Hepatitis B and C in the Liver Transplant Recipient

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Here are some interesting articles:

Hepatitis B and C in the Liver Transplant Recipient

from Seminars in Liver Disease

Hugo R. Rosen, M.D. 1 and Paul Martin, M.D. 2, 1 Division of Gastroenterology/Hepatology and Liver Transplantation Program, Portland Veterans Administration, and Oregon Health Sciences University, Portland, Oregon; 2Division of Digestive Diseases and Dumont-UCLA Transplant Program, Center for Health Sciences, University of California at Los Angeles; Los Angeles, California.

Abstract and Introduction
Abstract
Liver disease related to chronic viral hepatitis is the leading indication for orthotopic liver transplantation (OLT) worldwide. The evolution of our understanding of hepatitis B and C infection in the OLT recipient has been rapid in the last decade. The spontaneous risk for viral recurrence after transplantation is high but has been effectively decreased in hepatitis B infected recipients with the use of HBIG and lamivudine with dramatic improvements in patient and graft survivals. HCV recurrence as defined by histologic injury is almost universal although graft or patient outcomes for the first decade after OLT do not appear to be limited by HCV infection for most patients. However, individual patients do suffer severe graft injury and even graft loss due to recurrent HCV. With longer follow up into the second decade, the prevalence of HCV-related graft failure is likely to increase. In addition, the role of different immunosuppressive protocols on disease recurrence requires further study. Thus, although hepatitis B recurrence has been effectively contained by use of HBIG with or without lamivudine, the more intractable problem of managing recurrent HCV has as yet no obvious solutions. Optimal antiviral strategies for hepatitis C post-OLT have yet to be identified.

Introduction
Liver disease related to chronic viral hepatitis, such as hepatitis B and C, is the leading indication for ortho-topic liver transplantation (OLT) worldwide. In addition, viral reinfection of the liver allograft may lead to graft failure, death, or the need for retransplantation. Although additional viruses that may infect the liver (e.g., hepatitis G and TT-V) have been identified, their significance as major causes of liver disease remains unclear. Therefore, the focus of this review will be the hepatitis B and hepatitis C viruses, including their natural history following liver transplantation, mechanisms of recur-rence, pathogenesis, and treatment.

Overview Of Hepatitis B in the Liver Transplant Recipient
By the late 1980s, orthotopic liver transplantation (OLT) for patients infected with the hepatitis B virus (HBV) had been identified as having impaired graft and patient outcomes due to allograft reinfection by HBV following otherwise technically successful transplantation.[1] Many centers became reluctant to offer OLT to HBV infected patients and the number of transplants performed in the United States for this indication declined through the early 1990s.[2] Once the prognostic significance of active HBV replication pre-OLT had been recognized as well as the protective effect of long-term high dose hepatitis B immunoglobulin (HBIG) administration, strategies to prevent graft reinfection by HBV evolved.[3] More recently, the use of nucleoside analogues with efficacy against HBV has helped decrease the burden of recurrent hepatitis post-OLT.[4] Current concerns include the prevention of mutant forms of HBV that have been described with monotherapy with either nucleoside analogues [5] or HBIG [6,7] as well as providing adequate allograft protection against recurrent HBV without the prohibitively high cost of high dose HBIG particularly when administered by intravenous infusion. Overall, however, the management of HBV in the OLT candidate has undergone considerable change over the last decade and it is now possible to offer OLT with a low likelihood of graft reinfection for the candidate with HBV. Universal vaccination against HBV will eventually reduce the burden of HBV-related cirrhosis and hepatocellular carcinoma (HCC), as has been already demonstrated in Asia, [8] but it will be many years before HBV ceases to be an important indication for OLT as 300 million individuals worldwide are already chronically infected.

Natural History of Recurrent HBV: The Pre-HBIG Era
The burden of recurrent HBV was graphically illustrated in a report from the University of Pittsburgh before the introduction of effective immunoprophylaxis.[1] HBV recurrence was observed in over 80% of patients surviving more than 2 months post-OLT and was implicated in 73% of all post-OLT deaths beyond the first 60 days. Although the initial post-operative course was clinically indistinguishable from that of patients transplanted for other indications, in the next several weeks, biochemical evidence of graft dysfunction was accompanied by biopsy features of acute viral hepatitis. Within several months of OLT, features of chronic viral hepatitis would emerge with accelerated progression to cirrhosis and graft failure within an average of 2.5 years post-operatively. A more recent retrospective multicenter US experience has again highlighted the poorer out-come for the HBV infected patient in the absence of adequate prophylaxis when compared with patients transplanted for causes other than viral hepatitis.[9] Thus, the 1 and 5 year survivals were significantly diminished at 72 and 51% respectively for patients transplanted for HBV compared with a control group with cholestatic liver disease where the corresponding survival figures were 84 and 74% with the difference in survivals predominantly related to HBV recurrence. However, the tempo of graft injury can be even more rapid with graft cirrhosis developing within 1 year after OLT. A specific form of HBV recurrence, fibrosing cholestatic hepatitis (FCH), is associated with profound hepatic dysfunction and rapid graft failure.[10] The biopsy features of FCH are notable, in addition to cholestasis and fibrosis, for relatively little inflammation with periportal fibrosis and ballooning of pericentral hepatocytes. Immunohistochemical studies have shown abundant expression of HBsAg and HBcAg, which in conjunction with the modest degree of inflammation has lead to the suggestion that this form of graft injury is due to a direct cytopathic effect of HBV. Experimental evidence for this is provided by a transgenic mouse model of excessive surface antigen production and hepatocyte accumulation leading to liver injury similar to FCH [11] as well as the demonstration in patients with FCH of increased transcription of HBV.[12] HBV recurrence can also rapidly progress to severe acute hepatocellular injury and graft failure.

