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Management of Recurrent Viral Hepatitis B and C After Liver Transplantation
  Marzia Montalbano, MD and Guy W. Neff, MD
Guy W. Neff, MD
University of Cincinnati, 231 Albert Sabin Way, MSB Room 6560, Cincinnati, OH 45267-0595, USA.
Current Gastroenterology Reports Feb 2006, 8:60-66
ABSTRACT. Liver transplant teams are often faced with the challenges of managing viral recurrence after liver transplantation. Hepatitis C virus (HCV) remains the most challenging viral disease in the transplant community. Strategies to prevent and delay viral recurrence have slowly developed over the past 5 years. Hepatitis B virus (HBV), previously a contraindication for liver transplantation due to recurrence and cholestasis with allograft failure, is now one of the more favorable indications for liver transplantation as a result of current therapeutic options. This review investigates the up-to-date information on treatment outcomes for HCV and HBV in the period following liver transplant.
Chronic liver disease caused by chronic hepatitis C (HCV) and hepatitis B virus (HBV) infection is the leading indication for orthotopic liver transplantation (OLT). The treatment of HCV recurrence after liver transplantation is considered universal and is the biggest challenge for the managing transplant team. However, therapeutic interventions and preventive strategies for HCV recurrence are not standardized and vary according to institutional protocol. Conversely, therapies against HBV, primarily hepatitis B immune globulin (HBIg) and various oral therapies, have markedly improved the outcome in HBV transplant recipients. This article provides a comprehensive review of the literature and assesses the primary problems in the management of HBV and HCV patients after OLT.


Hepatitis C Virus
Chronic HCV is the most common cause of end-stage liver disease, with approximately 200 million people infected worldwide. It is also the indication for up to 42% of all the OLT performed, according to current statistics from the United Network of Organ Sharing (UNOS) and international data (European Association for the Study of Liver Disease [EASL] International Consensus Conference on Hepatitis C, 1999).
Hepatitis C virus recurrence in the post-OLT period is considered universal and tends to be more aggressive than in the pre-OLT setting, with evidence of cirrhosis in 20% to 40% of the HCV transplanted patients within 5 years of transplant [ 1, 2, 3, 4, 5, 6]. In these patients the 3-year survival after cirrhosis decompensation tends to be less than 10% [7]. Treatment options against HCV in the transplant setting have not advanced as anticipated over the past two decades. Thus, HCV recurrence continues to result in allograft failure and decreased long-term survival in transplant recipients. The rapid progression to cirrhosis or allograft dysfunction has led the post-transplant care community to examine alternate strategies and different anti-HCV therapies to reduce fibrosis progression.
Antiviral strategies for HCV
Transplant treatment regimens can be divided into the following three stages: pretransplant, pre-emptive, and established HCV recurrence (Fig. 1). Overall, the primary antiviral therapy in the post-transplant period has been standard interferon (IFN) formulations, which have been disappointing. Earlier studies focusing on the use of pegylated IFN products, which have a prolonged duration of effect produced by a large inert, water-soluble molecule, polyethylene glycol (PEG), attached to the active drug moiety, showed some promise [8]. This resulted in a longer half-life and increased trough levels. Ribavirin therapy is nearly always combined with IFN but must be cautiously administered in this population. Reports from nearly all trials using ribavirin reveal a high proportion of hemolytic anemia. Transplanted patients are more intolerant of high doses of ribavirin, compared with patients treated before hepatic decompensation. The exact disease mechanism is unknown but is thought to be a combination of post-transplant renal insufficiency, marrow suppression, and possibly erythrocyte fragility. The initial dosage often needs to be reduced to 400 to 600 mg daily to maintain acceptable hemoglobin levels.
Therapeutic interventions for HCV following transplant tend to be applied after established viral recurrence. The limited data regarding the use of pre-emptive treatment, therapy given before hepatitis recurrence, with PEG-IFN and ribavirin, did not show a significant advance. In fact, the difficulties with therapy were often related to a prolonged recovery period in liver transplantation and the commonly associated morbidity issues of anemia and renal insufficiency [9, 10*, 11].
Treatment following recurrence has been more commonly adopted, showing response rates of 25% to 35% [12, 13]. Sustained viral response (SVR) appears to occur in 10% to 30% of treated patients, and a reduction in the necroinflammatory index has also been reported in nonresponding patients [8]. Side effects are not uncommon and often lead to patients dropping out of studies. The most common drug-related complications are depression, with some trials reporting an incidence of more than 50%; anemia; and thrombocytopenia, leading to the reduction of dosage in up to 75% of patients [8, 14].
