Journal of Hepatology
Volume 30, Issue 4 , Pages 731-738, April 1999

The outcome of hepatitis C virus infection after liver transplantation - is it influenced by the type of immunosuppression?

Liver Transplantation Unit, Royal Free Hospital, London, UK

Article Outline

 

Hepatitis C virus (HCV) infection recurs almost universally after orthotopic liver transplantation in patients with HCV-related cirrhosis 1., 2., 3., 4., 5.. The natural history of post-transplant HCV-infection has been studied in several centres and progression of liver disease appears to be more rapid than that observed in immunocompetent patients (6). Although it seems evident that treatment with immunosuppressive drugs accelerates progression of chronic hepatitis C, the effect of different immunosuppressive regimens on the natural history of HCV recurrence remains unclear. This review focuses on the role of the immunosuppressive drugs in the course of post-transplant HCV infection and whether it is possible that altering immunosuppressive regimens could improve the outcome of the disease.

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Pathogenesis of HCV Infection 

Liver damage in HCV infection is believed to involve host-mediated immune responses 7., 8.. Thus, it seems a paradox that immunosuppressed patients may have a more aggressive course of HCV infection than immunocompetent patients. It is likely that the altered balance between viral factors and the host immune system represents the most crucial factor to explain this paradox.

The initial response to HCV infection is the non-specific immune defense consisting of macrophages, scavenging natural killer cell activity and interferon production. Subsequently, the specific immune defense develops with CD4+ T-helper lymphocytes (Th-cells) playing a pivotal role 7., 8.. Th-cells recognise viral antigens as peptides bound to major histocompatibility complex (MHC) class-II molecules on the surface of antigen-presenting cells and differentiate into two subtypes, Th1 and Th2. Th1 cells are responsible for induction of specific CD8+ cytotoxic T-lymphocytes (CTL), while Th2 cells induce the proliferation of specific B-lymphocytes (B-cells) and hence production of specific antibodies (8).

Specific CTL which recognise HCV antigens presented at the surface of hepatocytes by MHC class-I molecules may play an important role in fighting infected hepatocytes 8., 9., 10.. CTL not only directly attack the infected cells but secrete cytokines which elicit a secondary attack of non-specific inflammatory cells as well 9., 10. (Fig. 1). An efficient Th-cell immune response during the early phase of HCV infection has been suggested as a critical determinant of the course of the disease 11., 12., 13.. A vigorous Th-cell response against HCV has been detected in patients who clear the virus after acute infection compared to patients who progress to chronicity 11., 12., 13..

  • View full-size image.
  • Fig. 1. 

    Schematic representation of the possible role of common immunosuppressive drugs in the pathogenesis of acute hepatitis C virus (HCV) infection. Main sites for inhibitory effects of immunosuppressive drugs: cyclosporin or tacrolimus, principally on site 4 and less so on sites3,5,6; azathioprine, sites 1–8; steroids, sites 1–6,8. APC, antigen presenting cell; NK-cell, natural killer cell; Th cell, T-helper lymphocyte; CTL, cytotoxic T-lymphocyte; B-cell, B-lymphocyte; MHC-I or -II, major histocompatibility complex class I or II molecule; HCV Ag, antigen of hepatitis C virus.

The role of B-cells and antibodies in the elimination and pathogenesis of HCV infection remains unclarified. Farci et al. initially reported that chimpanzees infected with HCV did not develop humoral immunity which could protect against reinfection with the same or another strain of HCV (14). Neutralising antibodies against HCV (anti-HCV) were later detected by others after chimpanzee vaccination or in specific cell lines 15., 16., 17.. It seems possible that HCV elicits neutralising antibodies, which, however, are strain specific and ineffective against different HCV strains usually present in the initial inoculum or emerging over time (18). Recently, use of hepatitis B immunoglobulin, not screened for HCV and probably containing anti-HCV, was reported to decrease significantly the incidence of post-transplant HCV infection, which suggests a possible protective role of anti-HCV (19). Moreover, high titres of neutralising anti-HCV were found to correlate with natural resolution of chronic hepatitis C, but, interestingly, not with the outcome of acute HCV infection (20). Summarising the above data, competent B-cell immunity seems to be important for the outcome of HCV infection. This is further supported by clinical studies showing an aggressive course of HCV infection in patients with hypogammaglobulinaemia 21., 22., 23..