Charlton and colleagues [13] have also provided recent information from the prospectively collected NIDDK OLT database on the outcome of HBV-infected patients transplanted in the United States from three major participating programs between 1990-1994. Although the focus was hepatitis C virus (HCV) recur-rence following OLT, the survival of patients transplanted for HBV was significantly impaired when compared to the HCV infected group (P = .003), which in turn was worse (P = .001) than the benchmark cholestatic cirrhosis (e.g., primary biliary cirrhosis and primary sclerosing cholangitis) group, indicating that until the mid 1990s, HBV was a predictor of a diminished outcome post-OLT, indeed as poor as OLT for malignancy.

Predictors of HBV Recurrence
The importance of HBIG therapy and HBV replica-tive status pre-OLT as predictors of HBV recurrence was elucidated in a seminal multicenter European study of over 300 patients.[14] The highest risk of recurrence, 83% actuarial rate at 3 years, was observed in recipients who had markers of active replication, that is, HBeAg in serum and HBV DNA detectable by molecular hybridization pre-OLT. The lowest HBV recurrence rate (16%) occurred in patients transplanted for severe acute HBV leading to liver failure where paradoxically spontaneous clearance of HBV is frequent. Patients with chronic HBV without markers of active replication had an intermediate rate of HBV recurrence at 58%. Coin-fection with hepatitis delta virus (HDV) resulted in a rate of HBV recurrence at 32%. By multivariate analysis, HDV coinfection and acute rather than chronic HBV infection were significant predictors of nonrecurrence as was administration of high dose HBIG for more than 6 months post-OLT. A high level of HBV replication pre-OLT implies a larger circulating population of virus with the potential to rapidly recolonize the allograft with augmentation of replication by the immunosuppressive regimen. Asian race with presumed infancy or childhood acquisition of HBV was initially reported as a predictor of a poor outcome due to aggressive recurrence of HBV post-OLT.[15] However, a more recent experience suggested that this apparent association may be due to more advanced liver disease at the time of OLT rather than any unique effect of race, [16] and a recent update has indicated again no adverse effect on HBV recurrence due to race.[17] (Table 1).

Asubset of patients with a particularly poor outlook had been those patients retransplanted following initial graft failure due to HBV recurrence, [18] especially for the FCH pattern of recurrence with an even more accelerated recurrence in the second graft. However, this concern is now probably moot with the advent of effective prophylactic strategies to prevent HBV recurrence; a recent multicenter experience reported survival of 6 (86%) of 7 patients following retransplantation using high dose HBIG.[19] Similarly good results have also been reported from Europe using a variety of antiviral agents in combination with HBIG.[20]

Precore mutant forms of HBV which fail to secrete HBeAg have been implicated in severe liver disease in non-transplant patients [21] and some reports had also implicated analogous mutations in severe recurrent HBV post-OLT.[22] The presence of a precore mutant does not per se increase the likelihood of reinfection or graft failure whereas pre-OLT viral load does according to a recent European report which included many patients with this HBV mutant who had received high dose HBIG post-OLT.[23]

To be continued in next reply...

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HBV Recurrence and Coinfection by Other Hepatotropic Viruses
Coinfection with other hepatotropic viruses may attenuate HBV recurrence post-OLT. This has been best characterized with HDV coinfection (24) but there is also evidence that hepatitis C virus (HCV) coinfection may similarly reduce the impact of HBV recurrence.[25] Since all three viruses are parenterally spread, coinfection is not infrequent in OLT candidates although HDV has a lower background prevalence in North America compared to Western Europe both in the transplant and non-transplant setting. Thus, in a recent multicenter US study HDV coinfection was identified in only 6.2% of HBV infected OLT candidates [26] compared to an earlier European experience reported by Samuel et al. where one-third of HBV-positive recipients had HDV coinfection, and importantly, in this latter study, coinfection reduced the risk of HBV recurrence.[14] HDV coinfection typically results in reduction in HBV replication, which in turn diminishes the risk of HBV recurrence post-OLT. Even if HBV recurrence does occur, HDV coinfection is associated with a more indolent course than typically observed in its absence. In a recent report of long-term HBIG prophylaxis in HDV-coinfected OLT recipients, Samuel and coworkers observed a low overall rate of HBV recurrence of 10.3% and an absence of cirrhosis in patients with recurrence in a follow-up extending over a mean of 3 years, implying that HDV offered some protection even following HBV recurrence.[27] It remains un-clear why HDV coinfection is associated with more severe disease in the non-transplant setting yet following transplantation appears to be associated with viral interference and attenuated HBV disease progression.

Some earlier observations had suggested that HDV could recur in the graft in the absence of HBV. In one study, HDV antigen was present in hepatocytes and HDV RNA reappeared in serum without detection of HBV markers of reinfection such as serum HBV DNA or HBV core antigen in hepatocytes.[24] A recent study has revisited this issue and has detected evidence of HBV replication, albeit low grade, by molecular techniques.[28] The difficulty of detecting HBV replication in these circumstances may be due in part to the administration of HBIG. If HBV surface antigen does not reap-pear, isolated HDV markers are not durable, reflecting the inability of HDV to persist without established HBV reinfection.