Attention has recently been directed at reducing or clearing serum HCV RNA before transplant. However, it can be argued that these patients are particularly ill and may not tolerate treatment. Indeed, one of the first pretreatment trials had to be suspended due to the high proportion of serious complications and adverse events, leading to limited efficacy. This study, which evaluated a group of patients with decompensated disease and an average Child-Turcotte-Pugh (CTP) score of 12 points, was halted due to the marked increase in drug-related complications [15].
A recent study from the University of Colorado showed more promising results, yet with much lower CTP scores. These investigators treated cirrhotic patients, the majority of whom had complications of cirrhosis, and obtained a 46% response rate at the end of treatment and a 22% SVR. Eighty percent of the transplanted patients with negative HCV RNA at time of transplant remained negative at least 6 months after transplantation [16]. They used an escalating dose of antiviral therapy and achieved treatment response (polymerase chain reaction [PCR] negative) in 10 of 40 patients before living related donor transplantation, with a high SVR rate after transplantation. This study supports the potential of the therapeutic approach to lead to satisfactory results, especially when including the expansion of living donation. Patients affected with hepatocellular carcinoma with a low CTP score who can better tolerate antiviral therapy could benefit from transplant scheduled at the time of HCV negativity or, when possible, after SVR [16].
Limitations for the treatment of chronic HCV are complicated in the transplant recipient due to decreased response to antiviral therapy, poor tolerance of therapies, and lack of treatment standardization. The lack of ability to slow the progression of allograft failure and/or fibrosis continues to stifle transplant teams throughout the world. The end results of many transplant trials, whether pre-emptive, pretransplant, or after HCV recurrence, have not been successful in post-transplant patients, especially compared with non-transplant patients. Effective interventions to improve long-term survival and combat HCV-related cholestasis and allograft dysfunction appear to be years away. More importantly, newer regimens appear to have IFN-based treatment as a primary ingredient within the combination therapy cocktail.
The effects of non-antiviral-related strategies (immunosuppression agents and angiotensin-converting enzyme inhibitors)
Immune suppression has always been implicated as the primary reason for the poor response to antiviral therapy and the aggressive nature of HCV after liver transplantation. The use of steroids and calcineurin inhibitors has been analyzed and contested as promoting HCV recurrence in the post-transplant period [17]. Steroids have been either encouraged or disapproved of based on the retrospective analysis of different phases after transplantation. A tendency toward increase in serum HCV RNA levels seems to be associated with the early phase after transplantation when the use of immunosuppression is greatest and the use of a steroid bolus more frequent. In fact, Berenguer et al. showed in an analysis based on the historic timing of transplantation more aggressive HCV recurrence in those patients who were given a shorter course of steroids [18, 19, 20]. Several factors within this analysis, including treatment variations among transplant teams and the increased use of marginal donors, may have affected their outcomes. Recently the same group reviewed their position and concluded that severe recurrence of HCV tended to be lower in patients who received reduced immunosuppression and a longer duration of steroid therapy. In addition, no differences were shown between patients on cyclosporine as opposed to tacrolimus, as previously demonstrated when comparing the long-term histologic results in these two groups of patients [21, 22].
Stable immune suppression, in particular calcineurin inhibitors, is vital for long-term allograft function. We found that long-term allograft survival in transplant recipients with HCV was improved when immune suppression was well controlled and was maintained within normal ranges. In fact, calcineurin inhibitor maintained at normal serum levels (7-9 ng), when compared with groups with elevated or low calcineurin inhibitor serum levels, fared the best in terms of allograft survival and function [23]. Overall, the best strategy for liver transplant recipients with HCV seems to be associated with avoidance of both abrupt changes and overuse of immunosuppression [24*].
Sirolimus, another potent immune-suppressive agent, holds great promise in preventing chronic renal insufficiency in all liver transplant recipients. However, in a review of liver transplant recipients suffering from HCV recurrence, sirolimus-related hepatotoxicity was found to be an important complication. We concluded that immediate recognition is critical to avoid confusion with other causes of abnormal serum amino transferases after liver transplant, and the drug may need to be discontinued [25].
In addition to immunosuppression strategies, recent attention has focused on the less expensive and often used anti-hypertensive class of drug, angiotensin-converting enzyme (ACE) inhibitors. After initial reports of decreasing or slowing the progression to cirrhosis and the potential for a reduction in fibrosis progression index, others have found ACE inhibitors to be less promising [26, 27]. Also, these reports are based on retrospective analysis and not on prospective studies, which are needed to show overall impact.
