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Keywords:

  • Adefovir;
  • entecavir;
  • hepatitis B virus;
  • lamivudine;
  • liver transplantation;
  • nucleoside analogues

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Passive Immunoprophylaxis
  5. Preemptive Pretransplant Therapy With Antiviral Agents
  6. Prophylactic Post-Transplant Monotherapy with Antiviral Agents
  7. Prophylactic Post-Transplant Combined Approach
  8. Treatment of Post-Transplant HBV Recurrence
  9. Treatment of HBV Transplant Patients with Strains Resistant to Lamivudine
  10. Conclusions
  11. References

Post-transplant prophylaxis with hepatitis B immune globulin (HBIG) has significantly reduced hepatitis B virus (HBV) recurrence rates, but it is rather ineffective in patients with pretransplant viremia. Moreover, long-term HBIG administration is very expensive and may be associated with emergence of escape HBV mutants. Lamivudine has been widely used in the management of HBV transplant patients. Pretransplant lamivudine lowers HBV viremia, decreasing the risk of post-transplant HBV recurrence, but to try and minimize development of resistant HBV strains, it should start within the last 6 months of the anticipated transplantation timing. Preemptive post-transplant lamivudine monotherapy is associated with progressively increasing HBV recurrence rates, but combined therapy with lamivudine and HBIG at relatively low dosage is currently the most effective approach in this setting, even in HBV-DNA-positive patients, who also receive lamivudine in the pretransplant period. The most frequent therapy for post-transplant HBV recurrence is lamivudine, but the increasing resistance rates represent a rather challenging problem. Adefovir dipivoxil and entecavir are currently the most promising agents for lamivudine-resistant HBV strains. All these advances in anti-HBV therapy have made HBV liver disease an indication for liver transplantation irrespective of viral replication status, a complete turn around from 10 years ago.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Passive Immunoprophylaxis
  5. Preemptive Pretransplant Therapy With Antiviral Agents
  6. Prophylactic Post-Transplant Monotherapy with Antiviral Agents
  7. Prophylactic Post-Transplant Combined Approach
  8. Treatment of Post-Transplant HBV Recurrence
  9. Treatment of HBV Transplant Patients with Strains Resistant to Lamivudine
  10. Conclusions
  11. References

Early experience with liver transplantation for hepatitis B virus (HBV) liver disease, with no immunoprophylaxis or its use short-term, was rather discouraging with an extremely high rate of graft loss due to the almost universal and frequently aggressive HBV recurrence (1–3). Thus, HBV liver disease was initially considered a relative or even absolute contraindication for liver transplantation in many centers (4). However, the use of long-term hepatitis B immune globulin (HBIG) significantly decreased the post-transplant HBV recurrence rate and improved the prognosis of HBV transplant patients (5), resulting in revision of the transplant policy and allowing orthotopic liver transplantation (OLT) for HBV liver disease (4,6).

Although HBIG may remain the gold standard for prevention of post-transplant HBV recurrence, newer antiviral agents, mainly nucleos(t)ide analogues, are currently being used or evaluated, either as monotherapy or in combination with HBIG, in an effort to further improve the outcome, treat HBIG failures, and/or reduce the need for the use of the expensive HBIG preparations. This review focuses on the management of HBV-related liver transplant patients, reviewing the efficacy of newer antiviral agents, alone or in combination with HBIG.

Passive Immunoprophylaxis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Passive Immunoprophylaxis
  5. Preemptive Pretransplant Therapy With Antiviral Agents
  6. Prophylactic Post-Transplant Monotherapy with Antiviral Agents
  7. Prophylactic Post-Transplant Combined Approach
  8. Treatment of Post-Transplant HBV Recurrence
  9. Treatment of HBV Transplant Patients with Strains Resistant to Lamivudine
  10. Conclusions
  11. References

The efficacy of HBIG is associated with the pretransplant type of liver disease and viremic status, as well as with the dose and duration of HBIG treatment, while the most widely accepted recommendations for HBIG prophylaxis depend mainly on the pretransplant viremic status (4). Patients with detectable serum HBV-DNA by conventional hybridization assays, who may be transplanted only after clearance of HBV-DNA by lamivudine, are treated with more aggressive HBIG protocols compared to nonviremic patients (4). However, several practical questions, mainly about the ideal duration, but also about dosage, frequency and mode of HBIG administration, remain to be answered.