In patients who progress to chronic infection, specific CTL responses seem to be incapable of controlling viral replication but could induce liver damage 24., 25.. The number of infected hepatocytes is significantly higher than the number of CTL, and thus CTL unrelentingly attack the hepatocytes and recruit and activate other inflammatory cells against them. The genetic diversity of HCV may further provoke the immune attack. The degree of HCV quasispecies diversity has been correlated with severity of chronic liver disease 26., 27., although such a correlation has not been found by others (28). Irrespective of the type of stimulus, the immune attack results in death of hepatocytes by necrosis or apoptosis, which activates the hepatic stellate cells with subsequent development of fibrosis (29) (Fig. 2)

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  • Fig. 2. 

    Schematic representation of the possible role of common immunosuppressive drugs in the pathogenesis of chronic hepatitis C virus (HCV) infection. Main sites for inhibitory effects of immunosuppressive drugs: cyclosporin or tacrolimus, principally on site 1 and less so on site 2; azathioprine, sites 1–3; steroids, sites 1,2,5. Possible site of stimulating effect of cyclosporin of tacrolimus: site 4. Th1-cell, subtype 1 of T-helper lymphocyte; CTL, cytotoxic T-lymphocyte; B-cell, MHC-I, major histocompatibility complex class I molecule; HCV Ag, antigen of hepatitis C virus; TGFβ, transforming growth factor β.

Functional characteristics of T-cell responses to HCV infection have been found to be similar in non-transplanted, immunocompetent and transplanted patients under immunosuppression (30). Thus, a decrease in the number of the cells involved in immune defense, and not a qualitative defect during the initial phase of HCV infection, could be the most logical explanation for the high chronicity rate and the very high levels of viraemia in transplant patients under immunosuppression 31., 32., 33.. Escape of HCV from the immune defense by emergence of mutations does not seem to play an important role after liver transplantation. The diversity of viral quasispecies has been found to diminish after transplantation 34., 35. and severe HCV recurrence has been reported in transplant patients who maintained the major pre-transplant HCV strains (35). Since the severity of immunosuppressive treatment is related to the degree of competence of the immune system, more intense immunosuppressive regimens for longer periods could be related to increased viral replication in the graft. We have recently shown that higher serum HCV RNA concentrations at 12 months after transplant are significantly associated with longer duration of steroid treatment (36). Reduction of immunosuppression and partial recovery of immune competence might be associated with stronger immunological attack and increased lysis of infected hepatocytes. Indeed, specific CTL responses in liver infiltrate have been associated with more histologically active disease (25). Marked involvement of immunopathogenetic mechanisms has also been shown in severe forms of post-transplant HCV recurrence (37).

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Natural History of Post-Transplant HCV Infection 

Serum HCV RNA is frequently detected by PCR within the first 2 weeks after transplant and its levels increase thereafter, reaching values significantly higher than pre-transplant in 1–2 months 31., 32., 33., 38.. The initial decline in HCV RNA in serum could be due to uptake of the virus by the new liver. An episode of acute hepatitis is usually observed in more than 50% of patients within 2–6 months, although early (less than 1 month) and delayed (up to 48 months) cases have been reported 3., 39.. During the acute hepatitis phase, serum HCV RNA levels peak (31); aminotransferases also increase but usually at levels lower than observed during acute hepatitis in non-immunosuppressed patients 31., 39.. A severe form of cholestatic hepatitis has been reported in 2–8%, which rapidly progresses to liver failure requiring re-transplantation within 2 years in most of the cases 3., 40., 41.. Although a small proportion of patients may progress to a“healthy” carrier state with viraemia (sometimes with extremely high levels), but normal aminotransferase concentrations and normal liver or minimal histological changes 1., 3., 39., progression to histological chronic hepatitis occurs in the majority of HCV-positive transplant patients 3., 39..