Hepatitis B Virus
Hepatitis B virus accounts for approximately 4% to 5% of transplant volume in the United States and approximately 8% in Europe. Before the advent of effective immunologic or antiviral therapy for HBV infection, the role of liver transplantation was clouded in controversy [28]. In the early 1990s, many centers elected to discontinue transplantation in patients with chronic HBV because of high viral recurrence rates associated with poor graft and patient survival [29, 30, 31, 32].
Improvement in patient and allograft survival has resulted due to strategies based on the use of polyclonal anti-HBV globulin and the advent of several oral nucleoside analogs (Table 1). Thus, denying liver transplantation to HBV-cirrhotic patients is no longer justifiable [33].
Hepatitis B virus recurrence after transplantation also depends on HBV DNA negativity before transplant and its maintenance thereafter. A recent study showed a linear correlation between recurrence and viral load at the time of surgery and identified an HBV DNA viral level greater than 100,000 copies/mL to be significantly associated with HBV recurrence [34]. For this reason it is accepted practice in many centers to exclude HBV patients from OLT until HBV DNA is undetectable, and the most important strategies depend on preemptive treatment to avoid HBV DNA reactivation [35*, 36].
The primary goal in therapy for HBV is to maintain suppression of HBV DNA replication.
Hepatitis B immunoglobulin
The long-term use of hepatitis B immunoglobulin (HBIg) was the first successful strategy adopted to reduce the rate of HBV reinfection and to improve patient and graft survival. HBIg is administered intravenously or intramuscularly, and serum anti-HB levels are maintained at greater than 100 IU/L. The primary defense mechanism is based on a European report showing an improvement in allograft and patient survival when HBV reactivation is prevented [37]. The multicenter European study showed that the rate of recurrent infection was directly related to HBV DNA viral load before transplantation during HBIg prophylaxis [38]. The authors also noted that patients coinfected with hepatitis D virus (HDV) had a higher recurrence rate [39]. Other studies showed that HBIg reduced the risk of recurrence to 16% to 35% in pre-OLT replicating patients and to 0% to 15% in the absence of replication [40, 41]. HBIg is safe when administered at high enough doses to ensure protective anti-HB levels but is complicated by drug-related side effects and high cost. In addition, long-term HBIg administration is not only very expensive but also may be associated with emergence of escape HBV mutants and cholestatic HBV [42, 43]. Until nucleoside and nucleotide agents became available, these circumstances often resulted in patient death, as treatment options were limited.
Combining HBIg with lamivudine has brought promising results, in particular with long-term viral suppression [44*]. Review of the data showed the importance of stratifying patients according to disease specifics and other factors that may be associated with obtaining a lower recurrence rate, including negative hepatitis B e antigen and/or serum hepatitis B virus DNA before transplant, hepatitis D virus superinfection, and fulminant hepatitis B. Combination prophylaxis with HBIg and lamivudine was reported to reduce the overall rate of recurrent hepatitis B to 0% to 10%, versus 20% to 35% with HBIg monotherapy [44*]. These findings show the similarities of HBV and HCV in that the clinical setting should determine the type of therapy required to maintain viral suppression and allograft function. Treatment algorithms need to be created according to the multitude of variables within the clinical setting. Therapies based on HBIg are very effective, especially when combined with lamivudine, but they are costly and not without a multitude of drug-related side effects.
Nucleoside and nucleotide analogs
Therapy for HBV, in all settings, changed with the introduction of nucleoside and nucleotide agents. The introduction of nucleoside analogs such as lamivudine and adefovir dipivoxil, both orally administered and with absence of significant toxicity, had a significant impact on the management of HBV following transplantation.
Lamivudine has been used extensively in OLT candidates. It results in HBV DNA suppression in 60% to 100% of patients within 2 to 3 months, but uninterrupted therapy is required before OLT to bring patients to transplant with a negative HBV DNA level [45, 46, 47]. However, transplant recipients suffer a high mutation frequency to chronic HBV when treated with lamivudine alone, ranging from 23% to 50%. For this reason almost all transplant centers have adopted a combination therapy of HBIg plus lamivudine that is capable of reducing the reinfection rate to 0% to 18% within 2 years of treatment [48*]. Lamivudine resistance is commonly confirmed, either before or after transplant, by the selection of a mutation in the C region of the polymerase gene that has the YMDD motif. The detection before OLT of the presence of this YMDD mutation is important because of its association with viral breakthrough, which requires the temporary suspension of those patients from the waiting list and the addition of adefovir to their treatment. Its continuation after OLT, in association with HBIg and lamivudine, is also recommended, particularly for patients who experience breakthrough [49, 50]. In a recent study in pre-OLT patients a 15% incidence rate of adefovir resistance was detected in patients on adefovir monotherapy for 4 years after developing lamivudine resistance, whereas no resistance developed in patients maintained on double therapy [51].
