Introduction
Chronic hepatitis B virus (HBV) infection remains a major global health issue, affecting up to 350 million people worldwide. Patients with chronic HBV infection are at a significantly increased risk for the development of cirrhosis, hepatic failure, and hepatocellular carcinoma (HCC) and up to one million deaths occur annually from cirrhosis and HCC.[1, 2] Severe reactivation of chronic hepatitis B infection can lead to fulminant or subfulminant hepatic failure. The prognosis of patients with fulminant hepatic failure (excluding acetaminophen-induced hepatic failure) is extremely poor, with a mortality of 65%-93%.[3] For those with a high HBV DNA level, antiviral therapy should be given. Successful and prolonged inhibition of viral replication can prevent or delay the development of cirrhosis and hepatic failure, and reduce the risk for primary HCC. If cirrhosis and hepatic failure develop, the definitive treatment of choice remains orthotopic liver transplantation (OLT). In the absence of prophylaxis or treatment, HBV reinfection occurs in up to 75%-80% of persons who have undergone OLT.[4] Recurrent HBV infection after OLT often follows an aggressive clinical course and is associated with a significant decrease in graft and patient survival rates.[5, 6] Hepatitis B immunoglobulin (HBIg) first became available for use in 1975. This agent provides a means of passive immunity for the patient. Fortunately, the use of HBIg resulted in markedly improved patient and graft survival rates. Newer antiviral therapies (such as lamivudine and adefovir) as prophylactic strategies have been developed to reduce the risk of recurrent HBV infection after OLT. These newer approaches have led to significant improvements in graft and patient outcomes after OLT for HBV infection.
Antiviral therapy for fulminant hepatitis B before liver transplantation
For patients with significant viral replication, reflected by the serum HBV titre, antiviral therapy should be given. Successful and prolonged inhibition of viral replication can prevent or delay progression to cirrhosis, thus preventing the development of hepatic failure and reducing the risk for HCC. For patients with decompensated cirrhosis, antiviral therapy may stabilize or even improve liver function, delaying the need for transplantation. For patients waiting for liver transplantation, antiviral therapy may minimize the HBV titer at the time of transplantation, thereby reducing the risk of recurrent HBV infection after OLT.[7] For HBV carriers treated with chemotherapy or immunosuppressive agents, antiviral therapy demonstrated a clear benefit in terms of clinical and virological HBV reactivation, overall mortality, HBV-related mortality and interruptions or discontinuations of chemotherapy or immunosuppressive therapy.
Lamivudine
Lamivudine is a nucleoside analogue with potent suppression for HBV replication and an excellent safety profile in both compensated and decompensated cirrhotic patients. Early uncontrolled studies demonstrated conflicting results as to whether lamivudine therapy delays progression to death or liver transplantation.[8, 9] Recent findings demonstrate that lamivudine treatment reduces the incidences of hepatic decompensation and HCC in patients with chronic HBV infection and advanced fibrosis or cirrhosis,[10-13] and lamivudine alone or combined with corticosteroids probably decreases the risk of progression to fulminant hepatitis in patients with severe hepatitis B.[14] A large retrospective study of 1036 patients conducted in our department also demonstrated that the percentage of patients recovered or with improved outcomes was significantly higher in those who received lamivudine therapy than those who received no antiviral therapy (Table 1 and Fig. 1). We also found that the outcome would be better if the patients were treated early with nucleoside analogue (Table 2). The major drawback of lamivudine is the development of resistance to the drug caused by mutations in the region of the reverse transcriptase gene. The most common mutations are located in the domain C of HBV polymerase at the tyrosine-methionine-aspartate-aspartate (YMDD) motif.
The clinical consequences of lamivudine resistance vary according to the severity of underlying liver damage. The patients who develop lamivudine resistance always show a rebound in the HBV DNA load. ALT level and progressive hepatic failure have been described in association with the emergence of YMDD mutations.[15]
At present, hepatic failure due to reactivation of HBV in HBV carriers treated with chemotherapy or immunosuppressive agents has also attracted interest of researchers. A recent meta-analysis of fourteen studies involving 275 patients in the preventive lamivudine group and 475 control participants receiving chemotherapy reported that after use of preventive lamivudine, the relative risk for both HBV reactivation and HBV-related hepatitis ranged from 0.00 to 0.21. None of the patients in the preventive lamivudine group developed HBV-related hepatic failure (0 of 108 patients vs. 21 of 162 patients), and only 4 deaths were attributable to HBV (4 of 208 patients vs. 27 of 394 patients) in the preventive lamivudine group. Lamivudine was well tolerated, and no adverse effects were noted.[16] Another meta-analysis of 21 studies in immunosuppressed patients reported that clinical and virological reactivations were significantly reduced in the lamivudine group (0.09 vs. 0.04). All-cause mortality was significantly reduced in the lamivudine group. Lamivudine significantly reduced HBV-related mortality and discontinuations or disruptions of the immunosuppressive treatment. No adverse effects of lamivudine were recorded, and resistance to lamivudine occurred in low rates.[17] Thus, lamivudine should be administered prophylactically to the HBsAg-positive patients who are about to receive chemotherapy or immunosuppressive therapy.
