeks after transplantation, and then every 4 to 12 weeks until their last evaluation or death. The occurrence of hepatic events (acute hepatitis, chronic hepatitis, anicteric and icteric hepatitis, hepatic failure, veno-occlusive disease, hepatic
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Table 1. Patients Studied Group 1 (n ⴝ 20)
Group 2 (n ⴝ 20)
Preemptive use of lamivudine Yes No Median age (yr) (range) 38.5 (13-54) 32.0 (5-48) Sex Male 10 (50%) 16 (85%) Female 10 (50%) 4 (15%) No. with elevated pre-HCT ALT 4 (20%) 4 (20%) Median pre-HCT ALT (IU/L) (range) 31.5 (1-102) 24 (10-86) Underlying hematologic diseases Acute myeloid leukemia 8 (40%) 4 (20%) Chronic myeloid leukemia 5 (25%) 10 (50%) Others 7 (35%) 6 (30%) Conditioning regimen Bu-Cy 12 (60%) 11 (55%) Bu-Cy-TBI/Cy-TBI 6 (30%) 9 (45%) Others 2 (10%) 0 (0%) Prophylaxis against GVHD Short MTX ⫹ CSP 20 (100%) 20 (100%) Recipient HBV serology HBeAg positive 4 (20%) 4 (20%) anti-HBe positive 16 (80%) 16 (80%) HBV DNA positive‡ 9 (45%) 9 (45%) HBV genotype B 6 (30%) 6 (30%) C 10 (50%) 10 (50%) Others 4 (20%) 4 (20%) HBV DNA n (range) 3 (5-20) 3 (10-18) Mean ⫾ SD 10.0 ⫾ 8.7 12.7 ⫾ 4.6 Donor HBV serology HBsAg positive 9 (45%) 5 (25%) (HBeAg positive/anti-HBe positive/ HBV DNA positive)‡ (2/7/3) (3/2/3) Anti-HBs positive 4 (20%) 6 (30%) Anti-HBc positive 3 (15%) 4 (20%) HBV negative㛳 7 (35%) 9 (45%) HBV DNA n (range) 9 (5-220) 9 (2-330) Mean ⫾ SD 58.9 ⫾ 75.7 70.2 ⫾ 104.7
P
.037* .096†
1.000† .23* .238†
.348†
1.000† 1.000† 1.000† 1.000† 1.000†
.670§ .320†
.716† 1.000† .748†
.796§
Abbreviations: HCT, hematopoietic cell transplantation; ALT, alanine aminotransferase; Bu, busulfan; Cy, cyclophosphamide; TBI, total body irradiation; MTX, methotrexate; CSP, cyclosporine; HBeAg, hepatitis B e antigen; anti-HBe, antibody to hepatitis B e antigen; anti-HBs, antibody to hepatitis B surface antigen; anti-HBc, antibody to hepatitis B core antigen. *Wilcoxson rank sum test. †Fisher exact test. ‡Digene Hybrid Capture II assay. §Two independent sample t tests. 㛳Donors tested negative for serum HBsAg, anti-HBs, anti-HBc, and HBV DNA (by PCR).
