SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References

Hepatitis B virus (HBV) recurrence after liver transplantation is significantly reduced by prophylaxis with hepatitis B immune globulins (HBIG) or antiviral drugs in nonreplicating patients and by the combination of both drugs in replicating patients. However, the load of HBV DNA, which defines replicating status in patients undergoing liver transplantation, remains unclear. This study analyzes the correlation between the viral load, tested with a single amplified assay, at the time of liver transplantation, and the risk of hepatitis B recurrence in 177 HBV carriers who underwent transplantation in a single center from 1990 to 2002. Overall, HBV relapsed after surgery in 15 patients (8.5%) with a 5- and 8-year actuarial rate of recurrence of 8% and 21%, respectively. After liver transplantation hepatitis B recurred in 9% of 98 selected subjects treated only with immune globulins and in 8% of 79 viremic patients who received immune globulins and lamivudine (P = NS). A linear correlation was observed between recurrence and viral load at the time of surgery. In transplant patients with HBV DNA higher than 100,000 copies/mL, 200–99,999 copies/mL, and DNA undetectable by amplified assay, hepatitis B recurred in 50%, 7.5%, and 0% of patients, respectively. Overall, a viral load higher than 100,000 copies/mL at the time of liver transplantation was significantly associated with hepatitis B recurrence (P = .0003). In conclusion, spontaneous or antiviral-induced HBV DNA viral load at the time of surgery classifies the risk of HBV recurrence after liver transplantation and indicates the best prophylaxis strategy. (Liver Transpl 2005;11:402–409.)

In the last 10 years clinical practice for liver transplantation (LT) in hepatitis B surface antigen (HBsAg)-carriers has been influenced by innovative treatment options. The introduction of high doses of hepatitis B immune globulins (HBIG) or of lamivudine (LAM) as post-LT mono-prophylaxis has reduced the risk of hepatitis B recurrence to a variable cumulative rate ranging between 10% and 50%. During prophylaxis with LAM or HBIG a strict correlation between hepatitis recurrence and hepatitis B virus (HBV) DNA load at the time of surgery has been found, which is related to the emergence of viral mutants that are unresponsive to therapy, such as surface antigen (HBsAg) mutants and tyrosine-methionine-aspartate-aspartate (YMDD)-mutants.1–5 Moreover, neither HBV recurrence nor graft failure have been observed in patients with HBV DNA undetectable by polymerase chain reaction at the time of surgery and treated with HBIG.6

The risk of hepatitis B recurrence can be reduced to less than 10% by using LAM before and after LT, in association with HBIG.7–13 Moreover, although LAM therapy before transplantation can improve liver function and decrease mortality,14 long-term antiviral therapy can select YMDD mutants whose management needs the use of alternative drugs, such as adefovir dipivoxil (ADV), to reduce HBV recurrence after LT.15–19

However, a variety of issues still remain controversial. In particular, doubts remain as to what virological status has to be achieved in patients undergoing LT and which HBV DNA assays have to be performed. This study analyzes 177 HBsAg carriers who underwent transplantation in a single center between 1990 and 2002 with the aim of evaluating the prognostic role of the HBV DNA viral load at the time of surgery on the risk of hepatitis B recurrence.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References

Patients

One thousand LTs were performed at the San Giovanni Battista Hospital in Turin, Italy, between October 1990 and December 2002. One hundred seventy-seven HBsAg-positive cirrhotic patients survived more than 60 days after surgery and were included in this study. Cirrhosis was related to HBV alone or associated with different co-infections by hepatitis C virus (HCV) or hepatitis D virus (HDV) (Table 1). No patients with fulminant hepatitis and human immunodeficiency virus (HIV) infection were considered in our series.

Table 1. Clinical Features of 177 Patients at the Time of Enrollment on the Waiting List
 Viral infections in HBsAg carriers who underwent transplantationTotal
HBVHDVHBCHDC
  1. Abbreviations: HBV, hepatitis B virus; HDV, hepatitis delta virus; HBC, hepatitis B virus and hepatitis C virus coinfection; HDC, hepatitis delta virus and hepatitis C virus coinfection; HCC, hepatocellular carcinoma.