Since HBV-DNA can often be detected in the liver, serum, or peripheral mononuclear cells of HBsAg-negative patients on long-term prophylactic HBIG therapy (7–9), it seems that HBIG may only rarely lead to eradication of HBV infection and therefore indefinite HBIG prophylaxis is probably required. Long-term HBIG treatment, however, is extremely expensive, and therefore several variations in its administration protocol have been tried in order to reduce cost. The most cost-effective approach seems to be the individual tailoring of HBIG administration (4). Taking into consideration that the clearance of HBIG varies significantly among different patients and/or different HBIG preparations, and that it generally decreases with time after transplant (10), it is obvious that intervals between HBIG injections may significantly vary from patient to patient and may decrease with time after transplant, if an HBIG protocol based on monitoring of anti-HBs titers instead of fixed monthly HBIG doses is used. Intramuscular HBIG administration has also been tried in an effort to reduce the cost of long-term HBIG prophylaxis (11–13), but no long-term data for such an approach are currently available.

Long-term HBIG administration has been associated with emergence of escape mutant HBV strains, a phenomenon observed in many other cases of long-term selective immunologic pressure on chronic viral infections (14–16). Mutations in the HBV surface gene have been identified in about 50% of patients on HBIG prophylaxis for ≥ 6 months before therapeutic failure (15,17). The clinical significance of such escape mutants has not been completely clarified, but they seem to progressively accumulate over time and to be associated with increasing rates of graft failure (4,17). Since wild HBV usually dominates over the escape mutant strains in case of HBIG withdrawal (18), there is no consensus about continuation of HBIG therapy, or not, after the emergence of escape HBV mutants (4). However, most centers stop HBIG if escape mutants have been demonstrated.

Preemptive Pretransplant Therapy With Antiviral Agents

  1. Top of page
  2. Abstract
  3. Introduction
  4. Passive Immunoprophylaxis
  5. Preemptive Pretransplant Therapy With Antiviral Agents
  6. Prophylactic Post-Transplant Monotherapy with Antiviral Agents
  7. Prophylactic Post-Transplant Combined Approach
  8. Treatment of Post-Transplant HBV Recurrence
  9. Treatment of HBV Transplant Patients with Strains Resistant to Lamivudine
  10. Conclusions
  11. References

Preemptive therapy with antiviral agents is an alternative approach to prevent post-transplant HBV recurrence, which frequently starts during the pretransplant period, in order to lower or clear the viral load at the time of OLT (19). The use of preemptive pretransplant antiviral therapy was rather limited until the late 1990s, when the only available anti-HBV therapeutic option was interferon-α (IFNa), which is frequently contraindicated or causes intolerance in patients with decompensated cirrhosis (20). Thus, cirrhotics with HBV viremia were frequently excluded from transplant lists because of the high risk of post-transplant HBV recurrence, even with HBIG prophylaxis (4,5).

Lamivudine, a cytosine analogue with quite potent anti-HBV activity, is generally well tolerated even in severely ill cirrhotic patients and has an extremely good safety profile, with rare and generally mild side-effects. Lamivudine monotherapy is widely used in the pretransplant period, being an ideal drug for short-term therapy of patients with HBV decompensated cirrhosis, since it is potent, safe and may stabilize or even improve liver function (21–23), sometimes resulting in temporary withdrawal of patients from transplant lists. Unfortunately, the improvement or stabilization of liver function is not often long term (21,23), since the prolongation of lamivudine therapy is associated with progressively increasing rates of virologic and biochemical breakthroughs, due to selection of lamivudine-resistant mutant HBV strains (21,22,24–26). Besides the risk for severe exacerbation of liver disease, the pretransplant emergence of lamivudine-resistant HBV strains may worsen the post-transplant outcome by increasing the probability of HBV recurrence (27). The forthcoming availability of newer antiviral agents effective against such mutant HBV strains is expected to ameliorate the consequences of lamivudine resistance.

