Liver transplantation for chronic hepatitis B with lamivudine-resistant YMDD mutant using add-on adefovir dipivoxil plus lamivudine

Authors

  • Chung Mau Lo,

    Corresponding author
    1. Center for the Study of Liver Disease and the Departments of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China
    • Department of Surgery, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Rd., Hong Kong, China
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    • Telephone: 852 2855 4761; FAX: 852 2817 5475

  • Chi Leung Liu,

    1. Center for the Study of Liver Disease and the Departments of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China
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  • George K. Lau,

    1. Center for the Study of Liver Disease and the Departments of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
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  • See Ching Chan,

    1. Center for the Study of Liver Disease and the Departments of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China
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  • Irene O. Ng,

    1. Center for the Study of Liver Disease and the Departments of Pathology, The University of Hong Kong, Pokfulam, Hong Kong, China
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  • Sheung Tat Fan

    1. Center for the Study of Liver Disease and the Departments of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China
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Abstract

Lamivudine treatment in patients with chronic hepatitis B virus (HBV) infection may improve clinical state and suppress viral replication before liver transplantation. Emergence of lamivudine-resistant YMDD mutant is common. We report the results of liver transplantation in 16 patients with pretransplantation YMDD mutants after receiving lamivudine treatment for a median of 738 days (range, 400-1799 days). Adefovir dipivoxil (10 mg daily) was added on to lamivudine for a median of 20 days (range, 8-271 days) before (n = 11) or at (n = 5) liver transplantation, and the combination was continued indefinitely thereafter. Eight patients received additional intravenous hepatitis B immune globulin (HBIG) for a median of 24 months. Fifteen patients with known pre-adefovir HBV DNA levels had a median titer of 14,200 × 103 copies/mL (2 × 103 to 4,690,000 × 103 copies/mL), and 14 had HBV DNA >105 copies/mL. All but 1 patient remained positive for HBV DNA (by quantitative polymerase chain reaction [qPCR]) at the time of liver transplantation, and the titer was greater than105 copies/mL in 8 patients. The median follow-up after liver transplantation was 21.1 (range, 4.4-68.9) months. One patient (6%) died of an unrelated cause 12.2 months after transplantation, and 15 patients (94%) were alive with the original graft. All patients cleared HBV DNA and had no detectable HBV DNA by qPCR at the latest follow-up. Fourteen patients had cleared hepatitis B surface antigen (HBsAg), but 2 patients who received only adefovir dipivoxil and lamivudine without HBIG remained HBsAg positive after 7.7 and 9.5 months. Serum HBV DNA, however, was negative, and there was no biochemical or histological evidence of recurrence. Adefovir dipivoxil was well tolerated with no significant renal toxicity. In conclusion, a combination of add-on adefovir dipivoxil plus lamivudine therapy provides effective prophylaxis in patients with pretransplantation YMDD mutant that may be actively replicating. The cost effectiveness of additional passive immunoprophylaxis remains to be defined. (Liver Transpl 2005;11:807–813.)

Lamivudine is the first antiviral agent that has been approved for the treatment of chronic hepatitis B virus (HBV) infection. Lamivudine treatment has been shown to be safe and effective in suppressing HBV replication and in controlling chronic hepatitis.1 In patients with decompensated cirrhosis awaiting liver transplantation, treatment with lamivudine may improve liver function and result in clinical improvement and a better survival without transplantation.2 In addition, since the presence of active pretransplantation HBV replication is considered a major risk factor for graft reinfection,3, 4 lamivudine treatment has been advocated to suppress HBV replication before transplantation.5 The major drawback of lamivudine therapy, however, has been the development of drug resistance because of the emergence of mutations in the YMDD motif of the HBV DNA polymerase gene,6 and this risk increases with the treatment duration. With a wider and more prolonged use of lamivudine, the emergence of lamivudine-resistant YMDD mutant will be seen more often in patients on list for transplantation.