Number of patients9862116177
Male/Female88/1044/1810/14/2146/31
Age, years, median (range)49 (25–62)46 (24–61)51 (37–62)43 (38–51)48 (24–62)
HBV DNA-positive by non-amplified assay (≥5 Log10)6264173
HBV DNA-positive by amplified assay (2–5 Log10)23264255
HBV DNA-negative by amplified assay (<2 Log10)13303349
HBeAg positive1440119
Anti-HBe positive7646104136
HBe status unknown8121122
HCC44182266

The data analysis was carried out from the time of enrollment on the LT waiting list until the study closure date (December 31, 2002) or death. The data of patients lost to follow-up before study closure were included until the day they were last known to be alive, and this was considered their last day of follow-up.

Immunosuppressive Therapy

Immunosuppressive therapy changed according to the year of transplantation. Between 1990 and 1995 the immunosuppressive regimen consisted of cyclosporine, steroids, and azathyoprine. Steroids were gradually discontinued at 6 to 12 months after LT, and azathyoprine was stopped after 1 year or earlier if side effects (leucopenia) were present. After 1996 steroids were discontinued at 3 to 6 months, and tacrolimus was introduced as rescue therapy for steroid-resistant rejection or as primary therapy in selected patients.

Human HBV-Specific Immune Globulins

Prophylactic infusion of human HBIG (Hepatect, Biotest, Milan, Italy; Venbig, Farma-Biagini and Kedrion, Lucca, Italy) was administered intravenously to all patients who underwent transplantation as reported here below. During the peri-operative period we administered a total mean dose of 50,000 IU (subdivided into 10,000 IU during the anahepatic phase, 10,000 IU on the first postoperative day, and 5,000 IU daily for the next 6 postoperative days), followed by 500 IU weekly during the first month and 5,000 IU thereafter, every 2 to 4 weeks, in order to maintain the anti-HBs titer above 500 IU/L for the first 3 months.

Afterwards, a dose of 5,000 IU of HBIG was given routinely over the long term with the aim of keeping titers above 100 IU/L. Overall, a mean load of 5,000 IU monthly was used.

Pre-emptive Therapy and Post-LT Prophylaxis

Mono-prophylaxis Group

Ninety-eight patients did not receive LAM or adefovir before LT and were treated only with specific immune globulins indefinitely after surgery. No patient received LAM alone after surgery.

Combined Prophylaxis Group

From August 1996 onwards, seventy-nine patients were treated before and after LT with lamivudine (Zeffix, Glaxo Wellcome, Greenford, United Kingdom). The daily oral dose was of 100 to 300 mg before surgery and 100 mg afterwards. Before LT, patients received LAM for a mean period of 252 days (range 10–1,670). Moreover, in 6 of these patients (treated with LAM before LT for a mean of 1,148 days, range 822–1,670) Adefovir Dipivoxil (Gilead Sciences, Inc., Foster City, CA) was associated with LAM before and after LT, because of the evidence of LAM-resistant HBV mutants and HBV DNA breakthrough. Adefovir was administered at the oral dose of 10 mg daily, although this could be reduced to 5 mg or suspended in the case of nephrotoxicity or adverse events.

After LT, patients received the antiviral therapy used before surgery together with HBIG indefinitely. Some of these patients have been described previously.8, 17

The different protocols were in conformity with the ethical guidelines of 1975 Declaration of Helsinki, and informed consent was obtained from each patient before treatment.

Assays and Definitions

Assays

Virological and clinical data were collected at the time of enrollment on the LT waiting list, then every 3 months before surgery, at the moment of transplant, every month for the first 6 months after surgery, and subsequently every three months.

The serological markers of HBV were detected by radioimmuno assays (AUSRIA II and HBe Kit; Abbott Laboratories, North Chicago, IL). The titer of anti-HBs antibodies was measured by enzyme immunoassay (AB AUK 3, Sorin Biomedica, Saluggia, Italy). The HCV antibody was detected by a second-generation enzyme immunoassay (Ortho Diagnostic System, Milan, Italy). The total antibodies to HDV were determined by a commercial radioimmunoassay (Sorin Biomedica). At the time of referral and during pre-LT monitoring HBV DNA was tested by a nonamplified assay until 1996. Thereafter, HBV DNA-negative patients were tested first with a homemade, and then with a commercial, polymerase chain reaction (PCR) assay (COBAS Amplicor HBV Monitor, Roche, Branchburg, NJ). LAM-resistant mutants were evaluated with a commercial kit (Inno-LiPa HBV DR, Innogenetics NV, Ghent, Belgium).20

In relation to the aim of the study, the HBV DNA load at the time of LT was retrospectively analyzed in all patients with an amplified quantitative HBV DNA assay (COBAS Amplicor, sensitivity of 200 copies/mL) in stocked sera.