Virologic breakthroughs during lamivudine monotherapy are due to the emergence of HBV strains with mutations within the YMDD motif of HBV polymerase gene (28,29). Such mutations change the structure of HBV polymerase, resulting in reduced affinity with the nucleoside analogue (30,31). Currently, the post-transplant outcome of patients with pretransplant HBV viremia due to YMDD mutant strains is not clear. Post-transplant HBV recurrence was not observed during the first 32 months post transplant in a patient with pretransplant YMDD mutants, who received high-dose HBIG and lamivudine (32). However, two patients with pretransplant YMDD mutants were subsequently observed to rapidly develop post-transplant HBV recurrence despite combined prophylaxis with low-dose HBIG and lamivudine (33). Whether the dose of HBIG is an important factor for post-transplant HBV recurrence in patients who have already developed virologic breakthroughs during pretransplant lamivudine therapy, and what the risk of HBV recurrence is precisely in such patients, must be evaluated in larger and properly designed studies. However, transplant centers may be reluctant to perform OLT in patients with HBV cirrhosis and detectable serum HBV-DNA irrespective of the type of HBV strains (34). Given that other anti-HBV agents are not yet widely available and that the inhibitory effect of lamivudine starts within a few weeks with virologic breakthroughs usually emerging after the first 6 months of therapy, it is usually recommended that lamivudine therapy in transplant candidates should start within the last 6 months of the anticipated timing of transplantation. This poses several logistical problems.

Prophylactic Post-Transplant Monotherapy with Antiviral Agents

  1. Top of page
  2. Abstract
  3. Introduction
  4. Passive Immunoprophylaxis
  5. Preemptive Pretransplant Therapy With Antiviral Agents
  6. Prophylactic Post-Transplant Monotherapy with Antiviral Agents
  7. Prophylactic Post-Transplant Combined Approach
  8. Treatment of Post-Transplant HBV Recurrence
  9. Treatment of HBV Transplant Patients with Strains Resistant to Lamivudine
  10. Conclusions
  11. References

Lamivudine was first tried as monotherapy administered before and prophylactically after OLT at a daily dose of 100 mg, and gave promising short-term results in initial reports (35). However, it was subsequently shown that the efficacy of such a policy declines over time, with development of virologic breakthroughs and HBV recurrence in about 40% of cases at 2 years post transplant, and severe clinical outcomes in some patients (36–39). Moreover, recent multicenter US trials reported even worse results, with 1-year HBV recurrence rates of 40–50% among patients treated with post-transplant prophylactic lamivudine monotherapy (40).

The clinical significance of virologic breakthroughs in HBV transplant patients under post-transplant prophylactic lamivudine therapy is still under evaluation. In vitro studies of the biologic behavior of mutant strains resistant to lamivudine showed that their replication capacity is lower than wild-type HBV (41), while the clinical significance of virologic breakthroughs under lamivudine remains controversial in the nontransplant setting. In the HBV transplant population, liver deterioration and/or graft failure have been reported in only a proportion of patients following development of virologic breakthroughs under prophylactic post-transplant lamivudine monotherapy (37,39,42). Whether the follow-up periods of the latter studies were too short for all the patients to develop signs of liver damage or whether some patients may remain in long-term remission despite the emergence of virologic breakthroughs remains to be seen.

Prophylactic Post-Transplant Combined Approach

  1. Top of page
  2. Abstract
  3. Introduction
  4. Passive Immunoprophylaxis
  5. Preemptive Pretransplant Therapy With Antiviral Agents
  6. Prophylactic Post-Transplant Monotherapy with Antiviral Agents
  7. Prophylactic Post-Transplant Combined Approach
  8. Treatment of Post-Transplant HBV Recurrence
  9. Treatment of HBV Transplant Patients with Strains Resistant to Lamivudine
  10. Conclusions
  11. References

Post-transplant prophylactic combined administration of HBIG and lamivudine was tried in HBV transplant patients in an effort to improve the efficacy of post-transplant prophylactic monotherapy or to achieve similar results at a lower cost (43). The overall efficacy of such a combined regimen appears to be superior to the efficacy of prophylaxis with any of the two agents alone. In particular, in 12 recent studies of prophylactic therapy with HBIG and lamivudine, post-transplant HBV recurrence was observed in only 7/233 (3%) patients during a mean follow-up of 13–22 months (11,12,33,43–51) (Table 1). It should be mentioned that lamivudine monotherapy was given to viremic patients (81/154 by hybridization assays) during the pretransplant period in the most studies, and thus serum HBV-DNA just before OLT remained detectable in a minority of them (34 by hybridization assays) (11,12,33, 43–46,48,50). Of seven patients with post-transplant HBV recurrence, three had developed YMDD mutants during the pretransplant lamivudine therapy (33,46). In a more recent study with longer post-transplant follow-up, similar good results of the combined prophylactic approach were documented, with only 1/26 (4%) patients having HBV recurrence by a hybridization assay (52) (Table 1). However, a potentially important finding of the latter study was that serum HBV-DNA could be detected by polymerase chain reaction (PCR) in 16 (61.5%) cases (52). Thus, longer follow-up is probably required before definite conclusions about the efficacy of the preemptive combination of HBIG and lamivudine can be drawn. Since most cases of post-transplant HBV reinfection seem to occur within the first 3 years after OLT (34), a follow-up of 3 years should be sufficient for such a prophylactic approach to be validated.