A complex relationship also exists between HBV and HCV in the transplant and non-transplant setting. Co-infection has been implicated in more severe clinical liver disease in the latter situation although a suppressive effect of HCV on HBV replication has also been demonstrated.[29] A report from Huang and colleagues from San Francisco described improved survival in OLT recipients with recurrent HBV who had HCV coinfection compared to those with HBV infection alone.[25] A recent European report suggests that in coin-fected patients given HBIG (before anti-HCV screening was available in 1990) had a reduction in HCV recur-rence compared to those transplanted after anti-HCV positive lots were discarded, implying that passively acquired polyclonal antibodies also offered some protection against HCV recurrence.[30]

De Novo HBV Infection Post-OLT
Although most allograft HBV infection is clearly related to recurrence of infection, a number of reports have implicated the allograft as a source of HBV infection. Donor markers, typical of remote resolved HBV infection with IgG anti-HBc seropositivity with or without the presence of anti-HBs antibody, have been convincingly associated with the subsequent development of graft dysfunction with appearance of serum HBsAg positivity in the recipient following OLT with cadaveric [31] and living related donors.[32] The putative mechanism is amplification of minute amounts of viable virions in the graft by therapeutic immunosuppression following OLT. This postulate is further supported by a recent report of a high prevalence of HBV DNA detectable by PCR in patients with chronic HCV who had anti-HBc positivity but absent HbsAg.[33] The course of HBV acquired peri-OLT had initially appeared more indolent than that due to reinfection although poor graft and patient outcomes have been recognized following HBV acquisition under these circumstances.34,35 Experience with allografts from donors with anti-HBc seropositivity and absent HBsAg generated from the NIDDK data base indicates that these organs are highly likely to transmit HBV infection to HBV naive recipients. Dickson and colleagues [31] reviewed the outcome of HBV naive OLT recipients at four American centers who had received allografts from donors seropositive for anti-HBc but not HBsAg. Eighteen of 23 (78%) recipients developed HBV infection in contrast to only three of 651 (0.5%) recipients of anti-HBc negative grafts (p < .0001). Survival was also impacted in recipients who had acquired HBV with a diminished 4-year survival compared to patients who remained uninfected. In contrast, use of such donors in OLT recipients with preexisting HBV infection who receive adequate prophylaxis against HBV recurrence does not appear to increase the risk of allograft infection by HBV (Steve Han M.D., personal communication). In addition, markers of prior resolved HBV infection, notably anti-HBc +/- anti HBs seropositivity in the recipient, may also offer protection against graft HBV infection.[35] Given the critical shortage of donor organs, use of hepatic allografts from the anti-HBC positive donor should be considered in the HBsAg positive recipient who will require long term prophylaxis against HBV recurrence.

HBV and Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is a frequent complication of chronic HBV infection especially if cirrhosis has developed. OLT is potentially curative in a subset of patients with HCC with a small tumor burden. Generally accepted criteria are tumor diameter less than 5 cm if the lesion is solitary or less than 3 in number with the largest diameter less than 3 cm if multiple and with a negative metastatic workup.[36] However, the experience with OLT in the patient with both HCC and HBV infection had been discouraging until recently due to HBV recurrence rather than metastatic spread.[37] The confounding effects of adjuvant chemotherapy as well as absence of adequate immunoprophylaxis against HBV may have been important factors in the poor results. Recently, a large multicenter European experience has confirmed that only pre-OLT replicative activity and post-OLT immunoprophylaxis were significant predictors of HBV recurrence and that HCC per se does not increase the likelihood of HBV recurrence.[38] Thus, the current assessment of the OLT candidate with HCC and HBV should initially focus on the likelihood of cure of the tumor by OLT using the criteria described above and then on providing adequate prophylaxis against HBV recurrence.

Treatment Options: Current and Future
From the early 1990s, successful therapy to prevent HBV recurrence had been long-term immunoprophylaxis with HBIG albeit with significant limitations (Table 2). The causes of breakthrough, which occurs in 20% of patients receiving long-term HBIG, are multi-factorial and may include: inadequate anti-HBs titers following transplantation; resistance mutations in the region of the surface gene which encodes the "a" determinant, the immunodominant epitope and putative region for antibody binding or high levels of viremia which abrogate the ability of the antibody to neutralize circulating virus.[39]

Other interventions to manage or prevent HBV have included agents with efficacy in the treatment of HBV in the nontransplant setting. Interferon-alpha has limited efficacy in HBV recurrence following OLT. In a study by Terrault [40] and colleagues from San Francisco, 14 patients with recurrent HBV were treated subcutaneously with interferon-alpha 3 million units three times weekly for a mean period of 23 weeks. Four out of 14 had a complete virological response with loss of HBV DNA from serum. Among those 10 patients who failed to respond, 3 were retransplanted for HBV-related graft failure, 3 died, and 3 are alive with persistence of serum HBV DNA. However, interferon therapy has been implicated in graft rejection and loss when used for other indications (e.g., HCV) in renal transplant recipients. Side effects are frequent with interferon-alpha and therapy-induced hepatocellular dysfunction due to immune activation can cause clinical worsening of liver disease limiting its use in the pre-OLT HBV infected patient with advanced cirrhosis. Thus, interferon-alpha is unlikely to play a major role in the management of HBV either immediately pre-or post-transplant. In contrast, lamivudine, a cytosine analog that inhibits reverse transcriptase of HBV by interfering with the synthesis of the proviral DNA chain from pre-genomic viral messenger RNA, is safe, well tolerated, and effective in the treatment of HIV and HBV.

Lamivudine has been shown to have potent anti-HBV activity even in patients with hepatic decompensation awaiting OLT and those with recurrent HBV following transplantation.[41,42] A proportion of patients develop YMDD mutations although the full impact of these mutations on disease recurrence post-OLT remains undefined.[43] Recent reports are conflicting with regards to the prognosis following lamivudine resistance, ranging from allograft failure in all 4 patients with YMDD mutations in one series to intact allograft function in 3 patients from another series.[44,45] In addition, lamivudine in combination with HBIG is safe and highly effective in preventing HBV recurrence following liver transplantation, and at least in theory may be associated with a lower rate of resistance mutation(s) development. In a study from the University of California at Los Angeles, [46] 13 patients were treated prophylactically with lamivudine and high dose HBIG (starting with 10,000 IU during the anhepatic phase). There were no treatment failures, and patient survival at 1-year was 92%. An updated experience which now includes nearly 60 patients and larger follow-up confirm the efficacy of this approach with an absence of recurrent HBV.[47] In an effort to reduce the cost of long term HBIG prophylaxis and to reduce side effects associated with intravenous administration (e.g., myalgia), a number of centers have reported the use of intramuscular HBIG with dosing titrated to antibody levels in serum with a level > 500 iu/L of antibody to hepatitis B surface regarded as protective by some [47] or with lower target antibody levels when using combination HBIG and lamivudine.[47] Newer formulations for intravenous HBIG use have been developed, obviating some of the concerns with intramuscular HBIG (e.g., mercury accumulation). Moreover, a very provocative study from Barcelona has demonstrated that discontinuation of life-long HBIG treatment is an attainable goal in a subset of patients successfully vaccinated for HBV post-OLT.[48]