Definition

HBV recurrence was defined as the reappearance in the serum of HBsAg after LT.21

Statistical Analysis

Statistical analyses were performed by using the SPSS 10 statistical software (SPSS Inc. and Microsoft Corp., Chicago, IL).

Student's test, the chi-square test, Fisher's exact test, and the Wilcoxon procedure were used as appropriate to compare categorical and continuous variables. The Pearson correlation coefficient was calculated to investigate the relationships between continuous variables.

The univariate analysis to determine the predictive factors of HBV recurrence was performed using the Kaplan-Meier method and the log-rank test. A large series of variables were analyzed: hepatocellular carcinoma, viral infection (HBV or coinfections), HBeAg positivity, anti-HBe positivity, LAM therapy, days of LAM therapy, acute rejection episodes, HBV DNA load at enrollment on the waiting list, at admission and at the time of liver transplantation. For qualitative variables, patients were grouped according to the presence or absence of each variable. For quantitative variables, the cutoff level chosen was their median value. Variables reaching statistical significance in the univariate analysis were then included in a step-wise Cox regression analysis to identify the independent predictive factors of HBV recurrence after LT. A P value of less than 0.05 was considered statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References

After liver transplantation, patients were followed up for a median time of 1,328 days (44 months), with a range of 63 to 3,906 days.

Eleven patients (6%) died after LT; in 4 of them (36%), death was related to HBV recurrence complicated by liver failure occurring between 10 and 40 months (median time 20 months) after LT.

Overall, hepatitis B relapsed in 8.5% of the HBsAg carriers who underwent transplantation (15 of 177), with a 5- and 8-year actuarial risk of 8% and 21%, respectively. Recurrence occurred in 9 (9%) of 98 patients receiving mono-prophylaxis therapy and in 6 (8%) of 79 patients of the combined prophylaxis group after surgery (P = NS) (Table 2 and Fig. 1). In the combined group none of the subjects who experienced the hepatitis B recurrence had evidence of LAM-resistant HBV mutants and HBV DNA breakthrough at the time of transplantation or needed adefovir therapy for YMDD mutants before surgery.

Table 2. Antiviral Therapy Before Surgery and Clinical Outcome After Liver Transplantation in Different Infectious Groups
 Median HBV DNA at time of LT copies/mLNumber of Patients
HBVHDVHBCHDCTotal
  1. Abbreviations: HBV, hepatitis B virus; HDV, hepatitis delta virus; HBC, hepatitis B virus and hepatitis C virus coinfection; HDC, hepatitis delta virus and hepatitis C virus coinfection.

Overall3009862116177
HBV recurrence (%)300,00012 (12)03 (27)015 (8.5)
HBV recurrence free230866286162
Mono-prophylaxis group (% HBV recurrence)25336 (17)48 (0)9 (33)5 (0)98 (9)
Combined prophylaxis group (% HBV recurrence)36062 (9.6)14 (0)2 (0)1 (0)79 (8)
thumbnail image

Figure 1. Actuarial risk of hepatitis B recurrence after LT in 98 patients treated only with HBIG after surgery (mono-prophylaxis group) and in 79 subjects treated with LAM and immune globulins (combined prophylaxis group).

Download figure to PowerPoint

The retrospective quantitative analysis of HBV DNA levels by PCR assay showed an overall median viremia at the time of LT of 300 copies/mL (mean 227,293 copies/mL), ranging from an undetectable value to 16,500,000 copies/mL. The HBV DNA median value was 253 copies/mL (mean 378,496 copies/mL; range 199–16,500,000 copies/mL; SD ± 1,834,505) in the 98 patients of the mono-prophylaxis group and 360 copies/mL (mean 39,724 copies/mL; range 199–1,900,000 copies/mL; SD ± 219,422) in the 79 subjects of the combined prophylaxis group (P = NS) (Table 2).

A linear correlation between the levels of HBV DNA at the time of LT and risk of HBV recurrence was observed, particularly in the mono-prophylaxis group (Fig. 2A-B).

thumbnail image

Figure 2. Correlation between arbitrary groups of HBV DNA loads by PCR COBAS at the time of liver transplant and rate of HBV recurrence in monotherapy group (A) and in combined prophylaxis group (B).