Lamivudine and hepatitis B immune globulin (HBIG) are the 2 prophylactic agents that have been shown to be effective in preventing graft reinfection and improving survival after liver transplantation. To prevent the development of drug resistance, the 2 drugs are frequently used in combination.7–10 The emergence of YMDD mutant with lamivudine resistance before transplantation is, therefore, a serious concern, and HBV prophylaxis is a major clinical challenge in this setting. Without the effective suppression of viral replication by lamivudine, the presence of rapidly replicating HBV escape mutants may be regarded as a contraindication for liver transplantation. There is very little information in the literature regarding the outcome of liver transplantation in these patients. In two case reports,11, 12 recurrence was prevented by a combination of lamivudine and HBIG. In two other reports,9, 13 patients with pretransplantation escape mutants recurred despite the same combination of prophylaxis.

Adefovir dipivoxil is a nucleotide analog that has a potent inhibitory effect on the replication of both the wild-type and lamivudine-resistant YMDD mutants. Schiff et al.14 reported marked virologic response and significant improvement of liver function following treatment with adefovir dipivoxil in pretransplantation and posttransplantation patients with lamivudine-resistant YMDD mutants. The efficacy of adefovir dipivoxil as a prophylactic measure in patients with escape mutants, however, has not been tested. In this article, we report the use of a strategy of add-on adefovir dipivoxil plus lamivudine with or without additional HBIG prophylaxis in 16 patients who developed YMDD mutants before liver transplantation.

Abbreviations

HBV, hepatitis B virus; HBIG, hepatitis B immune globulin; HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B e antigen; anti-HBs, antibody against HBsAg; qPCR, quantitative polymerase chain reaction.

Patients and Methods

From March 1999 to June 2004, 16 patients with chronic hepatitis B had lamivudine-resistant YMDD mutants detected prior to liver transplantation and received treatment with adefovir dipivoxil add-on plus lamivudine with (n = 8) or without (n = 8) additional HBIG after liver transplantation as prophylaxis against graft reinfection. These constituted 8.6% of the 185 patients with HBV-related end-stage liver disease who underwent liver transplantation during the same period at Queen Mary Hospital, the University of Hong Kong. The presence of pretransplantation YMDD mutant was detected by a policy of surveillance for HBV viral breakthrough and escape mutant at 3-month intervals in patients who were on lamivudine therapy before transplantation. The baseline characteristics of these patients before transplantation are shown in Table 1. There were 15 men and 1 woman with a median age at transplantation of 48 years (range, 31-66 years), and all were Chinese. Eight patients had a diagnosis of hepatocellular carcinoma. Six patients had unresectable tumors as the primary indication for transplantation, and 2 who had previous liver resection underwent salvage transplantation for liver failure in the absence of recurrent tumor. Fourteen transplants were primary, and there was evidence of cirrhosis in all cases. The remaining 2 were retransplants for fibrosing cholestatic hepatitis secondary to recurrent hepatitis B under lamivudine monoprophylaxis. These 2 patients had been reported previously.15 At the time of transplantation, 3 patients required intensive care, 8 were in the hospital with complications of liver disease, and 5 were at home requiring regular medical care. Three patients had acute renal failure from hepatorenal syndrome. The grafts were from deceased donors in 7 and living donors in 9 cases.

Table 1. Baseline Characteristics Before Transplantation
Patient no.Age at OLT (yr)GenderDisease indicationHCCDuration of lamivudine treatment before emergence of YMDD mutant (days)Type of YMDD mutantDuration of adefovir dipivoxil treatment before OLT (days)HBV DNA before adefovir dipivoxil/before OLT (×103 copies/mL)
  1. Abbreviations: OLT, orthotopic liver transplantation; HCC, hepatocellular carcinoma; HBV, hepatitis B virus; FCH, fibrosing cholestatic hepatitis; NA, not available; neg., negative by Amplicor quantitative polymerase chain reaction with lowest detection limit = 300 copies/mL.