graft-versus-host disease [GVHD]), and death were recorded. Definition of Hepatic Events. Hepatitis was defined as a more than 3-fold increase in serum aminotransferase levels on 2 consecutive determinations at least 5 days apart in the absence of clinical features suggestive of veno-occlusive disease, GVHD, or infection by cytomegalovirus or herpes simplex virus. Icteric hepatitis was defined as hepatitis associated with clinical jaundice and a serum
bilirubin level that exceeded 30 mol/L (normal, ⬍19 mol/L). Hepatitis was defined as acute if the duration was less than 6 months and chronic if the duration was more than 6 months. Hepatitis was defined to be due to exacerbation of HBV when preceded or accompanied by an elevation of serum HBV DNA to more than 10 times that of the pre-exacerbation baseline, the serum HBV DNA turned from negative to positive, or the hepatitis B e antigen became positive and remained so for 2 consecutive readings 5 days apart. Histologic evidence of reappearance or enhancement of active necroinflammation was not obtained in our patients because most of our patients had thrombocytopenia and percutaneous liver biopsy carried an increased risk. Moreover, from our previous experience, hepatic histologic proof of reappearance or enhancement of active necroinflammation (obtained by transjugular liver biopsy) was not necessary if there was a more than 3-fold elevation of serum aminotransferase level on 2 consecutive determinations at least 5 days apart in the absence of clinical features suggestive of veno-occlusive disease, GVHD, or infection by cytomegalovirus or herpes simplex virus. In our present study, hepatic failure was defined as the presence of hepatic encephalopathy and deranged blood coagulation (prothrombin time prolonged for more than 10 seconds). Veno-occlusive disease was defined and graded as described by McDonald et al.,31 and acute GVHD of the liver was defined and graded in accordance with the Glucksberg criteria.32 Hepatitis Serology and HBV DNA Quantitative Assay. Hepatitis B serologic markers, including HBsAg, hepatitis B surface antibody, hepatitis B e antigen, hepatitis B e antibody, hepatitis C virus antibody (EIA II), anti– hepatitis D antibody, and human immunodeficiency virus antibody, were tested by commercially available enzyme immunoassays (Abbott Laboratories, Chicago, IL). Hepatitis B core antibody was tested by radioimmunoassay (Corab; Abbott Laboratories). For the quantitation of serum HBV DNA level, Digene Hybrid Capture II assays were used. Serum stored at ⫺70°C was tested, and serial serum samples from the same individual patient were tested within a single run to minimize interassay variation. The results were expressed in picograms per milliliter, with the manufacturer’s stated cutoff for detecting HBV viremia in clinical specimens of 0.5 pg/mL or 0.142 ⫻ 106 copies/mL.6 A nested PCR assay for the detection of serum HBV DNA was performed using primer sets from the HBV surface antigen and the core antigen coding region.6 Reverse-transcription nested PCR was used to detect HCV, whereas direct sequencing was used to determine the presence of precore (A1896) and basal core promoter (T1762/A1764) variants of HBV as described previously.6
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Determination of HBV Polymerase Gene by Direct PCR Sequencing. Oligonucleotides were synthesized by Geneworks (Adelaide, Australia). For amplification of the polymerase gene, the sense primer was 5⬘-GCC TCA TTT TGT GGG TCA CCA TA -3⬘ (nucleotides ⫺40 to ⫺21) and the antisense primer was 5⬘-TCT CTG ACA TAC TTT CCA AT -3⬘ (nucleotides 2831 to 2847). Each reaction was performed using 5 L of the extracted DNA as template, 1.5 U of Taq polymerase (Perkin Elmer Cetus, Norwalk, CT), 1 mol/L of sense and antisense primers, 200 mol/L each of deoxynucleoside triphosphates, 50 mmol/L KCl, 3.5 mmol/L MgCl, 10 mmol/L Tris-HCl (pH 8.3), and 0.01% gelatin. Amplification was achieved by 40 cycles of denaturation (94°C for 1 minute), annealing (55°C for 1 minute), and extension (72°C for 1.5 minutes) followed by a final extension of 7 minutes (Perkin-Elmer Cetus). A further heminested round of