The exact frequency and severity of chronic hepatitis C in HCV-positive liver transplant patients is difficult to evaluate, since a variety of inconsistent, descriptive histological terms have been used in most studies. Despite the problems with histological nomenclature, a degree of chronic hepatitis develops in 50–90% of patients at 12 months after transplant but cirrhosis is very rarely present(3,32,39). However, at 4–5 years after transplant, cirrhosis has been observed in about 20% of patients 3., 42. (Table 1). Knowing that it takes about 20 years for HCV infection to progress to cirrhosis in 20% of immunocompetent patients 43., 44., 45., it is obvious that HCV infection in transplant patients has a much more aggressive course. Although no difference in survival has been reported in HCV-positive and -negative liver transplant patients 3., 4., 39., this may be due to limited follow-up times. It was recently shown that HCV-positive kidney transplant patients have a poorer survival rate due to liver disease in the second decade compared to HCV- and HBV-negative patients, despite similar survival rates in the first posttransplant decade (46).

TABLE 1. Histological progression of post-transplant hepatitis C virus infection
1st author, year (Ref.)No of patientsFollow-up (months)ImmunosuppressionNormal liver, %Chronic hepatitis, %Cirrhosis, %
MildModerate/SevereTotal
Wright et al. 1992 (1)4112N.A.59N.A.N.A.410
Feray et al. 1994 (39)7912CYA+AZA+PREDN.A.N.A.30N.A.1
36or TACR+PREDN.A.N.A.61N.A.N.A.
Chazouilleres et al. 1994 (52)7812CYA or TACR+AZA+PRED501535500
Gretch et al. 1995 (32)1812CYA+AZA+PRED222850780
Gane et al. 1996 (3)8212CYA+AZA+PRED96229910
3960or TACR+PRED551237421
Gordon et al. 1997 (42)4238CYA+AZA+PRED62N.A.N.A.3819
Shuhart et al. 1997 (47)5040OKT3+ATG→CYA+AZA+PRED34N.A.N.A.606
Berenguer et al. 1998 (60)6312CYA+AZA+PRED362736632
4024 252055750

N.A., not available; CYA, cyclosporin; AZA, azathioprine; PRED, prednisolone; TACR, tacrolimus; OKT3, anti-CD3 monoclonal antibody; ATG, anti-T-lymphocyte globulin.

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Viral Factors and Outcome of Post-Transplant HCV Infection 

Since post-transplant HCV infection may have a quite variable course, ranging from virtually no liver damage on light microscopy or minimal changes to an aggressive course with development of cirrhosis in a few years, predictive factors have been sought in many studies. The two most frequently evaluated factors are the HCV genotype and levels of serum HCV RNA, but the data are quite conflicting. Several reports have suggested that the HCV genotype 1b or 1 may be associated with more aggressive course of post-transplant HCV infection 3., 33., 42., 47.. In contrast, no association between the HCV genotype and the histological severity has been found in several other studies 4., 48., 49., 50.. Recently, the HCV genotype was not found to be related to patient or graft survival (51).

Serum HCV RNA concentrations have been found to be significantly higher after compared to those before OLT 31., 32., 33., but the relationship between levels of viraemia and the long-term outcome of post-transplant HCV infection is contradictory. Serum HCV RNA concentrations have been found to be higher in patients with histologically active disease in a few studies 31., 33., but conversely no correlation between HCV RNA levels and histological severity has been reported by others 49., 52., 53.. In a large study of 166 HCV-positive transplant patients, pre-transplant serum HCV RNA levels were found to be significantly associated with survival (51). Interestingly, patients with higher pre-transplant viral load had a significantly higher 5-year death or retransplantation rate due to non-HCV infections or non-infectious causes but paradoxically not due to HCV-induced liver damage. In this report, no data about any relationship between HCV RNA and severity of histological recurrence were given (51).