Table 1. : Published studies using combination of hepatitis B immune globulin (HBIG) and lamivudine (LAM) for prevention of hepatitis B virus (HBV) recurrence after orthotopic liver transplantation (OLT) for HBV-related chronic liver disease
  Patients withPre-OLT,Post-OLT HBIG dose (IU),Post-OLTMeanHBVSurvival
StudyPtHBV-DNA (+)*,LAM[cumulative within 1st month]LAMfollow-uprecurrence(%)
(1st author, year)no.baseline/at OLT(mg)-after the 1st month(mg)(months)n (%) 
  • *

    Serum HBV-DNA detectable by hybridization assays. N.A. not available, Pt no.: patient number.

  • 1

    Plus 10000 iv during anhepatic phase in all patients and another 70000 iv during the first 7days in two HBV-DNA positive patients.

  • 2

    Another three patients had detectable serum HBV-DNA by a polymerase chain reaction (PCR) assay.

  • 3

    One patient received 80000IU of HBIG during the first month, while another patient received only 2000IU of HBIG during the anhepatic phase and 4 im injections of 650IU each within the first 6months after OLT.

  • 4

    Intravenous for the first 4weeks and im thereafter; 5 of the 12 patients received HBIG only for the first 4weeks after OLT.

  • 5

    Seven patients had detectable serum HBV-DNA by a PCR assay.

  • 6

    Two out of 4 patients tested had YMDD mutant strains, while another 3 patients had detectable serum HBV-DNA by a PCR assay

  • 7

    Serum HBV-DNA was detected by PCR in another 61.5% (16 patients).

  • 8

    Five patients, who died within month after OLT from unrelated to HBV causes, were not included in this survival estimation.

Markowitz, 1998 (44)145/1150[80000]-10000/month iv15013093
Yao, 1999 (11)109/2150[55551]-1111/3weeks im150161 (10)90
Yoshida, 1999 (12)74/0100[34720]-2170/1–4weeks im100181 (14)86
McCaughan, 1999 (45)962/620Low dose (no details)N.A.17089
Roche, 1999 (46)1515/4100No details-anti-HBs>500IU/L100161 (7)93
Angus, 2000 (47)32N.A.100[3200–6300]-400 or 800/month im 100181 (3)1008
Han, 2000 (43)5920/16150[80000]-10000/month iv15015098
Lee, 2000 (48)51/0100[26000]-2000/month iv310011080
Andreone, 2000 (49)19N.A.100[45000]-5000/month iv100171 (5)95
Buti, 2000 (50)129/0100[62000]-2000/month iv-im4100120100
Marzano, 2001 (52)269/05100[60000]-5000/month iv1003017 (4)92
Rosenau, 2001 (33)2112/56100–150[40000 – anti-HBs>500IU/L] -anti-HBs>100IU/L iv 100–150202 (10)90
Machicao, 2001 (51)30N.A.N.A.High doseN.A.22097

One particularly important aspect in all studies using combined HBIG and lamivudine prophylaxis is that such an approach achieved low HBV reinfection rates, with a relatively low HBIG dosage, similar to current recommendations for nonviremic HBV transplant patients (4), and despite the fact that >50% of cases had detectable serum HBV-DNA by hybridization assays before pretransplant administration of lamivudine (11,12,33,44,47,52). Moreover, in three studies with a mean follow-up of 12–18 months, HBIG was given intramuscularly with similar good results (11,12,47). The addition of lamivudine reduces the cumulative amount of HBIG required to effectively prevent post-transplant HBV reinfection, possibly through suppression of HBV replication and HBsAg production (34). Thus, the prophylactic post-transplant combination of HBIG and lamivudine preceded by short-term pretransplant lamivudine therapy appears to be the approach of choice in high-risk viremic HBV transplant patients, since it is associated with the lowest post-transplant HBV recurrence rate and probably has a reduced cost due to low HBIG dosage.

