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1Prophylaxis using the combination of lamivudine and high-dose intravenous hepatitis B immunoglobulin (approximately 10,000 IU monthly) reduces the long-term risk of recurrence of hepatitis B in hepatitis B surface antigen–positive transplant recipients to 5% to 10%. However, this therapy is expensive and inconvenient for patients.
2Recent studies have shown that similar results can be obtained, at far less cost, with much lower doses of intramuscular hepatitis B immune globulin (400-800 IU monthly) in combination with pretransplant and posttransplant lamivudine therapy.
3The development of lamivudine resistance pre-transplant can lead to hepatic decompensation and increases the risk of posttransplant recurrence in patients receiving hepatitis B immune globulin/lamivudine prophylaxis. Newer nucleos(t)ide analogues with lower resistance rates such as entecavir, adefovir, and tenofovir should therefore replace lamivudine in hepatitis B prophylaxis.
4Combination therapy with these newer agents and low-dose intramuscular hepatitis B immune globulin is likely to be the most cost effective hepatitis B immune globulin–containing regimen for the prevention of hepatitis B recurrence post-transplant.
5Some form of hepatitis B virus prophylaxis needs be continued indefinitely post-transplant. However, the use of antivirals with very low rates of drug resistance will make it possible to stop hepatitis B immune globulin therapy in many patients currently receiving hepatitis B immune globulin/nucleos(t)ide combination therapy.
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The early experience of liver transplantation (LT) for hepatitis B virus (HBV)–related disease was that the majority of patients developed recurrent infection in the early post-LT period. This resulted in rapidly progressive liver injury, early graft loss, and markedly reduced survival.1–3 These poor outcomes led a number of groups to question the role of transplantation in hepatitis B surface antigen (HBsAg)–positive patients, especially those with active viral replication who are at highest risk of disease recurrence. However, over the last 2 decades, the development of highly effective prophylaxis has almost eliminated the problem of HBV recurrence. As a result, long-term post-LT survival in HBsAg-positive patients now equals that of most other patient groups.
The most widely used prophylaxis has been long-term therapy with a combination of intravenous (IV) hepatitis B immune globulin (HBIG) and lamivudine. However, this treatment is very expensive, and its administration is inconvenient for patients. This has led to the development of a range of alternate strategies for the use of HBIG aimed at reducing costs and improving tolerability.
HBIG was the first agent to show efficacy in preventing HBV recurrence. Limited-duration (<12 months) HBIG therapy [10,000 IU IV at LT followed by 10,000 IU IV daily for 8 days post-LT and then at variable intervals to maintain trough hepatitis B surface antibody (anti-HBs) titers > 100 IU/L] delayed but did not prevent graft reinfection.4 A 1993 European multicenter retrospective study demonstrated that when treatment was continued indefinitely, IV HBIG reduced the actuarial risk of recurrence from 74% to 36% at 3 years and, as a result, significantly improved survival.5 Importantly, this treatment was relatively ineffective in patients with HBV cirrhosis and detectable HBV DNA in serum (by hybridization assay), with more than 90% developing recurrent infection versus 29% of those who were HBV DNA–negative.6 It is important to note, however, that the HBV DNA assays used in these early studies had a cutoff for detection of approximately 106 copies/mL, and thus many of the HBV DNA–negative patients would have detectable HBV DNA by modern quantitative assays. Recurrence rates were also much lower in the presence of hepatitis delta virus (17%) and in those with fulminant hepatitis B (no recurrence); in both conditions, HBV DNA levels are usually low or undetectable at the time of transplant.5 Thus, the efficacy of this therapy appeared to be highly dependent on the pretransplant viral load.