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Immunosuppressive Drugs and Post-Transplant HCV Infection 

Although it is widely accepted that immunosuppression significantly increases HCV viraemia, no clear association between HCV RNA levels and type or severity of immunosuppression has been shown. Steroids have been shown to increase HCV RNA levels in transplanted (31) as well as in non-transplanted patients (54). However, a direct stimulation of viral replication through a responsive element on the viral genome such that found in hepatitis B virus infection (55) seems unlikely. In studies of HCV viraemia and corticosteroid therapy, HCV RNA levels increase with withdrawal or reduction of steroids 31., 54. and not during treatment with high doses of steroids (38). We have recently found that HCV RNA concentrations did not differ at 1 or 2 weeks after transplant in patients treated with or without corticosteroids but, at 3 months, they were significantly higher in transplanted patients treated without corticosteroids (36). Thus, the high levels of viraemia in transplanted patients do not seem to be specifically related to steroid treatment per se but to the amount of immunosuppression which allows a high rate of viral replication without an appropriate immune response. Both liver and serum HCV RNA levels have been found to rise in the immediate post-transplant period, when immunosuppression is most intense, peak at the time of acute hepatitis, when the balance between the viral stimulus and the immune system may change, and decline thereafter 31., 56..

Data summarising the effect of different types of immunosuppression on the outcome of post-transplant HCV infection have also been conflicting. In one study (3) comparing triple (cyclosporin, azathioprine and prednisolone) to double therapy (tacrolimus and prednisolone) and in two 52., 57. comparing cyclosporinbased to tacrolimus-based triple therapy, no association between type of immunosuppression and severity of HCV recurrence was documented. Moreover, in a large multicentre study in which triple or double or quadruple therapy was initially administered, no effect of immunosuppression on survival of HCV transplant patients was found (51). In contrast, tacrolimus-based double therapy was recently found to be associated with better survival compared to cyclosporine-based triple therapy (58). Intravenous courses of methylprednisolone or use of OKT3 as anti-rejection treatment have been associated with earlier and more severe HCV recurrence in several studies 40., 59., 60., 61.. The highest rate of severe cholestatic hepatitis (18%) resulting in the death of half of the patients despite a decrease in immunosuppression has been reported in patients treated with high levels of tacrolimus (approximately 15 ng/dl) or cyclosporin (300–400 ng/dl) (57). In our centre, where initial immunosuppression with standard triple (cyclosporin or tacrolimus and azathioprine and prednisolone) therapy is most frequently used, but double (cyclosporin and prednisolone) or even single (cyclosporin or tacrolimus) initial therapy has also been used during study periods, more intense initial therapy was found to be significantly (p=0.03) associated with more frequent development of severe fibrosis or cirrhosis (62).

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A Hypothesis for the Role of Immunosuppression in the Outcome of Post-Transplant HCV Infection 

Cyclosporin or tacrolimus, azathioprine and steroids are the most common immunosuppressive drugs used after liver transplantation (63). Cyclosporin suppresses the activity of Th-cells by binding to intracytoplasmic cyclophilin receptors; it particularly inhibits production of cytokines (such as interleukin-2 and interferon-γ) by Th1 cells, and to a lesser degree of cytokines by Th2 cells 63., 64.. Tacrolimus has a mechanism of action which is similar to that of cyclosporin; it also suppresses the activity of Th-cells (63). Azathioprine is a purine analogue with non-specific antiproliferative effects; it inhibits lymphocyte function, primarily that of T-cells, but also possesses an anti-inflammatory effect by reducing the number of non-specific inflammatory cells such as monocytes and granulocytes 64., 65.. Steroids have completely non-specific immunosuppressive and anti-inflammatory activities; they suppress both specific and non-specific immune response 63., 64..

Based on the knowledge of pathogenesis of HCV infection, it seems logical that the type of immunosuppression may affect the outcome and course of the disease. Patients treated with cyclosporin or tacrolimus have impaired function mainly of Th cells, while the addition of azathioprine and/or prednisolone has a negative effect on the function of B-cells and of the non-specific defense and inflammatory cells (Fig. 1). Cells of non-specific defense are important in activating Th cells, and inflammatory cells complement CTL in their effort to eliminate the infected hepatocytes. Thus, the use of increased doses of immunosuppressive drugs, particularly of less selective drugs, not only augments the degree of immunosuppression but results in impairment of more immune defense pathways. The competence of the immune system during the acute phase of HCV infection seems to be particularly important for the progression of disease later on 11., 12., 13.. The importance of the early phase of HCV infection in the post-transplant setting has been suggested by data on early viraemia and on the efficacy of early antiviral treatment. Higher serum HCV RNA levels within the first 2 weeks after transplant have been associated with more severe disease later on (32), and early (within 2 weeks after transplant) prophylactic treatment with alpha-interferon was very recently shown to improve the outcome of disease in a randomised controlled trial (66), although the drug has been found to be ineffective when given after establishment of HCV recurrence 67., 68..