Adefovir
A significant number of patients may develop lamivudine resistant strains of HBV while receiving this drug in the pre-transplant setting. Furthermore, the patients primarily infected with lamivudine-resistant mutants are not uncommon in clinical practice.[18] In such conditions, lamivudine is of little benefit. Previous studies have demonstrated that adefovir has excellent activity against wild-type as well as lamivudine-resistant HBV strains.[19] Reassuringly, the development of adefovir dipivoxil resistance remains relatively rare (3% in 2 years of therapy and 18% in 4 years).[20] In addition, both the adefovir mutations, N236T and A181V, are susceptible to lamivudine though it has been found that tenofovir is more appropriate for A181V mutation. In patients with lamivudine-resistant HBV strains and those who received pre-OLT, adefovir was beneficial in HBV DNA reduction and normalization of ALT, albumin, bilirubin and prothrombin time.[21, 22] Unlike the use of lamivudine, no resistance to adefovir was identified after 48 weeks of therapy in this population.[23, 24] Many patients came off the transplant list because of reversal of the decompensated state.
Prevention and treatment of HBV recurrence
Great improvements have been made in graft and patient survival rates in HBV transplanted patients with antiviral prophylaxis. Without prophylaxis, clinically significant HBV recurred in the transplanted liver. The manifestations of disease varied from subacute graft failure (sometimes with characteristic histological features known as "fibrosing cholestatic hepatitis") to more conventional chronic hepatitis with progressive fibrosis leading to graft cirrhosis.[24] From our clinical experience, the mechanism for HBV recurrence post-OLT can be summarized as follows: 1) no antiviral treatment pre-OLT in HBV DNA negative patients; 2) insufficient antiviral treatment pre-OLT; 3) HBV mutations (mainly lamivudine resistance strains) pre-OLT undetected by real-time PCR; 4) short of professional guidance and insufficient or incomplete follow-up system; and 5) problem in compliance of patients. HBV reinfection after OLT may be due to either the presence of circulating viremia at the time of transplantation or reservoirs of hepatitis B virions in extrahepatic sites such as peripheral blood mononuclear cells.[25-27]
The most important factor that determines the risk of recurrent HBV infection after OLT is the HBV DNA level at the time of transplantation.[28-30] Early experience in Europe demonstrated that the risk of recurrence of HBV infection was greatest in patients with high virus levels before transplantation and that it approached 85% in patients who were found to be positive for HBV DNA with use of a hybridization assay (approximate lower limit of detection, 1¡Á106 copies/ml).[4] We also found that HBV recurrence rates between HBV DNA positive and HBV DNA negative pre-OLT patients were significantly different 1, 2 and 3 years post-OLT respectively (Fig. 2). The risk of a recurrence of HBV infection was significantly lower in HBeAg-negative patients, those with fulminant hepatitis B, and those with hepatitis D virus coinfection; these represent subgroups in which serum HBV DNA levels are typically lower. Therefore, one of the primary goals in the treatment of HBV-infected OLT recipients is to minimize the serum hepatitis B virus level at the time of transplantation.