139MFCH, retransplantNo575rtM204I8820,000/8,900
262FRecurrent HCC + cirrhosisYes662rtM204I05,377/5,377
357MHCC + cirrhosisYes735rtM204V0154,800/154,800
447MHCC + cirrhosisYes945rtM204I104,690,000/1,530
533MFCH, retransplantNo400rtM204I232,235,000/3,600
641MCirrhosisNo741rtM204I16502/NA
748MCirrhosisNo930rtM204I11224,790/2
849MCirrhosisYes563rtM204I047,600/47,600
948MCirrhosisNo504rtM204I02/2
1031MCirrhosisNo720rtM204I2711,054,000/neg.
1156MCirrhosis, postoperative liver failureYes646rtM204I0339/339
1257MHCC + cirrhosisYes1333rtM204I672,930/28
1366MCirrhosisNo1799rtM204I4514,200/326
1445MCirrhosisNo891rtM204V166NA/11
1555MHCC + cirrhosisYes1005rtM204I521,540/17
1641MHCC + cirrhosisYes1432rtM204V + rtM204I2012,790/44

Lamivudine Treatment and Escape Mutant

All 16 patients were positive for hepatitis B surface antigen (HBsAg) with chronic HBV-related liver disease before being started on lamivudine (100 mg daily). They had received lamivudine treatment for a median duration of 738 days (range, 400-1799 days) before escape mutants were detected (Table 1). Since many patients had lamivudine therapy started before referral for transplantation, a pre-lamivudine HBV DNA level was available in only 8 patients. In all cases, HBV DNA was positive with a median of 5,762 × 103 copies/mL (range, 4 × 103 to 336,000 × 103 copies/mL), and 6 of 8 patients had HBV DNA >105 copies/mL. At the time of viral breakthrough with YMDD mutants, HBV DNA level was not available in 1 patient, and the other 15 were all positive for HBV DNA with a median of 14,200 × 103 copies/mL (range, 2 × 103 to 4,690,000 × 103 copies/mL). All except 1 patient had HBV DNA >105 copies/mL, and 11 patients were seropositive for hepatitis B e antigen (HBeAg). Sequencing of the polymerase gene showed an rt M204I mutant in 11 patients, rt M204V in 2, mixed rt M204I and wild-type in 2, and mixed rt M204I and rt M204V in 1 patient. No patient was coinfected with hepatitis C virus or delta virus.

Add-On Adefovir Dipivoxil Treatment

Initially, patients were enrolled in a compassionate-use program for adefovir dipivoxil treatment that was approved by the Institutional Review Board, and informed consent was obtained from each patient. Adefovir dipivoxil was subsequently registered by the local regulatory authority for the treatment of chronic hepatitis B infection. In 11 patients, adefovir dipivoxil was added on to lamivudine therapy at a median of 20 days (range, 8-271 days) before transplantation, but the other 5 patients were started on adefovir dipivoxil treatment at or shortly after transplantation. In patient 1, adefovir dipivoxil was started at a dose of 30 mg daily with L-carnitine 250 mg daily. In the subsequent patients, adefovir dipivoxil was given at a dose of 10 mg daily except in 3 patients with renal impairment (creatinine clearance <50 mL/min) when the dosage was reduced to 10 mg alternate days. All patients continued to receive combination of lamivudine and adefovir dipivoxil treatment after transplantation. In addition, patients 1 to 8 received additional HBIG immunoprophylaxis. HBIG (BayHep B, Bayer Corp., Elkhart, IN) was given intravenously at a dose of 10,000 units during the anhepatic phase and daily for 6 days. Repeated doses were given to maintain an antibody against HBsAg (anti-HBs) titer greater than 100 mIU/mL. Because of the cost of HBIG, the increasing number of patients with YMDD mutants undergoing transplantation, and the availability of more clinical data supporting the efficacy of adefovir dipivoxil, the protocol was later modified. Eight other patients (patients 9 to 16) received a combination of adefovir dipivoxil and lamivudine only and did not receive any HBIG prophylaxis. Starting from November 2003, HBIG therapy was also discontinued in the first 8 patients at a median of 24 months (range, 9-59 months) after transplantation.