Another strategy using prophylactic combined therapy has been the withdrawal of HBIG administration after a certain period. In this context, the prophylactic combination of HBIG and lamivudine followed by maintenance lamivudine alone was reported to achieve similar results to HBIG prophylaxis in the short-term (53), but long-term data about this approach are still lacking. In a recent trial, 24 HBV transplant patients with pretransplant undetectable serum HBV-DNA by a hybridization assay, who had received HBIG for ≥ 6 months post-transplant without evidence of HBV recurrence, were randomized to continue HBIG or receive lamivudine alone (54). The HBV recurrence rate and the proportion of patients with detectable serum HBV-DNA by PCR, were similar in the two groups at 12 months, while 8/12 patients of the lamivudine group did not develop HBV recurrence during an additional follow-up of 6–22 months (54). Similarly, HBV recurrence was not observed in any of 16 HBV transplant patients who received HBIG continuously for 2 years and then switched over to lamivudine monotherapy for an additional period of up to 27 months (55). Thus, it seems that post-transplant HBIG prophylaxis might be replaced by lamivudine after ≥6 months post-transplant in selected HBV transplant patients with a low risk of HBV recurrence, but data on the long-term efficacy of such a strategy are still needed.

Another reported strategy is the substitution of HBIG by anti-HBV vaccination (56). Double-dose recombinant anti-HBV vaccine was given to 17 low-risk HBV transplant patients with pretransplant undetectable serum HBV-DNA by a hybridization assay (HBV-DNA by PCR-negative: 13, -positive: 1, -not done: 3), who had received HBIG for ≥ 18 months post-transplant without evidence of HBV recurrence; no HBV recurrence was observed in the 14/17 (82%) patients, who developed anti-HBs after vaccination, during a median follow-up of 14 months (56). However, in a more recent study, a highly reinforced anti-HBV vaccination resulted in development of anti-HBs in only 12–18% of 17 patients (57). Therefore, greater numbers of patients and longer follow-up periods are required before the long-term efficacy of such approaches for HBIG substitution can be determined.

Treatment of Post-Transplant HBV Recurrence

  1. Top of page
  2. Abstract
  3. Introduction
  4. Passive Immunoprophylaxis
  5. Preemptive Pretransplant Therapy With Antiviral Agents
  6. Prophylactic Post-Transplant Monotherapy with Antiviral Agents
  7. Prophylactic Post-Transplant Combined Approach
  8. Treatment of Post-Transplant HBV Recurrence
  9. Treatment of HBV Transplant Patients with Strains Resistant to Lamivudine
  10. Conclusions
  11. References

The primary targets of treatment of post-transplant HBV recurrence are the control of liver disease and stabilization of graft function. Lamivudine is currently the most frequently used agent for this indication (Table 2). In eight studies including about 200 patients with post-transplant HBV infection treated with lamivudine for a mean of 12–25 months, serum HBV-DNA levels usually became undetectable by hybridization assays and no significant clinical manifestations were observed (38,58–64). Whether initiation of lamivudine therapy earlier after the diagnosis of HBV reinfection is associated with better outcomes, as suggested in some reports (58,65), remains to be determined. Lamivudine has also given promising results for the treatment of patients with fibrosing cholestatic hepatitis (66,67). However, the progressively increasing rates of resistance to lamivudine, which were reported to be 27%, 40%, and > 50% at 1, 2, and 3 years of therapy (60,64, 68–70), may cause problems in the long-term. Although the clinical significance of resistance to lamivudine is not clear in both transplant and nontransplant patients, and lamivudine-resistant post-transplant reinfection cases have been suggested to follow a relatively milder course than cases with wild HBV recurrence (71), the emergence of such HBV mutants has been associated with rapid development of advanced histologic lesions and even liver failure and death in some HBV transplant patients (69,72,73).

Table 2. : Published studies of lamivudine (LAM) therapy for hepatitis B virus (HBV) recurrence or de novo HBV infection after orthotopic liver transplantation (OLT)
  Baseline serumBaselineMeanClearance ofClearance ofClearance ofYMDD
StudyPtHBV-DNA (+)*,HBeAg (+),duration ofserum HBV-DNA,HBeAg, n (%)HBsAg,mutants,
(1st author, year)no.n (%)n (%)LAM (months)hybridization-PCRn (%)n (%)n (%)
  • *

    Serum HBV-DNA detectable by hybridization assays. N.A. not available, Pt no.: patient number.