With regard to patients with established recurrent HBV infection, a multicenter analysis of 52 patients with detectable HBV-DNA post-OLT who received lamivudine 100 mg daily for 1 year demonstrated that 60% lost HBV-DNA and 31% of the initially positive patients lost hepatitis B e antigen.[42] Of note, 14 (27%) patients developed viral variants with mutations in the YMDD locus of the HBV polymerase gene. The investigators chose to maintain these patients with YMDD variants on lamivudine because the natural history of recurrent disease after emergence of these mutations has not been fully defined, and salvage therapy is not yet available, although adefovir holds promise.[49] In addition, there is concern that resurgence of "wild type" HBV after interruption of lamivudine therapy may be associated with clinical deterioration.

Despite these concerns, the management of HBV in the OLT candidate has improved substantially in the last decade with a low likelihood of serious graft reinfection for the OLT candidate with HBV. Thus, the natural history of HBV recurrence, particularly the prevalence of graft reinfection and graft loss, has been dramatically altered since the development of effective therapies.

Continued in next reply...

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Chronic Hepatitis C Infection
Background
Since its molecular characterization in 1989, the hepatitis C virus (HCV) has been identified as the major cause of parenterally acquired non-A, non-B hepatitis.[50] Moreover, HCV is an important co-factor in clinical expression of other primary liver diseases including alcoholic liver disease and possibly acute hepatitis A, as well as hepatitis B. Not surprisingly, by 1993, HCV had become the leading indication for OLT worldwide, surpassing alcoholic liver disease.[51] Moreover, human liver transplantation represents the only available model system to study HCV, as a suitable animal model (the endangered chimpanzee model has significant limitations) and tissue culture systems for its propagation do not exist.[52]

Despite significant advances in our understanding of the epidemiology and molecular biology of HCV, the mechanisms responsible for hepatocellular injury in chronic HCV infection remain poorly understood.[53,54]

While the contribution of a direct cytopathic effect of HCV is still controversial, several lines of evidence indicate that immune-mediated mechanisms are likely to play an important role in the pathogenesis of HCV.

Natural History Prior to Transplantation
Acute HCV infection is notable for its propensity to develop chronicity with approximately 85% of individuals demonstrating evidence of infection 6 months following acute infection.[55] Recent data suggest that the immune response at the time of acute infection is crucial in determining the outcome of infection. In a recent study by Missale et al., [56] 12 patients with self-limited infection who subsequently became HCV-RNA negative had more frequently detectable and significantly stronger T cell responses to HCV antigens as compared to 9 patients who developed persistent viremia and biochemical evidence of chronic liver injury.

Factors predictive of progression include the age of exposure (older age at acquisition associated with greater risk of cirrhosis), duration of infection, route of transmission (blood transfusion associated with greater risk of cirrhosis than intravenous drug use), coexistent alcoholism, severity of injury and degree of damage on initial liver biopsy and possibly HCV genotype.[57] In patients with established cirrhosis due to HCV infection, the 5-year risk of hepatic decompensation (ascites, jaundice, hepatic encephalopathy, or variceal bleeding) is 18% and that of hepatocellular carcinoma (HCC) is 7%.[58] It has been suggested that the number of deaths attributable to HCV-related chronic liver disease including hepatocellular carcinoma will increase substantially during the next 2 decades within the United States with a potentially staggering economic and clinical burden.

Outcome Following Liver Transplantation
The presence of HCV RNA in serum after OLT occurs universally in patients with pretransplantation viremia with 50 to 80% of these patients developing graft hepatitis.[59,60] However, overall graft and patient survival for the first decade following OLT appears to be unaffected.[61] In some series, approximately one-third of patients undergoing OLT for HCV-related liver dis-ease have HCC, with reduced survivals due to tumor recurrence rather than that of HCV.[51] An analysis of 304 HCV-seropositive liver transplant recipients from the University of California at Los Angeles showed that less than 5% develop graft failure due to recurrent HCV within the first 3 years.[62] The natural history of recurrent HCV infection was further elucidated by the King's College group in London by comparing one-and five-year protocol biopsies from OLT recipients with and without HCV infection.[63] Almost 90% of the HCV-infected patients (n = 149) had chronic hepatitis histologically by 5 years as compared to approximately 20% of the HCV-negative group (n = 623, in whom allograft hepatitis was predominantly related to recurrent HBV infection). Of concern, 20% of the HCV-infected recipients had progression to cirrhosis by 5 years on protocol biopsy; therefore, the natural history of HCV infection appears truncated in OLT recipients as compared to immunocompetent individuals. Although studies with longer follow-up are required to determine the proportion of patients who will ultimately develop allograft cirrhosis and graft failure related to HCV recurrence, it appears that fewer than 10% of patients with mild hepatitis at 1 year progress to allograft cirrhosis at 5 years. In contrast, two thirds of patients with at least moderate activity at 1 year progressed to cirrhosis by 5 years in the King's College series. A number of studies have confirmed that allograft findings at the onset of histological recurrence [64] and at one year [65] appear to be predictive of long-term HCV-related graft injury. Rosen and colleagues reported that transient hyperbilirubinemia (attributable to HCV recurrence and no other causes) and hepatocyte ballooning on allograft biopsy were predictive of progressive allograft injury.[64] In addition, as previously described in recurrent HBV infection, a severe progressive cholestatic syndrome due to HCV recurrence has been reported by a number of centers. The frequency of this syndrome appears to be 2-10% and is associated with extremely high circulating and intrahepatic levels of HCV RNA, suggesting a direct viral cytopathic effect.[66,67]

Mechanisms of HCV-Related Allograft Injury
Liver transplantation for HCV is analogous to acute HCV infection in that a naïve uninfected liver is placed into a viremic host with inevitable allograft infection. As such, the human liver transplant model offers an opportunity to study viral kinetics and immunopathogenic mechanisms of both acute and chronic HCV-related liver disease. The spectrum of allograft injury related to HCV recurrence ranges from mild histologic abnormalities to graft failure leading to death or need for retransplantation in a subset of patients. Several interrelated viral and host factors have been proposed to explain the variable outcomes, including HCV viral load, genotype and quasispecies, rejection and immunosuppression (Fig. 1).