Download figure to PowerPoint

  • Patients with HBV recurrence had a median viral load of 300,000 copies/mL (mean 1,793,847 copies/mL; range 350–16,500,000 copies/mL; SD ± 4,186,246) vs. 230 copies/mL (mean 82,241 copies/mL range 199–6,000,000 copies/mL, SD ± 555,352) in subjects without HBV recurrence (P = 0.0002).

  • Patients with HBV DNA ≥ 100,000 copies/mL at moment of LT had a rate of HBV recurrence of 50% (9 of 18 patients), which is significantly higher than the rate of 4% found in the patients with lower HBV DNA levels (6 of 159 patients) (P = 0.0003) (Fig. 3). Post-LT hepatitis B recurred in 8 (53%) of the 15 highly viremic patients treated only with mono-prophylaxis after LT, and in one of the 3 subjects of this group treated with the combined therapy (in these patients LAM was used before LT for a median time of 56 days, ranging between 13 and 150 days).

  • Conversely, hepatitis B recurred in none of the 79 patients (34 in the mono- and 45 in the combined prophylaxis group) who underwent a transplantation with a spontaneous or antiviral-induced undetectable viral load at the time of surgery.

  • In patients with a positive viral load below 100,000 copies/mL the rate of HBV recurrence was 7.5%. In this subgroup HBV recurred in 5 patients in the combined group (treated with LAM for a mean of 185 days, range 80–270, before LT) and in only one subject treated with mono-prophylaxis (P = 0.008) (Table 3 and Fig. 4).

thumbnail image

Figure 3. Risk of hepatitis B recurrence after LT in patients with HBV DNA load (COBAS PCR) higher or lower than 100,000 copies/mL at the time of surgery.

Download figure to PowerPoint

Table 3. HBV Recurrence After LT in 177 Patients Analyzed in the Basis of the Viral Load (COBAS) at the Time of Surgery, Post-Liver Transplantation Prophylaxis (Combined or Mono-prophylaxis) and Viral Co-infections
 HBV DNA at LT copies/mL
<200200–99,999≥100,000Total
CombMonoCombMonoCombMonoCombMono
  1. Abbreviations: Comb, combined prophylaxis; Mono, monoprophylaxis; N. rec, number of post-liver transplantation hepatitis B recurrence; pts, patients; HBV, hepatitis B virus; HDV, Hepatitis delta virus; HBC, hepatitis B virus and hepatitis C virus co-infections; HDC, hepatitis delta virus and hepatitis C virus co-infections.

HBV        
 Total pts23153612396236
 N. rec (%)005 (14)1 (8)1 (33)5 (55)6 (10)6 (17)
HDV        
 Total pts1024423011448
 N. rec (%)0000000
HDC        
 Total pts04110015
 N. rec (%)00000
HBC        
 Total pts12120529
 N. rec (%)00003 (60)03 (33)
Total        
 Total pts344542383157998
 N. rec (%)005 (12)1 (3)1 (33)8 (53)6 (8)9 (9)
thumbnail image

Figure 4. Actuarial risk of hepatitis B recurrence free after LT in patients with HBV DNA < 100,000 copies/mL (COBAS PCR) at the time of surgery, treated only with immune globulins (mono-prophylaxis group, Mono) or with immune globulins and LAM (combined prophylaxis group, Comb) after surgery.

Download figure to PowerPoint

Among the variables analyzed, only four (type of viral infection, HBeAg status, anti-HBe status, and HBV DNA load at the time of LT) correlated with the rate of post-LT HBV recurrence in the univariate analysis (P < 0.05 for all variables). In the multivariate analysis obtained using a stop-wise Cox regression model only the HBV DNA load by COBAS at the time of surgery was significantly associated with post-LT hepatitis B recurrence, which shows that it has an independent predictive value in this setting (P = 0.001, hazard ratio 5.93; 95% CI 2.01–17.52).

Discussion

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References

This study analyzes the risk of HBV recurrence after LT in 177 HBsAg carriers who underwent transplantation in a single Italian center. Overall, the HBV recurrence rate was low (8.5%), confirming that with correct selection the HBsAg carrier condition had become one of the best indications to LT in the late 1990s.