HBIg
The efficacy of HBIg in prevention of recurrent HBV infection after OLT was first demonstrated in a large, retrospective, multicenter trial conducted in Europe.[4] Improved patient survival rate at three years was noted among those patients receiving passive prophylaxis with HBIg, and long-term administration of HBIg was associated with a relative risk reduction of 3.3 for the development of recurrent HBV.[4] These findings have now been confirmed in multiple studies and the median rate of recurrent HBV in patients receiving long-term HBIg is approximately 20% over one to two years.[31-33] Drawbacks in the use of HBIg include high cost and significant side effects associated with infusion such as headache, flushing and chest pain. However, Takaki et al[34] reported a satisfactory experience with high-dose HBIg in the early period followed by low-dose HBIg combined with lamivudine. Subjects comprised five patients with fulminant hepatitis and 18 patients with liver cirrhosis who underwent liver transplantation. HBIg at a dose of 200 IU/kg per day was administered for one week postoperatively. Thereafter, HBIg was administered only for HBsAb titer <100 IU/L. After six months, HBIg was withdrawn in fulminant hepatitis patients and administered in liver cirrhosis patients only for HBsAb titer <10 IU/L. Lamivudine was given to two fulminant hepatitis and all liver cirrhosis patients. Although two patients with liver cirrhosis showed transient HBsAg recurrence, all patients remained HBsAg-negative at the end of follow-up. This method allows reliable and cost-effective control of hepatitis B recurrence. Furthermore, selection pressure from the use of HBIg may induce the development of mutations in the pre S/S region of the HBV genome. These HBIg escape mutants lead to alterations in the "a" determinant of the surface antigen protein, which has been associated with HBV reinfection and poor outcome after liver transplantation.[35] The notion that such escape mutants develop in response to selection pressure from HBIg is supported by the observation that withdrawal of HBIg therapy leads to reversion to wild-type virus.[36]
As antiviral therapy of patients with HBV cirrhosis becomes a routine practice, an increasing proportion of patients will come to transplantation taking the combination of lamivudine and adefovir, and many of them will have excellent liver function and the indication for OLT may be primary HCC. The need for HBIg post-OLT is not known when viral suppression has been achieved with the combination of lamivudine and adefovir pre-OLT.[37] It was presumed that adefovir shows no cross-resistance to lamivudine previously. However, Karatayli et al[38] reported a novel mutation pattern during lamivudine treatment showing cross-resistance to adefovir. Adefovir was added to a lamivudine-resistant patient for more than 40 months of antiviral treatment. Neither ALT normalization nor a stable decrease in HBV DNA was observed. Then the HBV pol region gene was sequenced. A novel mutation, A181S, in the reverse transcriptase gene was detected along with a M204I mutation. In vivo study showed that this A181S+M204I mutation pattern displayed more than 1000-fold resistance to lamivudine and emtricitabine and approximately six fold resistance to clevudine, while it confers 28.23- and 5.57-fold resistance for adefovir and tenofovir, respectively. In this condition, however, triple prophylaxis with lamivudine, adefovir and HBIg should be sustained post-OLT.
Lamivudine monotherapy
Several studies have examined the benefit of lamivudine monotherapy for the prevention of recurrence of HBV infection after OLT.[39-42] Overall, the results for lamivudine monotherapy are similar to those for HBIg monotherapy for prophylaxis against recurrent HBV infection. As in the pre-OLT period, it is clear that the major limitation of lamivudine monotherapy is the development of resistant YMDD mutants. The rate at which these mutations emerge is higher after OLT than it is among patients who have not undergone transplantation. Once the drug-resistance emerges, liver disease might worsen. For this reason, most transplantation centers currently advocate a combination of lamivudine with HBIg. Osborn et al[43] analyzed data from 122 patients enrolled in the NIH HBV OLT cohort to study the effects of pretransplant antiviral therapy on the transplant-free survival and the survival without transplant. The clinical outcomes of those who did or did not develop antiviral failure (virologic breakthrough or genotypic resistance) while awaiting transplant were also compared. They found out that after initiation of antiviral therapy, forty-four patients (36.1%) developed antiviral failure; all had lamivudine monotherapy as initial treatment. Forty-two patients started salvage therapy at a median of 5 months after lamivudine treatment failure; the median model for end-stage liver disease (MELD) score was 12. Twenty-one patients (50%) had a full response to salvage therapy. Eleven patients (26.2%) had a suboptimal virologic response but remained clinically compensated. Antiviral failure was not a significant predictor of transplant or death (P=0.09) or death without transplant (P=0.39). Multivariate predictors of transplant or death were high MELD score, HCC, and low albumin. High MELD score and low albumin were predictors of death without transplant. They concluded that antiviral failure in patients with HBV infection on the OLT waiting list does not impair clinical outcome, if recognized early and if salvage therapy is promptly initiated.