Immunosuppression and Follow-up

Immunosuppression consisted of a double regimen of tacrolimus with steroid in the first 6 patients with the addition of mycophenolate mofetil in 2 with renal impairment. The dosage of steroid was progressively reduced with the aim of complete withdrawal after 6 months. A quadruple regimen consisting of induction with interleukin-2 receptor antibody, 2 doses of steroid, mycophenolate mofetil, and tacrolimus was used in the last 10 patients. Upon discharge, all patients were followed weekly at the clinic and then with increasing intervals. Posttransplantation chemotherapy was not given to any of the 6 patients with hepatocellular carcinoma in the explanted liver. Standard laboratory tests for liver function, serum HBsAg/anti-HBs, and HBeAg/antibody against HBeAg were measured at each visit. Serum HBV DNA was measured quantitatively every 3 months. Liver biopsies were performed according to clinical needs. The samples were examined for histologic evidence of recurrent hepatitis and stained immunohistochemically for HBsAg and hepatitis B core antigen. No patient was lost to follow-up, and all follow-up information of the surviving patients was updated to November 1, 2004.

Hepatitis B Serology

Tests for serum HBsAg, HBeAg, anti-HBs, and antibody against HBeAg were performed by commercially available enzyme immunoassays (Abbott Laboratories, Chicago, IL). Serum HBV DNA level was initially measured by branched-chain DNA assay (Quantiplex, Chiron Diagnostics, Emeryville, CA) with the lowest detection limit of 700,000 copies/mL. Stored serum was subsequently retested by quantitative polymerase chain reaction (qPCR) assay (Cobas Amplicor, Roche Diagnostics, Branchburg, NJ) with the lowest detection limit of 300 copies/mL. Analysis of sequence variations in the polymerase gene was performed by PCR and direct sequencing as previously described.15

Results

Efficacy of Adefovir Dipivoxil Treatment and HBV Serology Before Transplantation

Before transplantation, only 2 patients had received adefovir dipivoxil treatment for >24 weeks, and another 5 had treatment for 4 to 24 weeks. The remaining 9 patients received adefovir dipivoxil for <4 weeks (n = 4) or none at all (n = 5). Among the 11 patients who were treated with adefovir dipivoxil for a median of 20 days (range, 8-271 days) before transplantation, 9 had both pre-adefovir and pretransplantation serum HBV DNA levels available, and there was a median reduction in HBV DNA level of 2 log10 (range, 1.6-6.6 log10). By the time transplantation was performed, only 1 patient (patient 10) who had been treated with adefovir dipivoxil for 271 days became negative for HBV DNA by qPCR. HBV DNA level was not available in 1 patient, and the remaining 14 patients had a median HBV DNA level of 333 × 103 copies/mL (range, 2 × 103 to 154,800 × 103 copies/mL). The titer was >105 copies/mL in 8 patients.

Clinical Outcome

At a median follow-up of 21.1 months (range, 4.4-68.9 months), 15 (94%) of the 16 patients were alive with the original graft. There was no hospital mortality, and there was 1 late death. Patient 6 received add-on therapy with adefovir dipivoxil for 16 days before living donor liver transplantation with additional HBIG immunoprophylaxis. He had small-for-size syndrome and also developed thrombotic thrombocytopenic purpura with severe hemolysis requiring treatment with plasmapheresis after transplantation. Tacrolimus was switched to sirolimus, and the patient's liver function improved steadily. He was discharged from hospital, and repeated liver biopsy at 1, 2, 3, and 4 months after transplantation showed acute cholangiolitis only. There was no evidence of recurrent hepatitis, and immunohistochemical staining for HBsAg and hepatitis B core antigen was always negative. He developed recurrent thrombotic thrombocytopenic purpura and pulmonary tuberculosis with recurrent pleural effusion. Despite active medical treatment, he died 12.2 months after transplantation. Immediately before his death, he remained seronegative for HBsAg or HBV DNA, and positive for anti-HBs. The 8 patients with hepatocellular carcinoma had remained tumor free at a median follow-up of 20.2 months (range, 4.4-42.9 months) after transplantation.