In this study the rate of HBV recurrence was strongly influenced by the Center's criteria during the 12-year period. Only 33 HBsAg carriers underwent transplantation before 1996, when eligibility for LT was considered negativity of HBV DNA, and 144 underwent transplantation after 1996, when combined therapy with LAM and immune globulins became available. The new treatment strategies significantly increased the number of transplantable HBsAg carriers and the number of transplants for HBV, while it decreased the actuarial rate of recurrence from 21% to 8% in the last 5 years of analysis.

In the study no difference in HBV recurrence rate was observed between patients treated with the mono- or combined prophylaxis, probably due to comparable viremic loads detectable in both groups at the time of surgery (median HBV DNA 253 vs. 360 copies/mL, respectively). The virologic features of the patients, reported in Tables 1 and 2, influenced the results of the study. Spontaneously low or nonreplicating patients (prevalently HDV-coinfected) were treated with immune globulins, while spontaneous replicating cases (with prevalently HBV-related cirrhosis) were treated with the combined prophylaxis, to achieve a low viremia before LT and to control escape-mutants after surgery. Consequently, we observed a lower than expected hepatitis B recurrence rate in the mono-therapy group and a higher one in the combined group.

Moreover, results were influenced by the HBIG protocol used in our Center, a medium-dose schedule in relation to the published data on HBIG prophylaxis2 and a high-dose protocol if referred to recent studies on combined prophylaxis.10–12 Consequently, the data of the study are not necessarily comparable to those reported by other centers using high-dose HBIG schedules in mono-therapy for replicating patients or low-dose HBIG protocols in combination with LAM. Despite the limitations of a retrospective analysis, a linear correlation between the spontaneous or antiviral-induced viral load at the time of LT and the risk of HBV recurrence was found. In particular, in patients receiving only HBIG after LT, a significantly lower risk of HBV recurrence was seen in those with low levels of viremia compared with those with higher loads at moment of surgery. This difference was not significant in the combined prophylaxis group, probably due to the low number of patients (only 3 patients) with HBV DNA higher then 100,000 copies/mL at transplantation (Fig. 2B).

In correlation to the HBV DNA load at the time of LT, three categories of HBV recurrence risk were identified: patients with undetectable HBV DNA by PCR and patients with HBV DNA lower or higher than 100,000 copies/mL. Patients with high levels of HBV DNA (≥100,000 copies/mL) at the time of LT maintained a high risk (33%–53%) of recurrence during both mono- or combined prophylaxis, although the small number of patients in the latter group and a single recurrence do not permit conclusions on the combined prophylaxis strategy in subjects with a high viral load at the time of surgery.

None of the 79 patients with negative HBV DNA by PCR at the time of surgery experienced hepatitis B recurrence, as reported in a previous study.6 This group included both patients treated with antivirals such as LAM or adefovir, and spontaneous nonreplicating patients.21 In this virological setting immune globulins were safely used as mono-prophylaxis in spontaneus nonreplicating patients and in association with antivirals (combined prophylaxis) in replicating patients. These data permit us to speculate that in spontaneous nonreplicating patients, mono-therapy with immune globulins could be safely shifted into mono-therapy with LAM, as recently proposed by other authors.22, 23 Moreover, LAM therapy before surgery could be appropriate in all patients in order to obtain the complete negativization of HBV DNA so as to minimize the risk of hepatitis B recurrence.

Transplantation with a detectable viral load below 100,000 copies/mL corresponded with a lower (7.5%), but not null, residual risk of hepatitis recurrence. Specifically, patients with a spontaneous viral load of with a similar load while on LAM therapy maintained a significant risk of post-LT relapse (P = 0.008, Fig. 4). Our data allow us to speculate that in patients with a spontaneous high viral fitness the persistence of a viral load while on LAM therapy could result in the proliferation of escape-mutants/drug-resistant strains to combined prophylaxis after surgery. Consequently in these subjects the shift to LAM as mono-therapy should be tested carefully and under strict virological monitoring. In any case, only patients whose results are negative for YMDD mutants, without evidence of HBV persistence post-LT24 should be candidates for LAM mono-therapy, perhaps even in association with effective vaccination schedules after a peri-operative HBIG prophylaxis.25, 26

In the multivariate analysis the only variable significantly associated with post-LT hepatitis B recurrence was the viral load at the time of surgery; the level able to identify the significant replicating status in HBsAg carriers undergoing liver transplantation was 100,000 copies/mL by PCR. A higher or lower load at the time of LT was associated with a hepatitis recurrence of 50% and 4%, respectively (P = 0.0003). This level could represent the HBV DNA value to reach through antiviral pre-emptive therapy before LT in active replicating patients in order to significantly reduce their risk of hepatitis B recurrence.