In the original European studies, variable dose intervals were used with the aim of maintaining trough anti-HBs concentrations > 100 IU/L. The putative explanation for the relative ineffectiveness of this therapy in HBV DNA–positive recipients was that there is increased clearance of anti-HBs from serum in patients with high circulating viral loads, and this results in a failure to maintain protective anti-HBs titers.7, 8 This problem was partially overcome with higher doses of HBIG. The administration of fixed doses of 10,000 IU of HBIG per month (which commonly achieves trough anti-HBs levels > 500 IU/L) or variable HBIG dosing adjusted to keep anti-HBs > 500 IU/L for the first 6 months post-LT reduced recurrence rates in HBV DNA–positive patients to 20% to 30%.7-9 However, the use of such high doses of HBIG (up to 200,000 IU in the first year) adds greatly to costs.
anti-HBs, hepatitis B surface antibody; HBIG, hepatitis B immune globulin; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HDV, hepatitis delta virus; IM, intramuscular(ly); IV, intravenous(ly); LAM, lamivudine; LAM-R, lamivudine resistance; LT, liver transplantation; NA, not assessable; NA, nucleos(t)ide analogue.
The early results using lamivudine as monotherapy to prevent recurrence were promising, with a reinfection rate of just 10% at 12 months post-LT reported in the initial study.10 However, 50% had developed recurrence by 3 years.11 Similarly, Perillo et al.12 reported a recurrence rate of 41% at 3 years in patients who received lamivudine alone for post-LT hepatitis B prophylaxis. These results were not surprising, given that in nonimmunosuppressed patients, resistance to lamivudine emerges at a rate of 15% to 20% per year as a result of selection of lamivudine-resistant mutations in the YMDD motif of the HBV DNA polymerase.13 As with HBIG, the risk of recurrence in patients receiving lamivudine monotherapy is most closely related to the HBV load prior to its initiation: at 3 years post-LT, patients with detectable HBV DNA by hybridization assay (equating to an HBV DNA of approximately 105–6 copies/mL) at the initiation of lamivudine pre-LT had recurrence rates of 60% versus 0% in patients who were HBV DNA–negative.11, 12 In most studies, HBV DNA–positive patients have commenced lamivudine treatment at the time of listing in order to reduce the level of viral replication at LT. Importantly, this can lead to improvements in liver function, which in some patients may be sufficient to allow removal from the waiting list.14, 15 However, prolonged lamivudine therapy exposes patients to the risk of developing lamivudine resistance pre-LT.12
HIGH-DOSE IV HBIG AND LAMIVUDINE
HBIG and lamivudine have very different mechanisms of action. It was therefore considered likely that in combination these 2 agents would have a number of independent effects that would increase antiviral activity and reduce the risk of recurrence. Indeed, the lowest reported rates of posttransplant hepatitis B recurrence (0%-10%) have been achieved with combined lamivudine and HBIG (see Table 1).16–20 As a result, for the last decade, combination therapy with conventional high-dose IV HBIG and lamivudine [or another nucleosid(t)e] has been the accepted standard of care for preventing post-LT HBV recurrence.
Table 1. Post-LT Hepatitis B Virus Recurrence with a Combination of High-Dose HBIG and Lamivudine
DNA+ at LT
Abbreviations: anti-HBs, hepatitis B surface antibody; HBIG, hepatitis B immune globulin; HBsAg, hepatitis B surface antigen; LAM-R, lamivudine resistance; LT, liver transplantation; NA, not assessable.