HBIg and lamivudine combination therapy
The combination of HBIg and lamivudine has been widely adopted for prophylaxis against recurrence of HBV infection after OLT. In contrast to monotherapy, lamivudine in combination with HBIg has been potent in preventing the recurrence of HBV in the post-transplant setting.[44, 45] HBV recurrence rate is usually less than 10% one to two years following transplantation. Furthermore, HBV DNA level determined by PCR is also typically undetectable.[46-49]
Adefovir
The efficacy of adefovir in lamivudine-resistant strains has also been demonstrated in the post-OLT situation. It is expected that the development of adefovir mutations will similarly become a problem in the post-transplant setting. Sequential selection of lamivudine and adefovir resistant strains of HBV after liver transplantation has also been selected recently in one patient.[48, 49] To avoid the occurrence of multi-drug-resistance, adefovir in combination with lamivudine should be used. There are several potential benefits with combination therapy. The chance for breakthrough mutations to either lamivudine or adefovir is significantly less when the agents are used in combination,[37, 50] and that resistance to adefovir is only seen in those patients who stop the treatment with lamivudine. Lo et al[37] concluded that add-on adefovir plus lamivudine should be the "preferred approach in those patients who have already developed resistance to lamivudine so as to avoid the emergence of multi-resistant viral strains." The efficacy of adefovir has been confirmed in the setting lamivudine-resistant graft infection whether it be the development of a mutant while on prophylactic therapy or de novo lamivudine-resistant HBV graft infection.[51] A previous study has shown that there is a low rate of HBeAg seroconversion when adefovir is used in patients with chronic hepatitis B, this is also found in the post-transplant infected patients.[52] Wang et al[45] reported that adefovir plus HBIg combination therapy was effective in prevention of HBV reinfection after OLT. Lo et al[53] also confered that for fibrosing cholestatic hepatitis patients bearing lamivudine resistance, adefovir and high-dose HBIg was a beneficial prophylaxis. Adefovir is thus an effective and safe drug to treat graft infection and prevent clinical deterioration of patients affected with lamivudine-resistant HBV graft de novo infection or to control lamivudine-resistant breakthrough mutants.
Other agents
Entecavir is a new guanosine nucleoside analogue exhibiting activity against lamivudine- and adefovir-resistant HBV strains. Entecavir can profoundly and rapidly inhibit HBV replication, therefore block the immuno-reaction induced liver necrosis due to HBV replication.[54, 55] It is expected that entecavir will be efficacious in the prevention and treatment of recurrent HBV following liver transplantation. Our department has monitored a chronic hepatitis B patient who developed virological breakthough after withdrawal of lamivudine therapy. Lamivudine and adefovir combination therapy was administered but HBV DNA titer still remained at a high level. In such condition, entecavir was used as salvage therapy (Fig. 3). Telbivudine is of some characteristics of entecavir, and furthermore it has better safety by its pregnancy grade B.[56] Tenofovir is also effective for lamivudine resistant mutants and for those patients who have failed in use of lamivudine and adefovir.[57, 58] In case reports, tenofovir produced a well tolerated, successful antiviral response in patients before and after OLT.[59, 60] Soejima et al[61] recently found that for some patients after living donor liver transplantation with anti-HBc-positive grafts or in patients who underwent living donor liver transplantation for fulminant hepatitis B, hepatitis B vaccination might be a replacement therapy of HBIg in consideration of high cost.
Summary
The prognosis of chronic HBV infection is being transformed by developments in antiviral therapy. Viral factors are emphasized in the pathogenesis of HBV-associated severe hepatitis, which has been demonstrated by the efficacy of antiviral therapy by nucleos(t)ide analogues. It appears that sustained suppression of viral replication can be achieved for the majority of patients with available drugs. Nucleos(t)ide analogues can effectively suppress HBV-induced liver inflammation and necrosis in short- term, and prevent hepatitis flares. HBIg, lamivudine, adefovir and combination therapy have demonstrated potential suppression for HBV replication, and that entecavir, telbivudine and tenofovir will be potentially used because of their strong potency. However, there are still some problems. The potential for HBV to reactivate from the liver of donors who have recovered from HBV with natural immunity, and the persistence and detection in serum of HBV DNA during long-term follow-up of patients during successful prophylaxis must remind us that HBV is controlled but never eliminated. The potential for reactivation during changes to prophylaxis and during changes in immunosuppression should be considered. Another problem would be the emergence of multi-drug resistant HBV species which are resistant to both lamivudine and adefovir (or to other current or future combinations).
Funding: This study was supported by grants from the National Basic Research Program of China (973 Program) (No. 2007CB512900) and National Natural Science Foundation of China (No. 30470964).
Ethical approval: Not needed.
Contributors: WYM proposed the idea, structure, and content of this article. TYZ did the literature search and wrote the first draft. WYM also did the revision and final proofread of the article. WYM is the guarantor.
Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.
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Received February 26, 2008
Accepted after revision December 20, 2008