In summary, this study indicates that the HBV DNA load at the moment of LT, as detected by an amplified sensitive assay, can quantify the risk of HBV recurrence after surgery and can suggest which prophylactic strategy is needed. A viral load of 100,000 copies, in analogy with the cutoff limit of 105 copies/mL proposed in the antiviral therapy of HBV immunocompetent patients,27–29 identifies the load of significant replication in HBsAg carrier candidates to LT. In our opinion this is the minimum value achievable to define the patient as suitable for transplant with an acceptable (<10%) risk of hepatitis B recurrence. The goal of a complete inhibition of replication, albeit desirable for the full protective effect, has to be assessed against the risk connected with a prolongation of the waiting time before LT and to the emergence of LAM-resistant mutants.

References

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References
  • 1
    Todo S, Demetris A, Van Thiel D, Taperman L, Fung J, Starzl T. Orthotopic liver transplantation for patients with hepatitis B virus-related liver disease. Hepatology 1991; 13: 619626.
  • 2
    Samuel D, Muller R, Alexander G, Fassati L, Ducot B, Benhamou JP, et al. Liver transplantation in European patients with the hepatitis B surface antigen. N Engl J Med 1993; 329: 18421847.
  • 3
    Shouval D, Samuel D. Hepatitis B immune globulin to prevent hepatitis B virus graft reinfection following liver transplantation: a concise review. Hepatology 2000; 32: 11891195.
  • 4
    Ghany MG, Ayola B, Villamil FG, Gish RG, Rojter S, Vierling JM, et al. Hepatitis B virus S mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxis. Hepatology 1998; 27: 213222.
  • 5
    Mutimer D, Pillay D, Dragon E, Tang H, Ahmed M, O'Donnell K, et al. High pre-treatment serum hepatitis B virus titre predicts failure of lamivudine prophylaxis and graft re-infection after liver transplantation. J Hepatol 1999; 30: 715721.
  • 6
    Naumann U, Protzer-Knolle U, Berg T, Leder K, Lobeck H, Bechstein WO, et al. A pretransplant infection with precore mutants of hepatitis B virus does not influence the outcome of orthotopic liver transplantation in patients on high dose anti-hepatitis B virus surface antigen prophylaxis. Hepatology 1997; 26: 478484.
  • 7
    Markowitz JS, Martin P, Conrad AJ, Markmann JF, Seu P, Yersiz H, et al. Prophylaxis against hepatitis B recurrence following liver transplantation using combination lamivudine and hepatitis B immune globulin. Hepatology 1998; 28: 585589.
  • 8
    Marzano A, Salizzoni M, Debernardi-Venon W, Smedile A, Franchello A, Ciancio A, et al. Prevention of hepatitis B virus recurrence in cirrhotic patients treated with Lamivudine before surgery and combined with passive immunoprophylaxis after liver transplantation. J Hepatol 2001; 34: 903910.
  • 9
    Rosenau J, Bahr MJ, Tillmann HL, Trautwein C, Klempnauer J, Manns MP, et al. Lamivudine and low-dose hepatitis B immune globulin for prophylaxis of hepatitis B infection after liver transplantation: possible role of mutations in the YMDD motif prior to transplantation as a risk factor for reinfection. J Hepatol 2001; 34: 895902.
  • 10
    Yao FY, Osorio RW, Roberts JP, Poordad FF, Briceno MN, Garcia-Kennedy R, et al. Intramuscular hepatitis B immune globulin combined with lamivudine for prophylaxis against hepatitis B recurrence after liver transplantation. Liver Transpl Surg 1999, 5: 491496.
  • 11
    Yoshida EM, Erb SR, Partovi N, Scudamore CH, Chung SW, Frighetto L, et al. Liver transplantation for chronic hepatitis B infection with the use of combination lamivudine and low-dose hepatitis B immune globulin. Liver Transpl Surg 1999; 6: 520525.
  • 12