  • 1

    All patients had acute HBV recurrence;

  • 2

    Three patients had de novo HBV recurrence and another two patients had been treated with famciclovir before start of LAM;

  • 3

    Four patients had de novo HBV recurrence;

  • 4

    22 patients had been treated with famciclovir therapy before start of LAM;

  • 5

    Two patients had de novo HBV recurrence.

Andreone, 1998 (58)11111 (100)2 (18)168 (73)−5 (45)2 (100)5 (45)3 (27)
Nery, 1998 (59)11210 (91)N.A.258 (73)–N.A.N.A.N.A.2 (18)
Perrillo, 1999 (60)5252 (100)45 (87)1231 (60)–N.A.14 (45)3 (6)14 (27)
Roche, 1999 (61)1616 (100)10 (63)167 (44)–N.A.3 (19)3 (19)6 (40)
Balan, 1999 (62)24N.A.N.A.259 (37)N.A.N.A.15 (63)
Malkan, 2000 (38)15314 (93)6 (40)2313 (87)–N.A.N.A.4 (27)2 (13)
Seehofer, 2000 (63)41441 (100)N.A.31231 (76)–N.A.N.A.9 (22)14 (34)
Fontana, 2001 (64)3129 (94)23 (74)2011 (36)–N.A.3 (9)013/29 (45)
Ben-Ari, 2001 (69)858 (100)5 (63)363 (38)–N.A.1 (20)05 (63)

Besides lamivudine, several other nucleos(t)ide analogues have been tried or are currently evaluated for the treatment of subgroups of patients with HBV infection, including those with post-transplant HBV recurrence. In the transplant setting, famciclovir, a guanosine analogue, has been tried (74), but it was found to be inferior to lamivudine (68,70,75). Ganciclovir, another guanosine analogue, was found to achieve reductions in both alanine aminotransferase (ALT) and serum HBV-DNA levels as well as improvement of liver histology (76,77), but it is of limited use as long-term therapy because of the low bioavailability of oral administration and the need for intravenous use.

Adefovir, a nucleotide analogue of adenosine that is administered esterified with two pivalic acid molecules as adefovir dipivoxil, seems to be the most promising new anti-HBV agent. It is well tolerated, but relatively high doses (30–120 mg daily) have been associated with an increased risk of nephrotoxicity after ≥20 weeks (78). Although nephrotoxicity is a potential adverse event that needs particular attention in transplant patients, the currently recommended daily dose of adefovir dipivoxil is 10 mg, with reduction to 5 mg in case of low creatinine clearance. Entecavir, a carboxylic analogue of guanosine, has initially been found to suppress satisfactorily the HBV replication in nontransplant chronic hepatitis B patients (79). The effectiveness of the last two antiviral agents, as well as of other newer nucleos(t)ide analogues, is currently under evaluation within ongoing clinical trials including transplant or nontransplant patients infected with wild or lamivudine-resistant HBV strains.

In the pre-lamivudine era, IFNa was a common therapeutic option for patients with post-transplant HBV recurrence. The role of IFNa as first-line treatment in this setting has currently almost disappeared, because of both its low efficacy (80,81) and a low but possible theoretic risk of graft rejection (80,81).

Treatment of HBV Transplant Patients with Strains Resistant to Lamivudine

  1. Top of page
  2. Abstract
  3. Introduction
  4. Passive Immunoprophylaxis
  5. Preemptive Pretransplant Therapy With Antiviral Agents
  6. Prophylactic Post-Transplant Monotherapy with Antiviral Agents
  7. Prophylactic Post-Transplant Combined Approach
  8. Treatment of Post-Transplant HBV Recurrence
  9. Treatment of HBV Transplant Patients with Strains Resistant to Lamivudine
  10. Conclusions
  11. References

Since lamivudine is currently used widely in HBV transplant patients either as preemptive therapy, alone or in combination with HBIG, or as treatment for HBV recurrence, the numbers of transplant patients with HBV strains resistant to lamivudine are expected to increase with time and they may comprise the most challenging problem in this setting in the near future. Several antiviral agents are currently being evaluated as candidates for the treatment of HBV strains resistant to lamivudine.