Several nucleoside and nucleotide analogs with activity against HBV are under evaluation for use in the transplant setting. One in particular, tenofovir disoproxil fumarate, a nucleotide analog, acts as a reverse transcriptase inhibitor and is approved by the US Food and Drug Association only for therapy in patients with HIV. However, tenofovir has been found to be effective against HBV when used in coinfected patients [52]. In the transplant setting, tenofovir was administered in a group of patients with lamivudine-related HBV-YMDD breakthrough mutations and found to be very effective [53]. Tenofovir decreased the replication of lamivudine-resistant HBV variants as evidenced by a decrease in HBV DNA among post-transplant recipients. This finding was accompanied by normalization of aminotransferases in the majority of patients. Viral suppression was rapid, in particular, when compared with adefovir [54]. These results demonstrate another potential option for the treatment of lamivudine-resistant HBV after liver transplant. However, this practice will require formal prospective evaluation to determine failure rates, adverse events, and emergence of tenofovir-resistant mutants.
All in all, the nucleoside and nucleotide analogs have changed the prospects of liver transplant recipients with HBV. Future therapies will be geared toward maintenance of viral suppression and most likely will be given in combination therapies that will include both a nucleoside and a nucleotide analog [53].
Use of graft at "increased risk"
Due to the shortage of organ donors, the use of extended criteria donor (ECD) organs has increased. One of the more common types of ECD organ is that of anti-HBc-positive donors. Due to the effectiveness of present therapies against HBV and the extreme organ donor shortages, this type of ECD organ has been routinely transplanted into HBV-positive or HBV-naive patients. This practice has been successful with prophylactic therapy using a combination of HBIg and lamivudine or even lamivudine alone [55, 56, 57, 58, 59]. Some authors have suggested that post-transplant pre-emptive antiviral therapy may not be needed with anti-HBc organs [60, 61, 62]. This strategy is often used when the recipient is anti-HBs positive before transplant, and it may provide viral suppression [58]. In liver transplantation using anti-HBc positive allografts, the development of post-transplant HBV infection appears to be related to the following factors: 1) the presence of the HBV genome in the donor liver; 2) detectable viral replication in the recipient prior to transplantation; and 3) negative anti-HBs status in the recipient [63, 64, 65, 66].
The Italian Association for the Study of the Liver reported their incidence of recurrence during monotherapy or combined therapy [67]. The recipients were divided in three groups based on the risk of activating infection: 1) high risk (33%-75%, recipient negative for anti-HB); 2) low risk (0%-13%, recipient positive for anti-HBs and anti-HBc); and 3) virtually no risk, in which the recipient is vaccinated with a protective titer or not vaccinated but anti-HBs positive and anti-HBc negative. The use of lamivudine plus HBIg has been suggested for group 1, and lamivudine or HBIg alone in groups 2 and 3.
Another group has investigated the use of HBsAg-positive donors. This bold attempt was made in recipients suffering from HBV-related cirrhosis with organs from HbsAg-positive donors. The most recent report from this group on three HbsAg-positive patients (two of whom were also HDV coinfected) was not encouraging [68]. In all patients, HBIg prophylaxis was ineffective. The two HDV coinfected patients had a prompt HDV reinfection with clinical and histologic evidence of hepatitis, and one of them required retransplantation. None of the patients cleared HBsAg, and only the non-HDV patient, who was started prophylactically on adefovir-dipivoxil treatment in addition to lamivudine, had an uneventful follow-up. This study is limited by the small number of patients but may suggest promise in the clinical setting with combination antiviral prophylaxis following transplantation.
HBV summary
Hepatitis B virus infection represents a currently approved indication for transplantation, and the potential for long-term survival is very high. A low viral titer, or better yet, negative HBV DNA, is recommended before transplant, and the use of nucleoside or nucleotide analogs to reach this target during the pretransplant waiting time is the standard practice. After transplantation, prophylactic treatment is mandatory, but the literature regarding post-transplant prophylaxis for prevention and/or suppression of HBV DNA tends to be center-dependent throughout the world. Due to the severe shortage of organs and to the new antiviral therapies, the use of HBc-positive donors is now accepted and routinely performed.
Management of viral hepatitis in liver transplant patients tends to be center-dependent. Controversies are often related to the variations that persist in the approach used by different centers and the lack of agreement to collaborate and determine best practices. Large multicenter prospective trials are needed to help standardize the post-transplant therapeutic regimens. Treatment algorithms are needed for aggressive treatment of HCV recurrence if we expect to improve long-term allograft survival in HCV transplant recipients. Meanwhile, new HBV treatments have made transplantation in this cohort one of the best suited for long-term survival.
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