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Figure 1. (click image to zoom) A number of host and viral factors have been postulated to explain the variable severity of HCV recurrence following liver transplantation.

Viral Load
The influence of the level of viremia on the severity of histologic recurrence has been assessed at different time points by a number of investigators. Chazouilleres et al. quantified HCV-RNA levels of 100 patients with HCV-RNA positivity before liver transplant and reported that most developed high-titer viremia with a mean ten-to twenty-fold increase following liver transplantation.[68] However, the levels of HCV-RNA following OLT did not correlate with levels of serum alanine transaminase or histological findings, and indeed, the patient with the highest circulating HCV-RNA did not demonstrate any evidence of histological recurrence. Although these early findings suggested that HCV per se probably does not have a direct cytopathic effect, a subsequent study by Gretch and colleagues demonstrated that serum HCV RNA levels in the first two weeks following OLT were significantly higher among patients who subsequently developed chronic active hepatitis within their allografts versus those patients who did not.[69]

A longitudinal analysis by Gane and colleagues [59] found that the onset of acute allograft hepatitis was associated with peak circulating levels of HCV RNA which in the majority of patients decreased over time. Moreover, an analysis of the NIDDK liver transplant database showed the predictive value of pre-transplant viral levels: patients with circulating HCV RNA levels >/= 1 10 [6] eq/ml just prior to OLT had significantly diminished graft and patient survival (Fig. 2), [13] suggesting that the size of the viral innoculum is crucial and provides a rationale for pre-emptive therapy in the pre-transplant period to diminish viral load and associated graft injury. In theory, direct hepatocellular damage may occur only above a critical threshold of intracellular virus accumulation, and this level may be reached in a larger proportion of hepatocytes in recipients with higher viral load. Alternatively, the greater viral innoculum may overwhelm the immune system's capacity to contain the virus. These data are reminiscent of the non-transplant setting in that acquisition of HCV infection from a blood transfusion is more likely to lead to cirrhosis than acquisition of HCV related to intravenous drug use.

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Figure 2. (click image to zoom) Survival was significantly diminished in patients undergoing OLT for HCV infection if their pre-OLT viral load was > 1 10 [6] eq/mL. Pre-LT, pre-liver transplantation. ( pre-LT RNA < 0.2; ( pre-LT RNA 0.2-0.49; (), pre-LT RNA 0.5-0.99; X, pre-LT RNA > 1 10 [6] eq/mL. Data from NIDDK Liver Transplantation Database.[13]

Viral Heterogeneity
The significance of infection by specific HCV genotypes following OLT remains the subject of debate. Several European groups have suggested that infection with genotype 1b is associated with a higher prevalence of histological recurrence and more severe allograft hepatitis.[70] However, series from major transplant centers in the United States have not confirmed this finding.[71,72] Conversely, others have found that genotype 1a, which shares 85% homology at the amino acid level with genotype 1b, is associated with higher histological severity scores than non-1 genotypes.[73] These discrepant results with respect to HCV genotype and recurrent disease may be related to the use of different histological criteria and varying length of follow-up to assess severity, use of different genotyping technologies, [74] or to the interplay of genotype with other unrecognized factors. Recently, a homogeneous series of HCV-1b OLT recipients demonstrated a correlation between cumulative steroid use and accelerated natural history of recurrent hepatitis.[75] The authors concluded that un-equivocal histological evidence of acute cellular rejection should be present before treatment of the HCV-1b infected patients with a steroid cycle.

Work by Gretch and colleagues has demonstrated that HCV genetic divergence post-OLT correlates with outcome.[76] In patients who develop severe HCV recur-rence, the major quasispecies variants are efficiently propagated, while patients without any evidence of significant histological recurrence show emergence of new quasispecies variants by the first month post-transplant, and consensus sequences of the quasispecies major variants present in pre-transplant serum are not detectable at any time after liver transplantation.[77] From a mechanistic standpoint, these data are in accord with the findings (described below) of an impaired HCV-specific immune response in patients with severe recurrence, that is, lack of immunological selection allows efficient propagation of a dominant quasispecies.  To be continued in next reply...

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Immunosuppression and Rejection
The majority of retrospective data indicate that the 3-year patient and graft survival for HCV-seropositive OLT recipients is not affected by the choice of induction immunosuppression, such as cyclosporine vs. tacrolimus.[78,79] Although use of tacrolimus did confer a 5-year patient survival advantage in HCV-positive recipients registered in the United States FK506 Study Group, [80] this difference may have been a reflection of the significantly lower rates of rejection in the tacrolimus group. Moreover, an ongoing, prospective, randomized trial at UCLA (using lower doses of FK506 than the initial trials) has failed to show any difference in prevalence or severity of HCV recurrence or impact on survival according to the calcineurin inhibitor.[81] There is no controlled data concerning the impact of newer immunosuppressive agents (mycophenolate mofetil, rapamycin, IL-2 antibodies) on the natural history of HCV post-OLT.