amplification was performed, if required, using 2 L of first-round product as template and the sense primer 5⬘- CAC AAC ATT CCA CCA AGC T -3⬘. The amplification conditions were the same as the first round of amplification, with only 25 rounds of cycling. The PCR product was analyzed by gel electrophoresis through 1.5% agarose and visualized by UV irradiation after staining with ethidium bromide. The specific amplified product was purified using PCR purification columns from MO BIO Laboratories Inc. (Solana Beach, CA) and directly sequenced using Big Dye terminator cycle sequencing Ready Reaction Kit (Perkin Elmer Cetus). The antisense PCR primer was used as a sequencing primer as well as an internal primer 5⬘AAA TTC GCA GTC CCC AAA –3⬘ to sequence the entire polymerase catalytic domain. Statistical Analysis. The 2 test or Fisher’s exact analysis was used to compare the baseline characteristics, hepatic events (acute hepatitis, chronic hepatitis, and hepatic failure), serologic outcome, and death among patients in groups 1 and 2. Relative hazard of hepatitis due to exacerbation of HBV in patients treated preemptively with lamivudine (group 1) to those without any preemptive anti-HBV treatment (group 2) was examined using the proportional hazards model. Independent factors such as the recipient’s sex, age, presence of precore and basal core promoter variants, preemptive lamivudine therapy, recipient’s serum HBV DNA level before hematopoietic cell transplantation, donor’s serum HBV DNA level before hematopoietic cell transplantation, and HBV serology were individually examined in relationship to hepatitis due to exacerbation of HBV after hematopoietic cell transplantation in a simple Cox proportional hazards regression analysis. Important determinants among these factors were also explored by a Cox proportional hazards
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regression model together with a forward stepwise variable selection procedure. This selection procedure was chosen because it is one of the most widely used and accepted automatic search methods for the best model. The validity of all Cox proportional hazards models was examined by checking the corresponding martingale and deviance residuals. Kaplan-Meier curves for estimating cumulative survivals and 95% confidence intervals for all estimates were also provided where appropriate. P values less than an ␣ of .05 (probability of type I error) were considered to be significant throughout this study. Statistical analyses were performed using the SAS Release 8.02 system in Windows 2000.
Results Comparison of Baseline Characteristics of Groups 1 and 2. There were no differences between groups 1 and 2 in sex, underlying hematologic diseases, conditioning regimen, prophylaxis against GVHD, and donor HBV serology and serum HBV DNA level at marrow harvest (Table 1). Hepatitis Due to Exacerbation of HBV After Allogeneic Hematopoietic Cell Transplantation. After hematopoietic cell transplantation, there were significantly more episodes of hepatitis and hepatitis due to exacerbation of HBV in group 2 than group 1 (Table 2). The onset of hepatitis was 252 days for patients in group 1 and 116.7 ⫾ 166.8 days for patients in group 2 (P ⫽ NS). The single patient in group 1 who had hepatitis due to exacerbation of HBV developed mutations in the polymerase gene related to lamivudine, namely at M204V and L180M,33 preceding the hepatitis (Fig. 1). Of the remaining 19 patients in group 1, only 7 were found to be HBV Table 2. Hepatic Events After Allogeneic Hematopoietic Cell Transplantation Clinical Events
Hepatitis No. of hepatitis events Transient/persistent Anicteric/icteric/hepatic failure Cause of hepatitis HBV exacerbation related Clearance of HBsAg/HBeAg Relapse Infection Hepatic GVHD Veno-occlusive disease Death Cause of death Hepatic failure/relapse/sepsis
Group 1 (n ⴝ 20)
Group 2 (n ⴝ 20)
P*
8 (40%) 8/0 7/1/0
16 (80%) 12/4 8/5/3
.023 .262 .242
1 (5%) 4 (20%) 0 (0%) 3 (15%) 3 (15%) 7 (35%) 3 (15%)
9 (45%) 5 (25%) 1 (5%) 1 (5%) 9 (45%) 14 (70%) 9 (45%)
.008 1.000 1.000 .605 .082 .056 .082
0/3/0
2/6/1
1.000
Abbreviation: HBeAg, hepatitis B e antigen. *Fisher exact test.