Adefovir dipivoxil, which has now been approved for the treatment of HBV in some countries, appears to be the most promising agent for the treatment of lamivudine-resistant HBV mutant strains (82); in two recent clinical trials, which included patients with decompensated HBV cirrhosis or post-transplant HBV recurrence, treatment with adefovir dipivoxil achieved significant reduction in serum HBV-DNA levels and improvement of transaminase activity (83,84). Besides clinical trials, protocols of compassionate use of adefovir dipivoxil in HBV transplant or pretransplant patients are currently running in many centers worldwide. In addition, adefovir dipivoxil in combination with HBIG effectively prevented HBV recurrence after OLT for fulminant liver failure resulting from lamivudine-resistant HBV stains in a renal transplant recipient (73). Moreover, adefovir dipivoxil was recently reported to be a successful therapy in one case with post-transplant fibrosing cholestatic hepatitis and one with acute liver graft failure, both due to lamivudine-resistant HBV strains which had emerged during combined HBIG and lamivudine prophylaxis (85,86). Viral resistance to adefovir dipivoxil has not been reported to date (87).

Entecavir is also effective against resistant to lamivudine HBV strains (88,89) and is currently under evaluation in the transplant setting. Famciclovir is not a useful agent for this indication, since there is cross resistance with lamivudine (90,91). Although IFNa has been almost abandoned as first-line therapy of post-transplant HBV recurrence, it may still have a role, alone or in combination with other antiviral agents, as a second-choice therapeutic option for patients who develop resistance to lamivudine or other nucleoside analogues (19). The addition of IFNa to lamivudine therapy has been used for the treatment of a few transplant and nontransplant patients with resistance to lamivudine HBV mutant strains, showing promising initial results (92). However, more studies with greater patient numbers are certainly needed before any conclusion can be drawn about the effectiveness of IFNa for lamivudine HBV mutant strains.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Passive Immunoprophylaxis
  5. Preemptive Pretransplant Therapy With Antiviral Agents
  6. Prophylactic Post-Transplant Monotherapy with Antiviral Agents
  7. Prophylactic Post-Transplant Combined Approach
  8. Treatment of Post-Transplant HBV Recurrence
  9. Treatment of HBV Transplant Patients with Strains Resistant to Lamivudine
  10. Conclusions
  11. References

Prevention is always preferable to treatment of any infection. This is particularly important in HBV transplant patients, for whom safe and effective prophylactic agents are available. HBIG prophylaxis has significantly reduced the risk of post-transplant HBV recurrence, and has increased graft and patient survival. However, the high cost, low availability, HBIG failures, and emergence of escape mutant HBV strains led to the search for alternative agents. The introduction of lamivudine gave the opportunity to transplant many HBV viremic patients by inducing potent inhibition of HBV replication during the pretransplant period. The preemptive post-transplant combination with HBIG and lamivudine appears to significantly reduce the risk of HBV recurrence, and it is expected to improve the long-term outcome of pretransplant viremic patients. All these advances have established a far more optimistic outlook for HBV transplant patients, and thus HBV-related liver disease is now a universal indication for OLT, irrespective of initial replicative HBV status.

The management of YMDD mutant HBV strains that progressively develop with time during lamivudine therapy represents the most challenging task for the near future, in transplant as well as nontransplant patients with chronic HBV infection. All such patients are certainly candidates for newer antiviral drugs effective against YMDD mutant HBV strains, but lamivudine therapy is currently continued by most physicians, since its discontinuation may result in the reappearance of the wild HBV and exacerbation of liver disease (93). Whether ab initio combinations of drugs with complementary mechanisms of antiviral activity, as with antiviral therapy in HIV infection, or sequential therapy with different antiviral agents, represents the most cost-effective approach is currently unknown. However, long-term and maybe perennial prophylaxis for HBV transplant patients is required, which will be an added cost for these patients, since HBV eradication with therapy seems to be an almost impossible target for the time being and residual virus can be detected even after many years of post-transplant effective prophylaxis (9).

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Passive Immunoprophylaxis
  5. Preemptive Pretransplant Therapy With Antiviral Agents
  6. Prophylactic Post-Transplant Monotherapy with Antiviral Agents
  7. Prophylactic Post-Transplant Combined Approach
  8. Treatment of Post-Transplant HBV Recurrence
  9. Treatment of HBV Transplant Patients with Strains Resistant to Lamivudine
  10. Conclusions
  11. References
  • 1
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  • 3
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