Patients undergoing OLT for HCV-related liver failure appear to experience frequencies of acute cellular rejection (ACR) and steroid-resistant rejection that are comparable to those of patients undergoing OLT for other indications. Undoubtedly, the most difficult challenge facing the transplant physician caring for the HCV-positive liver transplant recipient is the differentiation between ACR and HCV recurrence which have considerable histological overlap.[82] Our current approach in a patient with equivocal findings of rejection -- hold off on presumptive treatment, repeat daily labs, and repeat an allograft biopsy several days later -- is predicated on the reported increase in mortality in HCV-infected recipients (relative risk 2.9) treated for ACR.[83] In contrast, a single episode of ACR in the non-HCV infected OLT recipient appears to confer a survival advantage.[82] Intuitively, in patients with progressive HCV-related allograft injury the level of immunosuppression should be reduced, particularly in light of recent data showing the safety of steroid withdrawal; however, no study to date has specifically addressed this important question.

Sheiner and colleagues from Mt. Sinai in New York demonstrated that the incidence of HCV recurrence directly correlated with the degree of post-OLT immuno-suppression for rejection, approaching 72% in patients treated for multiple or steroid-resistant rejections as compared to 18% of patients never treated for rejection.[84] In patients with rejection, whether viral reactivation is related to increased steroids or alloreaction per se is unclear. In a case control study from the University of California at Los Angeles, patients who had received OKT3 for steroid-resistant rejection developed earlier and more severe recurrence as compared to a contemporary cohort matched for key variables, including total of steroid dose.[85] Five of 19 (26.3%) of patients who received OKT3 ultimately developed allograft cirrhosis versus 2 of 33 (6%) of patients treated for steroid-responsive rejection (p < .03). A subsequent analysis combining data from both centers demonstrated that HCV-positive patients receiving OKT3 experienced nearly a 10-fold increase in graft loss.[86]

Cellular Immune Response
In addition to the association of OKT3 administration for steroid-resistant rejection with augmented severity of HCV recurrence, several lines of indirect evidence suggest that deficient cell-mediated immunity plays a contributory role in the pathogenesis of HCV-related liver injury following transplantation. Co-infection with cytomegalovirus (CMV), which has been shown to induce cell-mediated immune defects and consequently a higher risk of opportunistic infections following transplantation, has been associated with a higher risk of HCV-related allograft cirrhosis.[87] A follow-up study from the NIDDK database has also confirmed the independent association of CMV infection with allograft cirrhosis and mortality.[88]

Failure to mount an efficient immune response to HCV antigens, either because of selective defects in the host immune system or because of viral interference with the normal function of the immune cells could account for the inability of the large proportion of HCV-infected transplant recipients to eradicate HCV. A recent analysis has shown that approximately 40% of patients with minimal or self-limited recurrent HCV demonstrate proliferative responses to HCV antigens whereas none of the patients with severe recurrence do so (Figs. 3A and B). [89] These emerging data suggest inability to generate adequate virus-specific T cell responses plays at least a contributory role in the pathogenesis of progressive HCV-related graft injury following OLT. Characterization of the immunoregulatory mechanisms involved in this setting will hopefully lead to the development of highly specific therapeutic strategies. Moreover, the roles of non-specific (bystander) T cell activation within the allograft, cytokine activity, and nitric oxide production remain to be defined. Immunohistochemical analysis has demonstrated that patients with severe recurrence show marked and aberrant intrahepatic expression of molecules involved in lymphocyte activation and antigen presentation, as well as intercellular and vascular adhesion.[90] In another study, a strong correlation was shown between expression of hepatic and soluble TNF-alpha receptor p75 and histological activity of allograft hepatitis.[91] Accord-ingly, an analysis of TNF-alpha promoter polymorphisms has shown that recipients of a donor liver expressing an allele associated with higher constitutive and inducible expression of TNF-alpha are more susceptible to severe HCV recurrence (Fig. 4).[92] In summary, the cellular immune response appears to play a pivotal role in the pathogenesis of HCV following OLT. The converse also appears to be true; that is, recurrent HCV disease induces defects in the cellular immune response, as suggested by a University of Pittsburgh report of a higher incidence of major and late infections in OLT patients with recurrent HCV.[93]

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Figure 3A-D. (click image to zoom) (A) Proliferative responses of peripheral blood T-helper cells to control non-HCV antigens (either tetanus toxoid or CMV) were detectable in all liver transplant patients. However, while 40% of the patients with minimal recurrence responded to at least one of the HCV antigens, none of the patients with severe histological recurrence demonstrated any significant proliferation to the HCV proteins (p < .05). A stimulation index 3 was considered significant. (B-D) Proliferation assay results from 3 representative liver transplant recipients. (B) Patient with HCV genotype 1b who developed allograft failure from severe HCV recurrence and persistently had no HCV-specific response (tested 5 times). (C) Patient with HCV genotype 1a and minimal histological recur-rence with vigorous T-cell responses to HCV proteins 6 years after transplantation. (D) CMV-negative recipient of a CMV-negative donor organ, this patient with HCV genotype 1a and minimal recurrence had a vigorous response to tetatus toxoid with no evidence of HCV-specific responses

Click to zoom    
Figure 4. (click image to zoom) HCV recurrence-free survival was diminished in patients receiving a donor liver with a TNF308.2 (high TNF producing).[92]

The Humoral Immune Response
Negro et al. found that anti-HCV core IgM antibodies were persistently undetectable more often in patients who did not develop any evidence of recurrent hepatitis after liver transplantation.[94] Another study of 25 OLT recipients confirmed these findings, demonstrating a significant correlation between the presence of anti-HCV core IgM before OLT, at 15 days, 90 days, and 1 year post-OLT with the presence of recurrent hepatitis.[95] A more recent analysis utilizing a recombinant immunoblot assay found that patients with minimal recur-rence had significantly lower titers of antibody reactivity to NS4 and NS5.[96] However, the HCV-related humoral immune response likely does not play an important direct role in the pathogenesis of graft injury. Approximately one-third of HCV-infected individuals have detectable cryoglobulins following OLT, and a possible association between immune complex deposition and more severe allograft hepatitis as well as late hepatic artery thrombosis has been suggested.[97] Moreover, HCV-related membranoproliferative glomerulonephritis may account for significant renal impairment in an unknown proportion of HCV-positive patients before and after OLT. In one experience, six of 28 (21%) of patients awaiting OLT had histologically confirmed GN and significant proteinuria.[98]

To be continued in next reply...