10,000 IU daily until HBsAg is cleared, then aim for anti-HBs > 100 IU/L
8% (3 out of 4 LAM-R pre-LT)
In most centers, lamivudine is begun pre-LT with the aim of reducing the viral load in the peri-LT period. IV HBIG is given at a dose of 10,000 IU daily for the first postoperative week and subsequently either at a fixed dose of 10,000 IU/month or with variable dosing to maintain trough anti-HBs titers >100 IU/L.16–19, 21 Some centers have targeted anti-HBs titers of >500 IU/L for 3 to 6 months post-LT in HBV DNA–positive patients. In contrast to the experience with HBIG or lamivudine monotherapy, all of these various combinations are highly effective, regardless of the peritransplant viral load.19, 22
However, there are a number of problems with this treatment. Patients receiving prolonged lamivudine therapy while on the LT waiting list may develop resistance, and this can precipitate worsening liver failure. Post-LT HBV recurrence rates are also increased in patients who have lamivudine-resistant HBV at the time of transplant (see Table 1).18, 22, 23 Furthermore, combination HBIG/lamivudine regimens using fixed IV HBIG dosing are very expensive, with an estimated cost of >$100,000 in the first year post-LT and >$50,000 yearly thereafter.24
ALTERNATIVE COMBINATION IV HBIG/LAMIVUDINE REGIMENS
The expense and inconvenience of long-term IV HBIG/lamivudine therapy has led to the development of a number of strategies for reducing IV HBIG use. Several groups have attempted to individualize HBIG doses by allowing for interpatient variability in HBIG elimination kinetics. Di Paolo et al.25 estimated a >50% saving in cost by the use of on-demand administration of 2000 IU (aiming for a trough anti-HBs of >100 IU/L) in comparison with the regular administration of 5000 IU/month. In another study, 200 IU/kg HBIG was administered daily for 1 week post-LT. Until 6 months post-LT, 2000 IU of HBIG was given when the anti-HBs titer was <100 IU/L, but thereafter doses were given only when the anti-HBs was <10 IU/L. There was no recurrence at a median of 30 months (range, 7-73), despite a mean HBIG use of only 464 IU/month in years subsequent to the first post-LT year.26 This suggests that in the presence of lamivudine, it may not be necessary to achieve anti-HBs levels of >100 IU to minimize recurrence.
LOW-DOSE INTRAMUSCULAR (IM) HBIG AND LAMIVUDINE
A number of studies have shown that the use of IV HBIG is not necessary to maintain effective anti-HBs titers and that in equivalent doses, IM HBIG has similar kinetics and produces trough concentrations roughly equivalent to those produced by IV dosing but at less cost.27 The largest reported experience with the use of IM HBIG prophylaxis comes from investigators in Australia and New Zealand, where IV HBIG preparations are not available. In 2000, it was reported that IM HBIG in combination with lamivudine prevented recurrence in 31 of 32 HBsAg-positive LT recipients with a median follow-up of 18.4 months post-LT.28 All HBV DNA–positive patients commenced lamivudine at transplant listing, and no patient developed lamivudine resistance. These promising results were notable given that the amount of HBIG used (800 IU/day IM for 7 days and then 400-800 IU/month IM thereafter) was <10% of that used in standard high-dose IV HBIG protocols: approximately 15,000 IU in the first year versus 150,000 to 200,000 IU. Trough anti-HBs levels observed during follow-up with this regimen ranged from 27 to 181 IU/L. Importantly, prior to the initiation of lamivudine pre-LT, 50% of the patients in this study were HBV DNA–positive by hybridization assay and therefore at high risk of recurrence.
Long-term results with this protocol have recently been published. In 147 HBsAg-positive patients transplanted over 8 years, the actuarial rate of HBV recurrence was 4% at 5 years.29 Prior to the commencement of lamivudine pre-LT, 31% were HBeAg-positive, and 85% had detectable serum HBV DNA (polymerase chain reaction assay, lower limit of detection = 300 copies/mL) with a median viral load of 6 log10 copies/mL. Over the same period, 8 patients with lamivudine resistance were transplanted with a combination of low-dose IM HBIG, lamivudine, and adefovir, and none developed recurrence. On multivariate analysis, the only factor associated with HBV recurrence–free survival was HBV viral load prior to lamivudine (P = 0.004).
