Journal of Hepatology
Volume 34, Issue 6 , Pages 943-945, June 2001

Liver transplantation and hepatitis B virus infection: the situation seems to be under control, but the virus is still there

  • Didier Samuel

      Affiliations

    • Corresponding Author InformationTel.: +33-1-45-59-33-31; fax: +33-1-45-59-38-57

Centre HépatoBiliaire, Hôpital Paul Brousse, Faculté de Médecine Paris Sud, Upres 1596, EPI 99-41, Villejuif, Paris, France

See Articles, pages 888–894, 895–902, 903–910

Article Outline

 

Over the last years, major advances have been made in the management of hepatitis B virus (HBV) transplant candidates. The advent of long term anti-HBs immunoglobulin administration as a prophylaxis of HBV recurrence was a major breakthrough in the management of these patients [1], [2]. Several studies have shown that, using this prophylaxis, HBV recurrence can be reduced to 20–30% in HBV infected patients, related to the initial liver disease and the level of HBV replication at time of transplantation. The rate of HBV reinfection was reported to be 0–10% in fulminant hepatitis B patients, 10–20% in HBV-HDV coinfected cirrhotic patients, 20-35% in HBV cirrhotic patients without HBV replication, and 30–80% in HBV cirrhotic patients with HBV replication [2].

The anti-HBs Ig (HBIG) administration is well supported particularly in countries where the IV form has been licensed. The side effects are usually minor and rare. Mercury poisoning has been reported anecdotally in a few patients receiving an IM form of HBIG via the intravenous route perfusion [3] but has never been reported in Europe where the IV form is licensed. Some cases of immune reactions have been reported but are easily prevented by infusion of steroids, antihistaminic drugs and longer duration of perfusion. Despite a relatively good long-term tolerance, long-term HBIG administration has several drawbacks: First, HBIG administration is expensive; the cost is highly variable, depending on the country and on the manufacturer, but remains high particularly on a long-term basis [2]. Second, HBIG administration remains constraining because of the need for close monitoring of the level of serum anti-HBs antibody and frequent reinjection every one or 2 months, depending of these levels. Third, HBV reinfection rate remains high in high-risk groups (i.e. patients in whom HBV DNA is detected in serum by conventional hybridisation techniques).

For this latter reason, until recently, the detection of serum HBV DNA was considered as a contraindication to liver transplantation [4]. Several attempts have been proposed to overcome this. Using very high doses of HBIG, it has been shown that it is possible to reduce the rate of HBV reinfection in HBV replicative cirrhotic patients [5]. Further, the advent of lamivudine, a potent anti-HBV drug, has been a major breakthrough in controlling HBV replication prior to transplantation. Lamivudine is well tolerated even in severely ill cirrhotic patients, and is effective by achieving a negativation of HBV DNA (by molecular hybridisation) in 90% of patients [6], [7], [8], [9]. It has also been proposed to continue lamivudine after transplantation as prophylactic monotherapy without concomitant HBIG administration. Good initial results were reported using post-transplantation lamivudine monotherapy prophylaxis with low rate of HBV recurrence at one year [10]. Recent data have shown that this policy of post-transplant monotherapy prophylaxis with lamivudine failed in 30–50% of patients. These patients developed HBV recurrence with the YMDD escape HBV mutant [11] and sometimes had a severe clinical outcome [12]. A recent multicenter US study in patients receiving lamivudine alone pre-and post-transplantation reported disappointing results with an overall HBV recurrence rate of 40% at 1 year [13]. Several groups developed a more rationale approach by giving lamivudine pre-transplantation and a combination of lamivudine and HBIG post-transplantation [[7], [14], [15], [16]]. The initial results were very encouraging demonstrating disappearance of HBV DNA prior to transplantation and absence of HBV recurrence. In these studies, the HBV recurrence rate at 1–2 years was less than 20%. In addition HBV DNA was found to be negative by PCR in most cases at one year. The papers by Marzano and colleagues [17] and Rosenau and colleagues [18] in this issue of the Journal of Hepatology are based on this approach. Marzano and colleagues reported on 26 patients who received lamivudine pre-transplantation and all became HBV DNA negative at time of transplantation. Following transplantation, patients were given a combination of HBIG and lamivudine and HBV recurred in one (4%) at a median follow-up of 31 months. Using a similar protocol of combined post-transplant prophylaxis, Rosenau et al. reported 2 cases of HBV recurrence in a series of 21 patients. Both groups described several interesting aspects: (a) Lamivudine co-administration permits the reduction of the overall amount of HBIG given post-transplantation in comparison to an historical group receiving HBIG alone. This suggests that HBV suppression by lamivudine reduces the production of HBsAg and therefore reduces the need for HBIG. (b) These studies confirm the excellent results of a combined prophylactic approach in those patients who became HBV DNA negative at time of transplantation.