[hanklive39]

Use of HCV-Infected Grafts
In a preliminary analysis of the UNOS database, [99] use of HCV-positive donor livers in HCV-positive recipients (n = 71) was associated with comparable graft/patient survival to use of HCV-negative donor livers (n = 2257), suggesting such a policy might be a feasible means of expanding the donor organ pool. Furthermore, Vargas et al.[100] observed that the histological outcome in HCV-positive liver recipients who received an HCV-positive graft was at least as good as those who received an HCV-negative graft. Whenever genotypes 1a or 1b were present in the donor/recipient pair, they eventually became the prevalent genotype, suggesting a possibly replicative advantage for these strains.

Retransplantation

The prevalence of HCV infection in patients under-going liver retransplantation has increased significantly from 6.5% in 1990 to 38.4% in 1995 (p < .0001, Fig. 5).[101] Although this rising prevalence in part may represent the increase in HCV-related liver failure as a primary indication for OLT and more accurate testing for HCV infection, it does raise concern about the relative contribution of HCV to graft failure. Recent data have suggested that survival following retransplantation is particularly poor in patients with recurrent HCV, even in those with other causes of graft failure. For example, an analysis of 27 HCV-positive patients undergoing re-transplantation at the University of Pittsburgh demonstrated a mortality rate of 67% at a median follow-up of 120 days.[102] Twelve of these patients had concurrent chronic rejection and 3 had vascular thrombosis. A study by Feray and collegues of 119 French patients undergoing liver retransplantation demonstrated a significantly diminished 1-year graft survival (40%) in the subset of 20 patients who had developed allograft cirrhosis due to recurrent HCV, even when compared to patients retransplanted for hepatitis B-related graft failure.[103] Of note, all 20 patients developed evidence of histologic recurrence in their second grafts, leading to recurrent graft failure in 3 patients. Moreover, 15 of the 54 (28%) patients retransplanted for chronic rejection had histologic evidence of HCV infection. In a more recent study from the University of California at Los Angeles, retransplantation in 20 patients with HCV infection was associated with a four-fold increase in mortality as compared to primary transplantation for HCV-related liver failure, irrespective of the etiology of graft failure chronic rejection versus recurrent HCV.[62] These reports have led to the suggestion by some transplant physicians that retransplantation for recurrent HCV be abandoned.[104] Analysis of the UNOS database indeed demonstrated significantly diminished patient survival following retransplantation in the HCV positive group: at 1, 3, and 5 years, 57, 55, and 54% as compared to 65, 63, and 61%, respectively, in the HCV negative group (p = .0038, log-rank test).[101] However, using a mathematical model, acceptable results following liver retransplantation for severe recurrent HCV are attainable in highly selected patients, such as those without severe hyperbilirubinemia or renal failure. New FN 1046 retransplantation remains the only viable option for patients whose allografts fail because of recurrent HCV disease.

Click to zoom    
Figure 5. (click image to zoom) The relative prevalence of HCV infection in patients undergoing liver retransplantation has dramatically increased since 1990.

Treatment
Alternative approaches can be taken to treat HCV recurrence following OLT: treatment of established recurrence, early post-transplant antiviral therapy prior to documented histologic recurrence, and pre-emptive antiviral therapy in the patient awaiting OLT. There is minimal information about preemptive antiviral therapy in the patient awaiting OLT as patients with decompensated cirrhosis are generally poor candidates for currently available therapies with proven efficacy in the treatment of chronic HCV (i.e., the interferons with or without ribavirin). Although there is emerging evidence that interferon therapy may reduce the risk of hepatocellular carcinoma in patients in patients with HCV-related cirrhosis, by the time a patient is listed for OLT manifestations of their disease limit their tolerance for inter-feron therapy. Generally, HCV treatment trials have precluded patients with clinically florid cirrhosis so it is not known how frequently sustained virological responses are possible in these patients and whether such a response is durable post-OLT.

More information, although not particularly encouraging, is available about treatment of established recurrent HCV with interferon monotherapy. A number of studies have been reported describing interferon monotherapy. Biochemical responses can be seen in up to a quarter of treated patients but convincing virological or histological responses have not been seen. There may be a number of factors contributing to the low efficacy of interferon monotherapy for established HCV recurrence including the typically high HCV RNA levels post-OLT and therapeutic immunosuppression.

In a recent review, Lavezzo and Rizzetto summarized reported studies of interferon monotherapy for HCV recurrence (Table 3).[106] Of the 64 treated patients in 5 studies, only 1 (1.5%) had sustained HCV RNA clearance from serum. No significant histological benefit was observed. Concern has been raised by Feray et al.[108] that chronic rejection could be precipitated by interferon therapy as it occurred in 5 of their 14 treated contrast to only 1 of 32 controls. However, other groups have not experienced such a frequent complication of therapy although a case of acute vanishing bile duct syndrome has also been observed following inter-feron-alpha for recurrent HCV.[110] Ribavirin has failed to establish a role as monotherapy for established recurrent HCV. Although biochemical improvement may occur, histological progression is not prevented nor is there a durable antiviral effect.[111] Furthermore, hemolysis is an important complication of therapy in OLT recipients. With recognition of the increased efficacy of interferon alpha when combined with ribavirin in the non-transplant setting, a number of groups have reported on this combination for established recurrent HCV. Bizollon and colleagues initiated combination therapy with interferon alpha, 3 million units thrice weekly with ribavirin 1200mg daily a mean of 9 months post-OLT.[112] All 21 treated patients normalized ALT levels by the end of 6 months with 10 patients (47%) clearing serum HCV RNA. During a subsequent ribavirin monotherapy maintenance phase, ALT levels remained normal in 17/18 (94%) although five patients became viremic again. A similar protocol has been reported by Lavezzo et al. using initial combination therapy followed by ribavirin for established recurrent HCV.[113] Of 40 treated patients, 9 (22%) cleared serum HCV RNA. In a follow-up of less than 6 months 8 of these 9 virological responders remained non-viremic. Other groups have also reported preliminary combination data indicating that virological responses can be obtained in a significant minority of patients even in severe recurrence.[114] Moreover, although rejection has not been a feature of combination therapy, significant hemolysis (due to ribavirin) has been frequent.