Similar results with IM HBIG and lamivudine have been reported by other groups; however, most have used larger doses or have targeted specific anti-HBs levels (see Table 2). Karademir et al.30 administered 4000 IU of IM HBIG at LT, 2000 IU of IM HBIG daily until an anti-HBs of 200 IU/L was reached, and then 1200 to 2000 IU of IM HBIG when anti-HBs levels fell below 100 IU/L.30 Although the mean total HBIG dose with this protocol was 34,000 IU in the first year post-LT (compared to ∼15,000 IU in the Australasian protocol), in subsequent years, this decreased to ∼5000 IU (compared to 9600 IU in the Australasian protocol). At a median of 16 months post-LT, 2 of 35 patients developed recurrence; however, both had lamivudine resistance pre-transplant and were transplanted prior to the availability of adefovir or other antivirals effective against lamivudine-resistant HBV. IM HBIG has also been used as long-term maintenance therapy following initial therapy with high doses of IV HBIG in the first week post-LT (10,000 IU of IV HBIG daily for 1 week).31 In this study, doses of 1200 IU of IM HBIG were given in an attempt to maintain anti-HBs > 100 IU/L. Over a mean of 20 months (range, 7.8-43) post-LT, only 1 of 28 patients developed recurrence, and this was attributed to noncompliance. The mean anti-HBs achieved was 62.3 IU/L. This protocol reduced the estimated cost of HBIG after the first post-transplant years by 90% versus conventional fixed high-dose therapy.
Table 2. Post-LT HBV Recurrence with a Combination of Low-Dose HBIG and LAM
DNA+ at LT
Abbreviations: anti-HBs, hepatitis B surface antibody; HBIG, hepatitis B immune globulin; HBV, hepatitis B virus; IM, intramuscular; IV, intravenous; LAM, lamivudine; LAM-R, lamivudine resistance; LT, liver transplantation; NA, not assessable
800 IU (IM) at LT and daily for 6 days, then 800 IU (IM) monthly
A recent large retrospective Chinese study reported a higher rate of recurrence with combined low-dose IM HBIG/lamivudine prophylaxis than the rates in previous studies.32 Sixteen of 114 patients (14%) in that study developed recurrence at a mean of 15.8 months (range, 8-36) post-LT. The likely explanation is that only 15 of 114 patients commenced lamivudine prior to LT, even though approximately one-third were high-risk patients with HBV DNA levels pre-LT greater than 105 copies/mL. Not surprisingly, most of the recurrence occurred in these patients. These findings suggest that in patients with high levels of HBV replication, the efficacy of low-dose HBIG therapy may be lessened if the viral load is not reduced with pretransplant antiviral therapy.
The excellent results achieved with very low doses of HBIG/lamivudine therapy challenge conventional thinking about the mechanism of action of HBIG and the doses and target serum levels of anti-HBs required to optimize protection against recurrence. The therapeutic premise behind the original use of high doses of IV HBIG monotherapy was that it prevented graft infection by clearance of circulating virions by antigen-antibody binding or that entry into allograft hepatocytes via a putative HBsAg receptor blockade was blocked. However, Roche et al.21 demonstrated that nearly half of all patients treated with high-dose IV HBIG who were HBsAg-negative at 10 years post-LT had detectable HBV DNA in serum, liver, or peripheral blood mononuclear cells. Similarly, HBV DNA can be detected in more than 80% of allograft livers in patients who have remained serum HBsAg–negative and HBV DNA–negative under combination high-dose IV HBIG/lamivudine prophylaxis.33
Thus, neither high-dose IV HBIG nor combination HBIG/lamivudine prophylaxis prevents graft infection. This explains the life-long need for prophylaxis in most patients. However, the experience with very low dose IM HBIG therapy suggests that in the presence of lamivudine or other powerful inhibitors of HBV replication, relatively low levels of anti-HBs are required to prevent the emergence of resistant mutants and progression from low-level infection to overt disease recurrence.9
CAN HBIG BE STOPPED?