Efficacy of HBV Prophylaxis

There was no viral breakthrough in any of the 16 patients. All patients became HBV DNA negative (by qPCR, <300 copies/mL) after transplantation and remained so at the latest follow-up (Table 2). The 8 patients on HBIG therapy received a median total amount of HBIG of 135,000 units (range, 100,000-200,000 units) before HBIG was stopped. All cleared HBsAg, and the 7 survivors remained HBsAg negative at a median of 35.2 months (range, 22.3-68.9 months) after transplantation or 11.5 months (range, 9.7-13.3 months) after stopping HBIG therapy. One patient had measurable anti-HBs at the latest follow-up. All but 2 patients (patients 5 and 8) had completely normal liver chemistry. Patients 5 and 8 had mildly elevated serum alanine aminotransferase. The latest liver biopsy showed mild acute cellular rejection in patient 5 and significant fatty change up to 50% in patient 8. Of the 4 other patients who had liver biopsy performed, 2 had normal histology and 2 had nonspecific changes. None had histologic evidence of hepatitis, and immunohistochemical staining for HBsAg or HBeAg was negative.

Table 2. Reinfection Prophylaxis and Status at Latest Follow-Up After Transplantation
Patient no.LamivudineReinfection adefovirProphylaxis HBIG/duration (mo)ALT (IU/L)Bilirubin (μmol/L)SerumStatusFollow-up post-OLT (mo)
HBsAgHBeAgHBV DNA*
  • Abbreviations: HBIG, hepatitis B immune globulin; ALT, alanine aminotransferase; HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B envelope antigen; HBV, hepatitis B virus; OLT, orthotopic liver transplantation.

  • *

    By Amplicor quantitative polymerase chain reaction, lowest detection limit = 300 copies/mL.

1YesYesYes/592518Alive68.9
2YesYesYes/334210Alive42.9
3YesYesYes/294622Alive40.5
4YesYesYes/242213Alive35.2
5YesYesYes/237114Alive34.7
6YesYesYes/101,650402Dead12.2
7YesYesYes/222714Alive31.7
8YesYesYes/9838Alive22.3
9YesYesNo/02316Alive26.0
10YesYesNo/04029Alive19.9
11YesYesNo/02618Alive18.0
12YesYesNo/0359Alive12.2
13YesYesNo/0349+Alive9.5
14YesYesNo/01815+Alive7.7
15YesYesNo/0167Alive6.4
16YesYesNo/01618Alive4.4

Of the 8 patients who received only add-on adefovir dipivoxil plus lamivudine and did not receive any HBIG prophylaxis, all were alive with the original graft and had normal liver chemistry at a median follow-up of 10.9 months (range, 4.4-26 months). Six had HBsAg seroconversion and were negative for both HBsAg and HBV DNA at a median follow-up of 15.1 months (range, 4.4-26 months). The other 2 patients (patients 13 and 14) remained HBsAg positive at 7.7 and 9.5 months after transplantation. On retesting serial stored serum samples, these 2 patients had become HBV DNA negative by qPCR since posttransplantation day 7 and day 31. At the latest follow-up, serum HBV DNA remained negative, and the liver chemistry was completely normal. A liver biopsy performed at 7 and 9 months after transplantation showed normal liver histology with negative immunohistochemical staining for HBsAg or hepatitis B core antigen.

Immunosuppression and Graft Rejection

Five patients (31.3%) each had 1 episode of acute cellular rejection that was confirmed on histologic examination of liver biopsy and was treated by steroid pulse therapy (n = 4) or increase in dosage of maintenance tacrolimus (n = 1). As of the date of the last follow-up, the maintenance immunosuppressive therapy in the 15 surviving patients included tacrolimus alone in 14 patients, and tacrolimus with steroid in 1 patient.