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DNA positive by PCR at week 52 and none had developed mutations in the HBV polymerase gene. Two patients (10.0%) in group 1 experienced hepatitis after withdrawal of lamivudine, and both responded to retreatment with lamivudine. Of the 9 cases of hepatitis due to exacerbation of HBV in group 2, 5 were anicteric hepatitis, one was icteric hepatitis, and 3 were hepatic failure, whereas the single patient in group 1 had icteric hepatitis. Survival After Allogeneic Hematopoietic Cell Transplantation. The 1-year actuarial probability of survival without hepatitis due to exacerbation of HBV was higher in group 1 than group 2 (94.1% vs. 54.3%; P ⫽ .002). In simple Cox proportional hazards regression analysis, only preemptive lamivudine therapy (Fig. 2) effectively reduces hepatitis due to exacerbation of HBV in HBsAg-positive patients treated with allogeneic hematopoietic cell transplantation (Table 3). Cox proportional hazards regression of all factors with the forward stepwise selection procedure did not show additional significant factors, such as recipient’s precore A1896, basal core promoter T1762/A1764, HBV genotype, serum HBV DNA, donor’s serum HBV DNA, and HBV serology, of hepatitis due to exacerbation of HBV. Marrow Engraftment and Adoptive Clearance of HBsAg After Allogeneic Hematopoietic Cell Transplantation. The mean time of marrow engraftment was similar in group 1 (22.4 days; SEM, 6.5 days) and group 2 (24 days; SEM, 5.0 days). There were 4 cases of hepatitis in group 1 and 5 cases of hepatitis in group 2 that were related to serologic clearance of HBsAg. Serologic clear-
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Fig. 2. Cumulative survival without hepatitis due to exacerbation of HBV after allogeneic hematopoietic cell transplantation in accordance with preemptive use of lamivudine. The cumulative probability of hepatitis for HBsAg-positive patients treated preemptively with lamivudine (group 1) and case-matched historical control (group 2) were constructed based on the time to hepatitis due to exacerbation of HBV. The number at risk refers to the number of patients who were still at risk for hepatitis due to exacerbation of HBV at the corresponding time after allogeneic hematopoietic cell transplantation. The dots (●, group 1; E, group 2) correspond to the occurrences of hepatitis due to exacerbation of HBV. Patients treated with lamivudine had significantly lower risk of hepatitis due to exacerbation of HBV (relative hazard, 0.08; P ⫽ .016).
ance of HBsAg was sustained in all 4 patients (100%) in group 1 but in only 2 patients (40%) in group 2 (P ⫽ .167). The median time of serologic clearance was 93.4 ⫾ 72.6 days in group 1 and 71.8 ⫾ 62.5 days in group 2 (P ⫽ .65).
Discussion
Fig. 1. A patient in group 1 who had hepatitis due to exacerbation of HBV. The occurrence of HBV virologic exacerbation was preceded by the development of dual mutations of M204V and L180M at the HBV polymerase gene (at week 28) associated with lamivudine resistance. This was followed by biochemical exacerbation with elevation of serum alanine aminotransferase level that peaked at 566 IU/L. The hepatitis subsequently resolved spontaneously.
Hepatitis B due to exacerbation of HBV is a serious cause of morbidity and mortality in HBsAg-positive patients undergoing allogeneic bone marrow transplantation. Because these episodes of hepatitis are preceded by a substantial increase in HBV replication during the immunosuppression phase, a rational approach to patient management would include the use of specific nucleoside analogues that selectively block HBV replication. Previously, we have obtained encouraging results in this clinical setting using famciclovir, an anti– herpes virus agent that has moderate anti-HBV activity.21-23 However, some patients still experienced hepatitis due to exacerbation of HBV, indicating only partial antiviral suppression.30 Lamivudine is a more potent anti-HBV agent than famciclovir,34 and a recent uncontrolled smaller study has shown that the use of primary prophylaxis with lamivu-
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Table 3. Cumulative Survival Without Hepatitis Due to Exacerbation of HBV Cox Proportional Hazards Regression Analysis of All Factors With a Forward Stepwise Selection Procedure
Cox Proportional Hazards Regression Analysis of Individual Factor
Factor
Preemptive use of lamivudine Yes No Sex Female Male Age Precore A1896 variants present Yes No Basal core promoter T1762/A1764 variant present Yes No HBV genotype C B Recipient HBV DNA Positive Negative Donor HBV DNA Positive Negative Donor HBV serology* Donor HBsAg Positive Negative Donor HBV negative† Yes No
Hazard Ratio
Adjusted Hazard Ratio
95% CI
P
.016
0.09 1
(0.01, 0.69) —
.021
(0.03, 1.66)
.139
—
—
—
(0.93, 1.03)
.418
—
—
—
3.20 1
(0.85, 11.99)
.085
—
—
—
0.41 1
(0.08, 1.95)
.260
—
—
—
2.32 1
(0.67, 42.60)
.115
—
—
—
2.62 1
(0.73, 9.38)
.138
2.69 1
(0.69, 10.50)
.153
—
—
—
0.47 1
(0.14, 1.64)
.238
—
—
—
0.53 1
(0.15, 1.85)
.320
—
—
—
95% CI
P
0.08 1
(0.01, 0.62)
0.21 1 0.98
Abbreviations: anti-HBs, antibody to hepatitis B surface antigen; anti-HBc, antibody to hepatitis B core antigen. *Cox regression for anti-HBs–positive donors was not performed because no recipients with anti-HBs–positive donors had hepatitis due to exacerbation of HBV after hematopoietic cell transplantation. †Donors tested negative for serum HBsAg, anti-HBs, anti-HBc, and HBV DNA (by PCR).