Several authors have investigated whether it is feasible to stop HBIG following an initial successful period of prophylaxis with combination HBIG/lamivudine. In the largest prospective study, 29 patients who were HBV DNA–negative at LT received HBIG/lamivudine for 1 month post-LT and were then randomized to continue combination prophylaxis or change to lamivudine monotherapy.34 The early results were promising, with no recurrence recorded in either group at 18 months. However, with longer follow-up, 15% to 20% of the patients who were switched to lamivudine monotherapy had viral breakthrough due to lamivudine resistance.35, 36 The previous experience with lamivudine monotherapy prophylaxis suggests that the risk of resistance following cessation of HBIG is likely to be considerably lower in patients with low HBV DNA levels (<105 copies/mL) prior to commencing lamivudine therapy.11, 12
An alternative approach is to switch from HBIG/lamivudine to a combination of antiviral agents that present a greater barrier to the development of resistance than lamivudine. Several studies suggest that this approach may be highly effective.37, 38 In a recent randomized prospective study, 16 of 34 patients receiving low-dose IM HBIG/lamivudine prophylaxis who were at least 12 months post-LT were switched to adefovir/lamivudine combination therapy, whereas the remaining patients continued low-dose IM HBIG/lamivudine.38 At a median of 21 months post-switch, no patient in either group had disease recurrence, although 1 patient in the adefovir/lamivudine group had a low titer of HBsAg in serum but was repeatedly HBV DNA–negative according to sensitive polymerase chain reaction. This change in therapy produced significant cost savings and improved patient quality of life.
Other authors have used active posttransplant HBV vaccination with the aim of achieving a durable endogenous anti-HBs response, thus eliminating the need for continued HBIG. Two small studies reported that between 60% and 80% of patients achieved an anti-HBs titer of >10 IU/L following cessation of HBIG and active immunization with 1 to 3 courses of triple vaccination with recombinant IM HBV vaccine.39, 40 However, other studies using a very similar vaccination protocol have failed to replicate these findings.41, 42
The most successful trial of post-LT HBV vaccination achieved anti-HBs titers of >500 IU/mL in 80% of patients.43 Potential reasons for these very impressive results may be that HBIG was continued during the course of vaccination (possibly leading to greater immune stimulation) and that 2 vaccine adjuvants were used to potentiate vaccine immunogenicity. However, other studies using other adjuvants44 and concomitant HBIG administration45 have failed to replicate these results, and this approach, although attractive, remains experimental.
OTHER NUCLEOS(T)IDE ANALOGUES AND HBIG
The development of a range of new oral inhibitors of HBV replication has greatly expanded the therapeutic options available for both the prevention and treatment of post-LT HBV recurrence. These drugs have also altered the natural history of HBV disease. Indeed, many studies have shown that successful antiviral therapy can halt the progression of HBV disease, leading to clinical stabilization and even reversal of liver failure. As a result, the number of transplants being performed for HBV-related liver failure is falling, and HBsAg-positive patients are now more likely to be listed for transplant because of the development of hepatocellular cancer.
The high rate of resistance with prolonged lamivudine therapy makes it a far from ideal drug for use in patients awaiting LT, as failure to maintain suppression of HBV replication may precipitate liver decompensation and increase the risk of HBV recurrence post-LT. This has become of greater concern as waiting times for LT have increased.