Adverse Effects of Prophylaxis

There was no adverse effect attributed to lamivudine, adefovir dipivoxil or HBIG that necessitated the discontinuation of any of the drugs. The etiology of thrombotic thrombocytopenic purpura in patient 6 was attributed to tacrolimus and was thought to be unrelated to any of these 3 drugs, although such a possibility could not be completely excluded. Before starting adefovir dipivoxil treatment, 3 patients had significant renal impairment with creatinine clearance <50 mL/min. Another patient had hepatic decompensation and hepatorenal syndrome (creatinine clearance 35 mL/min) at the time of transplantation. In all 4 cases, the creatinine clearance did not decrease further but improved after transplantation despite the concurrent use of tacrolimus (Fig. 1). Overall, with a median duration of adefovir dipivoxil treatment of 24.1 months (range, 8.2-69.2 months), the serum creatinine increased by more than 50 μmol/L compared with the baseline level in only 1 patient, and the median serum creatinine at the latest follow-up was 106 μmol/mL (range, 79-178 μmol/mL). The creatinine clearance was less than 50 mL/min in 2 patients with pre-adefovir renal impairment, and none of the patients required renal replacement therapy.

Figure 1.

Serial changes in creatinine clearance at various stages of treatment.

Discussion

In this study, we used a combination of add-on adefovir dipivoxil plus lamivudine therapy to prevent graft reinfection in 16 patients with lamivudine-resistant YMDD mutants that might be actively replicating prior to liver transplantation. Additional passive immunoprophylaxis was also used in half of the patients. The combination was safe and effective. At a median follow-up of 21 months, the graft survival was 94%, and there was no evidence of graft reinfection.

The risk of emergence of lamivudine-resistant YMDD mutant increases with the duration of lamivudine treatment. In this study, all patients had received lamivudine for more than 1 year, and the average duration of lamivudine therapy was 2 years before the development of YMDD mutants. When mutants with lamivudine resistance are present prior to transplantation, lamivudine monoprophylaxis would certainly not be effective. Even with combination prophylaxis using lamivudine and HBIG, the presence of pretransplantation YMDD mutant is a risk factor for graft reinfection.9, 13 Hence, in patients receiving long-term lamivudine therapy, it is important to screen for evidence of viral breakthrough by monitoring the HBV DNA level before transplantation. We measured the HBV DNA level every 3 months in patients who were receiving lamivudine therapy before liver transplantation. When a rise in the HBV DNA level suggested the possibility of viral breakthrough, the presence of YMDD mutants would be tested by direct sequencing. Using such a protocol, about 9% of our patients who underwent transplantation during this period had YMDD mutants detected prior to transplantation. As the incidence of pretransplantation YMDD mutants was on the rise and is likely to increase further in the near future, an effective prophylactic strategy against recurrence in these patients is of great importance.

Adefovir dipivoxil has been shown to be effective for the treatment of chronic hepatitis B16, 17 and it has in vitro as well as in vivo activities against lamivudine-resistant mutants.18–20 In contrast to lamivudine, which was associated with a drug-resistance mutant rate of about 15% per year of therapy, the emergence of viral mutants resistant to adefovir dipivoxil appears to be delayed and infrequent.21, 22 Although adefovir-resistant mutants with a polymerase mutation N236T in the D domain of the reverse transcriptase gene have been reported,23 these mutants have remained sensitive to lamivudine therapy. The lack of cross-resistance of the escape mutants to these 2 drugs19 suggests that the use of combination antiviral agents by add-on adefovir dipivoxil plus lamivudine therapy should be the preferred approach in those patients who have already developed resistance to lamivudine so as to avoid the emergence of multiresistant viral stains.