Thus in the high-risk situation it is suggested than the combination prophylaxis approach will give excellent results and may be at a reduced cost.

The other important aspect in the long-term management of HBIG prophylaxis is the possibility to stop HBIG and to replace it by lamivudine. The aims are to reduce the long-term cost of HBIG administration and the constraint of long-term HBIG administration. In this issue of the Journal of Hepatology, Naoumov and colleagues conducted a well-designed study comparing HBV reinfection rate in a group of transplanted patients randomized to receive HBIG or lamivudine after a minimum of 6 months administration of HBIG [19]. Patients were selected on a low risk HBV reinfection basis (i.e. absence of detectable HBV DNA at time of transplantation and no HBV reinfection after a minimal follow-up of 6 months after transplantation). At 1 year, HBV reinfection rate was not significantly different: two of 12 and one of 12 in the lamivudine and HBIG groups, respectively. Authors conclude that HBIG can be safely stopped if replaced by lamivudine in this selected group of transplant patients.

These three different studies [17], [18], [19] with different objectives showed the favourable influence of lamivudine in the management of HBV chronically infected patients either before or after liver transplantation. However, looking carefully at the results, it is important to underline the limitations of lamivudine. First, in the pre-transplant setting, lamivudine is very effective but has several drawbacks: the risk of HBV escape mutation is high and increases with time. This becomes frequent in patients waiting for a long period of time before transplantation. In a recent case report, it has recently be claimed that HBV escape mutation before transplantation does not contraindicate transplantation and that HBV reinfection will not recur with appropriate prophylaxis [20]. However, Rosenau et al. [18] showed that two patients who underwent liver transplantation, despite emergence of YMDD mutant prior to transplantation, rapidly developed HBV reinfection after transplantation despite adequate combined post-transplantation prophylaxis. This suggests that liver transplantation should be contraindicated in case of emergence of HBV escape mutations before transplantation. The advent of adefovir dipivoxil which is active against HBV resistant strains to lamivudine may solve this problem in the future [21]. In the study by Marzano et al., despite the use of a combined prophylactic approach, HBV DNA was detected by PCR at a low level (103–105) in 16 of 25 patients without HBV recurrence [17]. In the study by Naoumov et al. [19], after withdrawal of HBIG, HBV DNA was also detected in the serum of seven of ten patients without HBV recurrence by PCR. This should keep us alert. Indeed, the follow-up of all these studies is limited, around 1–2 years, and it has been clearly shown that the risk of escape mutations with lamivudine increase with time. In a recent study by the Barcelona group, HBIG administration was discontinued in a select group of patients and replaced by anti-HBV vaccination [22]. The authors also claimed good results with anti-HBs antibody production and absence of HBV reinfection. However, looking carefully at the results, the antibody level was low in most patients and was declining with time in the majority of patients and follow-up was limited. This emphasises the important principle in liver transplantation for HBV, that a minimal follow-up of 2 years is required before drawing any conclusion on the risk of HBV recurrence.

An important issue arising from these three important papers is the need for a virological basis to all these new therapeutical approaches. The finding that HBV DNA was detected at a low level in several patients, despite combined or mono-prophylaxis, emphasises the need for HBV DNA monitoring based on PCR methods. In addition, when stopping HBIG it is important to determine which patients should be chosen. Naoumov and colleagues has chosen patients without HBV replication at transplantation and who were a minimum of 6 months post-transplantation. This delay may be too short since the two patients who become reinfected were less than 1 year post-transplantation. In our experience, most cases of HBV reinfection occurred during the 3 first years post-transplantation and rarely thereafter (Samuel, personal communication). We have recently shown in our HBV transplanted patients who are HBsAg negative on HBIG long-term therapy, that HBV DNA is still present in serum, liver or peripheral blood mononuclear cells at a low level in 50% of the patients at 10 years post-transplantation [23]. This is irrespective of the initial liver disease. This would suggest that HBV DNA testing by PCR in serum should be performed before discontinuation of HBIG. One of the important challenges in the future will be to identify patients who have cleared HBV post-transplantation and in whom prophylaxis can be stopped safely.

In conclusion, these studies confirm the major therapeutic improvements made in the prevention of HBV reinfection after liver transplantation for HBV chronic infection. HBV reinfection seems now to be under control with the use of lamivudine and HBIG prophylaxis. However, this should not make us too confident. We need to keep in mind the difficulties in determining that HBV is cleared in these patients, and that lamivudine escape increase with the duration of treatment. We need also to keep in mind that the patients who are at high risk of HBV reinfection (i.e. those with HBV replication) should receive the stronger prophylaxis post-transplantation in order to maintain these patients free of HBV recurrence long term.

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Acknowledgements 

I thank Dr E Hagopian for helpful comments.

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References 

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PII: S0168-8278(01)00102-7

Journal of Hepatology
Volume 34, Issue 6 , Pages 943-945, June 2001

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