New drugs with lower rates of resistance have largely replaced lamivudine as first-line therapy for chronic HBV, and these drugs clearly should also supplant lamivudine in the LT setting. The newer drugs with which there has been greatest clinical experience in the treatment of chronic hepatitis B are adefovir and entecavir. Entecavir is the more potent of the two, and long-term studies have shown that resistance to this drug occurs in just 1% of patients after 3 to 4 years of continuous therapy.46, 47 Adefovir resistance rates are significantly higher, and several studies have reported primary nonresponse rates to the standard 10-mg dose of adefovir of 25% or more.48
Thus, entecavir appears to be a more attractive candidate than adefovir for use in the transplant setting. However, resistance and nonresponse appear to be extremely uncommon when adefovir is initiated at the same time as lamivudine, and this combination has recently been used successfully in LT prophylaxis studies.38, 49 The addition of adefovir while lamivudine is continued may also be the treatment of choice in patients who present for transplantation with established lamivudine resistance.50 A recent study suggested that adefovir is very effective in preventing HBV recurrence post-transplant in patients with lamivudine resistance (with or without the use of HBIG).51 Unfortunately, data were not available from this study to determine how many patients received lamivudine/adefovir or adefovir alone. In contrast, entecavir has relatively modest antiviral activity against lamivudine-resistant virus, and the presence of lamivudine resistance predisposes to subsequent entecavir resistance; this makes this drug a less attractive option for use as monotherapy in lamivudine-resistant patients.52
Another drug that has considerable potential for use in HBV prophylaxis is tenofovir, an acyclic adenine nucleotide, which can be used in higher doses and has greater antiviral activity than adefovir. It is also highly effective against lamivudine-resistant virus.53
Thus, entecavir, adefovir/lamivudine, and tenofovir are all candidates to replace lamivudine for the treatment of HBsAg-positive patients awaiting LT and for use in combination with HBIG post-LT. All have potent antiviral activity in treatment-naïve patients, and their use should lead to further improvements in post-LT outcomes in HBsAg-positive patients. In patients with preexisting lamivudine resistance, adefovir/lamivudine (or adefovir/entecavir) or tenofovir/lamivudine therapy is a logical treatment option. Of course, individualized combinations will be required to provide optimal protection in patients with more complex patterns of drug resistance.
These new drugs have largely replaced lamivudine in the treatment of chronic hepatitis B; however, their safety and efficacy in the transplant setting have yet to be determined. It is also unknown whether, either alone or in combination, they will provide a sufficient barrier to the emergence of resistant mutants to allow for further reductions in HBIG dosing or elimination of HBIG prophylaxis altogether. A number of studies are currently underway that should answer these tantalizing questions.
CONCLUSION: THE BEST HBIG REGIMEN
The guiding principles in developing strategies to prevent HBV recurrence should be to maximize the virological hurdle for resistance while minimizing costs, side effects, and inconvenience to patients. For the last decade, high-dose IV HBIG/lamivudine combination therapy has been the gold standard for hepatitis B prophylaxis. There is now convincing evidence that in the presence of a potent inhibitor of HBV replication such as lamivudine, much lower doses of HBIG are required than were used in the early IV HBIG protocols. Until studies of other antiviral drug combinations are completed, the major cost savings associated with the use of low-dose IM HBIG suggest that this preparation, in combination with a potent inhibitor of HBV replication, is the most cost-effective hepatitis B prophylaxis. The use of newer antivirals such as entecavir, tenofovir, and lamivudine/adefovir in combination with low-dose IM HBIG will further reduce the risk of recurrence, and this will make it even more difficult to justify the continued use of high-dose IV HBIG preparations.
For patients referred for transplantation who are not already receiving anti-HBV therapy, there are clearly a number of excellent candidate drugs or drug combinations that should be used in preference to lamivudine to suppress HBV replication before LT and as part of combination post-LT prophylaxis. Patients who are receiving lamivudine therapy when they present for LT should be switched to an alternative drug or combination, with the choice depending on whether or not they have lamivudine resistance (Fig. 1).
Finally, prophylaxis for HBV recurrence needs to be life-long, as the virus persists indefinitely in the allograft. Consideration should be given to switching from combination HBIG/nucleos(t)ide prophylaxis to oral prophylaxis at 1 or 2 years post-LT, particularly in those patients with low viral loads before commencing antiviral therapy who are HBV DNA–negative at transplant and in patients with fulminant hepatitis B or hepatitis D coinfection, as these groups are at lower risk of breakthrough once HBIG is ceased.3
Table 3. Cost of HBIG/LAM Combination Prophylaxis
Cost: Initial Year Post-LT
Cost: Subsequent Years Post-LT
NOTE: Costs are given in US dollars.
Abbreviations: HBIG, hepatitis B immune globulin; IM, intramuscular; IV, intravenous; LAM, lamivudine; LT, liver transplantation.