Recognition of the rapid return of HCV viremia following OLT has provided a rationale for initiating antiviral therapy in the early postoperative period. Sheiner et al. started interferon monotherapy in 30 patients within 14 days of OLT.[115] Graft injury due to recurrent hepatitis was significantly less frequent than in untreated controls although no effect on HCV viremia could be established. Reddy in a similar protocol reported that 6 of 36 (16.6%) patients were serum HCV RNA negative 6 months into therapy.[116] Singh and colleagues observed that although interferon alpha mono-therapy did not reduce the overall incidence of HCV recurrence when given for 6 months post-OLT it did delay its onset to a median of 408 days compared to 193 days in untreated controls.[117] Typically, patients are more robust with longer post-operative recovery, are on lower doses of immunosuppressants and may be more tolerant of antiviral therapy.

More recent efforts have focused on combination therapy started in the early post-operative period. Mazzaferro reported that graft hepatitis was absent one year post-OLT on biopsy in 17 of 21 (81%) patients and 9 had absent serum HCV RNA.[118] As in other studies in OLT recipients, hemolytic anemia was frequent when ribavirin was used. At present, preemptive therapy post-OLT (but prior to the development of histologic recurrence) appears to be the most promising approach to reducing the burden of HCV recurrence post-OLT and the results of ongoing trials should provide important information.

Aparticular problem is to identify candidates for preemptive therapy in the absence of clearly defined markers of a high likelihood of more severe recurrent HCV although factors such as viral load [13] and genotype[119,120] continue to receive scrutiny. The availability of pegylated interferon with a more prolonged duration of action has lead to interest in exploring its role both in the early post-operative period as well as for established recurrent HCV.

Click to zoom    
Figure 6. (click image to zoom) Biochemical and viral load profile in a patient treated for severe HCV recurrence with interferon plus ribavirin and ultimately G-CSF. The patient developed evidence of severe cholestasis within 4 months post-OLT. The total bilirubin levels the day of initiation of antiviral therapy, 3 months, and 6 months were 7.1mg/dL, 10.2 mg/dL, and 0.9 mg/dL.[114]

Respectfully,
Hanklive Lives for Today and Tomorrow!!!

[hanklive39]

Concluding Perspectives
The evolution of our understanding and management of HBV and HCV infection in the OLT recipient has been rapid in the last decade. The risk of viral recur-rence after transplantation is high but has been effectively decreased in hepatitis B-positive recipients with the use of HBIG and lamivudine. The introduction of additional nucleoside analogues with efficacy against HBV in the future offers the promise of effective prophylaxis without protracted HBIG administration although at least in the short term its use remains crucial to ensure adequate graft protection. HCV recurrence as defined by histologic injury is almost universal and although graft or patient outcomes for the first decade after OLT do not appear to be limited by HCV reinfection, some patients clearly do poorly. Recognition of the difficulty of reliably distinguishing rejection from HCV recurrence has led to caution about over vigorous treatment of possible rejection. In addition, less tangible effects of recurrent HCV such as diminished quality of life and a possible association with other end organ damage notably renal, are receiving increased attention.[121,122] As effective prophylactic regimens that alter the natural history of HCV re-infection have yet to be identified, and with longer follow-up into the second decade, the prevalence of HCV-related graft failure is likely to increase. HCV recurrence has already surpassed HBV recurrence as the major challenge in viral hepatitis facing transplant programs.[119]

Acknowledgements
HRR is supported in part by research funding from the American Society of Transplant Physicians, American Digestive Health Foundation, and a Merit Review Grant, Washington, DC.

Tables for:
Hepatitis B and C in the Liver Transplant Recipient

[Semin Liver Dis 20(4):465-480, 2000. © 2000 Thieme Medical Publishers]

Table 1. Predictors of HBV Recurrence Post-OLT

    Positive Predictors
       

    Negative Predictors

    High Replication (HBeAg, HBV DNA)
       

    Administration of high-dose HBIG

    Absence of viral coinfection (HCV, HDV)
       

    Lamivudine therapy

    OLT for cirrhosis
       

    OLT for Fulminant Hepatic Failure

       

    Unproven Predictors

       

    Ethnicity

       

    Concomitant Hepatocellular carcinoma


Table 2. Limitations of Long-Term HBIG Use

    Lack of efficacy in 20% patients

    Reduced availability with increased drug cost (single 10,000 IU
    dose: $3000 to $4700)

    Need for parenteral administration with variable patient tolerance
    (chest or back pain in 90%, headaches in 20%)

    Indefinite treatment likely required


Table 3. Interferon Monotherapy for Recurrent HCV: Response and Rejection Rates


       

    No. of
    Treated
    Patients
       

    ALT
    Normal
       

    ALT
    Clearance
       

    Rejection

    Wright [107]
       

    18
       

    5 (28%)
       

    0
       

    1 (5%)

    Feray [108]
       

    14
       

    2 (14%)
       

    1 (7%)
       

    5 (35%)

    Gane [109]
       

    14
       

    6 (42%)
       

    0
       

    0

    From Rosen104b

Respectfully,
Hanklive Lives for Today and Tomorrow!!!

[hanklive39]

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[hanklive39]

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