    McCaughan GW, Spencer J, Koorey D, Bowden S, Bartholomeusz A, Littlejohn M, et al. Lamivudine therapy in patients undergoing liver transplantation for hepatitis B virus precore mutant-associated infection: high resistance rates in treatment of recurrence but universal prevention if used as prophylaxis with very low dose hepatitis B immune globulin. Liver Transpl Surg 1999; 6: 512519.
  • 13
    Steinmuller T, Seehofer D, Rayes N, Muller AR, Settmacher U, Jonas S, et al. Increasing applicability of liver transplantation for patients with hepatitis B-related liver disease. Hepatology 2002; 35: 15281535.
  • 14
    Yao FY, Terrault NA, Freise C, Maslow L, Bass NM. Lamivudine treatment is beneficial in patients with severely decompensated cirrhosis and actively replicating hepatitis B infection awaiting liver transplantation: a comparative study using a matched, untreated cohort. Hepatology 2001; 34: 411416.
  • 15
    Seehofer D, Rayes N, Steinmuller T, Neuhaus R, Berg T, Muller AR, et al. Liver transplantation in hepatitis B patients with preoperative resistance formation during lamivudine treatment. Transplant Proc 2002; 34: 22741175.
  • 16
    Peters MG, Singer G, Howard T, Jacobsmeyer S, Xiong X, Gibbs CS, et al. Fulminant hepatic failure resulting from lamivudine-resistant hepatitis B virus in a renal transplant recipient: durable response after orthotopic liver transplantation on adefovir dipivoxil and hepatitis B immune globulin. Transplantation 1999; 68: 19121914.
  • 17
    Marzano A, Ciancio A, Salizzoni M, Rizzetto M, Negro F. Hepatitis B virus sub types and lamivudine resistance. Lancet 2001; 358: 153154.
  • 18
    Perrillo R, Schiff E, Yoshida E, Statler A, Hirsch K, Wright T, et al. Adefovir dipivoxil for treatment of lamivudine-resistant hepatitis B mutants. Hepatology 2000; 32: 129134.
  • 19
    Schiff ER, Lai CL, Hadziyannis S, Neuhaus P, Terrault N, Colombo M, et al. Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients. Hepatology 2003; 38: 14191427.
  • 20
    Lok AS, Zoulim F, Locarnini S, Mangia A, Niro G, Decraemer H, et al. Monitoring drug resistance in chronic hepatitis B virus (HBV)-infected patients during lamivudine therapy: evaluation of performance of INNO-LiPA HBV DR assay. J Clin Microbiol 2002; 40: 37293734.
  • 21
    Lok AS. Prevention of recurrent hepatitis B post-liver transplantation. Liver Transpl 2002; 8: S67S73.
  • 22
    Dodson SF, de Vera ME, Bonham CA, Geller DA, Rakela J, Fung JJ. Lamivudine after hepatitis B immune globulin is effective in preventing hepatitis B recurrence after liver transplantation. Liver Transpl 2000; 6: 434439.
  • 23
    Naoumov NV, Lopes AR, Burra P, Caccamo L, Iemmolo RM, de Man RA, et al. Randomized trial of lamivudine versus hepatitis B immunoglobulin for long-term prophylaxis of hepatitis B recurrence after liver transplantation. J Hepatol 2001; 34: 888894.
  • 24
    Roche B, Feray C, Gigou M, Roque-Afonso AM, Arulnaden JL, Delvart V, et al. HBV DNA persistence 10 years after liver transplantation despite successful anti-HBS passive immunoprophylaxis. Hepatology 2003; 38: 8695.
  • 25
    Bienzle U, Gunther M, Neuhaus R, Vandepapeliere P, Vollmar J, Neuhaus P. Immunization with an adjuvant hepatitis B vaccine after liver transplantation for hepatitis B-related disease. Hepatology 2003; 38: 811819.
  • 26
    Buti M, Mas A, Prieto M, Casafont F, Gonzalez A, Miras M, et al. A randomized study comparing lamivudine monotherapy after a short course of hepatitis B immune globulin (HBIg) and lamivudine with long-term lamivudine plus HBIg in the prevention of hepatitis B virus recurrence after liver transplantation. J Hepatol 2003; 38: 811817; 35: 176–181.
  • 27
    Lock AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B:2000-summary of a workshop. Gastroenterology 2001; 120: 1828.
  • 28
    Conjeevaram HS, Lok AS. Management of chronic hepatitis B. J Hepatol 2003; 38: S90S103.
  • 29
    EASL international consensus conference on hepatitis B (short version). J Hepatol 2003; 38: 533540.