dine was well tolerated and may be a more effective approach to reduce the frequency of chemotherapy-induced exacerbation of HBV in HBsAg-positive patients.35,36 In our present case-controlled study, using simple Cox proportional hazards regression analysis, only preemptive lamivudine therapy was shown to effectively reduce episodes of hepatitis due to exacerbation of HBV in HBsAgpositive patients treated with allogeneic hematopoietic cell transplantation. Other HBV virologic factors such as recipient’s HBV precore A1896 variants, basal core promoter T1762/A1764, HBV genotype C, HBV DNA level, donor’s serum HBV DNA level, and HBV serology were not additional significant factors of hepatitis due to exacerbation of HBV. This is in keeping with our previous observation that a high serum HBV DNA level before hematopoietic cell transplantation is the most significant HBV virologic factor predictive of hepatitis due to exacerbation of HBV after hematopoietic cell transplantation.6
Previously, lamivudine has been associated with red cell aplasia.37 However, in our present study, there was no significant adverse event associated with the use of preemptive lamivudine. Most importantly, marrow engraftment was not affected. This is in contrast to interferon, which is myelotoxic.38 In fact, the rate of serologic clearance of HBsAg due to adoptive immunity transfer from HLA-identical siblings marrow with natural immunity39 against HBV was not affected. All patients in group 1 had sustained clearance of HBsAg after hematopoietic cell transplantation, whereas one half of the patients in group 2 who had serologic clearance of HBsAg were not sustained, suggesting that treatment with lamivudine enhanced the adoptive clearance of HBsAg. This is in keeping with earlier observations that lamivudine could partially restore the CD4-positive T-cell responsiveness toward HBV by reducing the HBV viral load.40 The lack of statistical difference found in this study might be due to the small number of patients involved.
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Two HBsAg-positive patients (12.5%) had hepatitis due to HBV after withdrawal of 52 weeks of treatment with lamivudine. Both patients were still on low-dose immunosuppressive therapy for chronic GVHD, suggesting that treatment with lamivudine should be prolonged in these patients. However, lamivudine-withdrawal hepatitis can occur in up to 20% of patients within 6 months of stopping therapy.41 Importantly, in both patients, hepatitis resolved on resumption of lamivudine therapy. One of the shortcomings of the use of lamivudine monotherapy is the occurrence of resistance, which increases with the duration of therapy; 15%, 38%, 49%, and 67% in the first, second, third, and fourth years, respectively.42 In our present study, one patient treated with lamivudine had icteric hepatitis due to exacerbation of HBV at week 40. This was preceded by the emergence of dual mutations of rtM204V and rtL180M in the HBV polymerase gene, confirming the potential pathogenicity of some strains of lamivudine-resistant HBV.43,44 Following the lessons learned from treating human immunodeficiency virus infection, resistance typically develops as a result of ineffective suppression of viral replication (i.e., no resistance with no replication).45 Hence, the use of more potent nucleoside analogues, ideally in combination regimens with at least additivity or preferably synergistic effects, should be considered for these patients in the future.45,46 Acknowledgment: The authors thank Yuen Wing Sze, R.N., and Amy Kwok, R.N., for their assistance in data management.
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