At the time of viral breakthrough, all but 1 of our patients showed evidence of active viral replication with HBV DNA >105 copies/mL. Initially, adefovir dipivoxil was available through a compassionate-use program, and there was usually a delay in the process of application and drug delivery. As a result of rapidly progressive hepatic decompensation, liver transplantation had to be performed shortly after or before adefovir dipivoxil therapy was initiated. With easier access to adefovir dipivoxil in the later part of the series, more patients received treatment with adefovir dipivoxil earlier before transplantation. Pretransplantation adefovir dipivoxil treatment was effective in suppressing the HBV DNA level by about 2 log10 copies/mL after an average of 20 days. However, the duration of adefovir dipivoxil treatment was short, and 9 out of 16 patients received the drug for less than 4 weeks or none at all before transplantation. At the time of transplantation, only 1 patient was seroconverted to HBV DNA negative by qPCR, and 8 patients had HBV DNA >105 copies/mL.

We did not regard a high HBV DNA level as a contraindication for transplantation, and combination of add-on adefovir dipivoxil plus lamivudine therapy proved to provide effective prophylaxis even for the patients with actively replicating YMDD mutants at the time of transplantation. The role of the additional passive immunoprophylaxis is not clear. In our initial experience, the majority of the patients had highly active HBV replication, including 2 with fibrosing cholestatic hepatitis secondary to YMDD mutants. Since adefovir dipivoxil was only available just before transplantation, we conceived that it was imperative to add HBIG prophylaxis to the combination of antiviral agents. The triple combination of adefovir dipivoxil, lamivudine, and intravenous HBIG proved to be effective. Although HBIG had been discontinued for almost 1 year, there was no serological or virological evidence of recurrence at a median follow-up of 3 years after transplantation. This triple combination of prophylactic agents, however, was very expensive and might not be cost-effective. The disadvantages of HBIG, including high cost, potential toxicity, and the need for parenteral administration, are all well known. With more readily available adefovir dipivoxil and more clinical data on its safety and efficacy, our protocol was modified, and the last 8 patients received a combination of adefovir dipivoxil and lamivudine alone without any HBIG. All but 1 of these 8 patients were positive for HBV DNA at the time of transplantation, and the risk profiles were similar to those of the first 8 patients who received additional passive immunoprophylaxis. Although the follow-up was shorter, with a median of 10.9 months, the results of prophylaxis with this combination of antiviral agents were promising. There was no biochemical or histologic evidence of recurrence, and all 8 patients had no detectable HBV DNA in serum by the very sensitive qPCR assay. Six of these 8 patients had already cleared HBsAg from serum, and only 2 had remained HBsAg positive less than 10 months after transplantation. The follow-up of these patients must continue to determine whether they would clear HBsAg subsequently or whether they may be at risk for virologic breakthrough and clinical recurrence. Considering the low frequency of adefovir-resistant mutants and its lack of cross-resistance to lamivudine, the possibility of viral breakthrough due to an HBV mutant with resistance to both drugs should be very low. There is a need for more studies with longer follow-up on the use of combination of adefovir dipivoxil and lamivudine alone as prophylaxis in patients with pretransplantation YMDD mutants.

A major drawback of treatment with adefovir dipivoxil is its renal toxicity particularly in the face of preexisting renal impairment and concomitant long-term use of other nephrotoxic drugs such as tacrolimus in liver transplant recipients. Our experience indicated that treatment with adefovir dipivoxil at 10 mg daily for a median of 24 months in this setting was well tolerated. Only 1 patient had elevation in serum creatinine >50 μmol/L above baseline, and none of the patients required discontinuation of the drug because of a renal event. Patients with pretransplantation renal impairment were able to receive adefovir dipivoxil treatment with dose reduction, but there was no adverse effect on the recovery of the renal function or efficacy of the prophylaxis.

In conclusion, patients who receive lamivudine therapy should be monitored for the emergence of YMDD mutants prior to transplantation. In the event of viral breakthrough, a combination of antiviral agents by add-on adefovir dipivoxil plus lamivudine provides safe and effective prophylaxis even in patients with active viral replication. The cost effectiveness of additional HBIG remains to be determined by more prospective studies.

Ancillary