When the initial host immune defense has been overwhelmed and chronic HCV infection has been established, continuing immune attack against the infected hepatocytes may result in liver cell damage without achieving viral clearance. If this is the case, it seems strange that patients under immunosuppression have a more aggressive course of a disease in which liver damage is mostly mediated through the immune system. The most logical explanation seems to be that the impairment of the immune system may be outweighed by the high viral load which develops during the acute phase of infection because of the defective immune defense. Moreover, the very high number of infected hepatocytes and the subsequent high level of expression of HCV antigens may enhance not only immune attack but cellular susceptibility to the immune attack as well (Fig. 2). It has been suggested in vitro that a high level of expression of HCV core antigen is associated with an enhanced sensitivity to cytotoxic effects of TNF alpha which is a key mediator for CTL induced apoptosis (69).

An additional mechanism for the rapid development of severe fibrosis in the post-transplant setting might be a direct effect of cyclosporin and tacrolimus on fibrogenesis, possibly by increasing levels of transforming growth factor β (TGFβ) 70., 71. (Fig. 2). TGFβ has been directly linked to hepatic fibrosis by several mechanisms (29), and cyclosporin and tacrolimus have been shown to increase the production of TGFβ in both animals and humans 72., 73., 74..

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Conclusions and Practical Considerations 

One of the primary aims of any physician or surgeon who treats HCV-positive liver transplant patients should be to prevent progressive liver disease. Overall, two distinct therapeutic strategies appear to be possible in this setting: antiviral treatment and/or modification of immunosuppression. Antiviral treatment may be tried before transplantation in an effort to lower HCV RNA levels. Both antiviral treatment and modification of immunosuppression may be applied separately or in combination after transplantation in two situations: (i) if and when moderate or severe HCV recurrence develops, or (ii) pre-emptively in the early post-transplant phase.

Based on the very recent report that high pre-transplant HCV RNA levels are strongly associated with significantly worse 5-year survival (51), one would hope that a decrease of pre-transplant viraemia may improve the course of recurrent disease after transplant. However, antiviral therapy in patients with decompensated cirrhosis is poorly tolerated or may be limited by thrombocytopenia or neutropenia and thus the applicability of this therapy may be difficult. Moreover, there are no data supporting any effect of interferon or ribavirin on viraemia in this setting 75., 76..

The question of“how and when” a transplant patient with recurrent chronic hepatitis C should be treated raises important practical issues. There are no data to suggest when treatment for HCV recurrence should be started (for example, when acute hepatitis presents or moderate or severe chronic hepatitis develops). Monotherapy with alpha-interferon or ribavirin has been found to be ineffective 67., 68., 77., 78. and the only promising results have been reported with the combination of interferon and ribavirin (79). However, no randomised controlled trial of any therapy has been reported 76., 80..

The other therapeutic option, when recurrent chronic hepatitis C is established, would be to change the immunosuppressive regimen. Although common sense suggests that immunosuppression should be decreased, and in many centres steroids and/or azathioprine are withdrawn whenever moderate or severe hepatitis C is detected at a liver biopsy 3., 6., the effect of significant decrease of immunosuppression in the late post-transplant period remains unclear. A possible deleterious effect of such a policy should be considered, since a decrease in immunosuppression a few months after transplantation increases the competence of the immune system and subsequently enhances the immune attack against the already highly infected liver. Reactivation of chronic hepatitis C and even fulminant hepatitis have been reported with decrease or discontinuation of immunosuppression in chronic HCV carriers treated with steroids or chemotherapeutic agents 81., 82., 83., or after bone marrow transplantation (84).

If the above assumptions for the pathogenesis of the post-transplant HCV infection are correct, then management of the early phase of infection becomes extremely important and strategies to prevent an aggressive course of HCV recurrence must be concentrated in this phase. Since the outcome of infection depends on the balance between the virus and the host immune response, early treatments that inhibit the virus coupled with less immunosuppression must be tried. Very recently, a 12-month course of prophylactic treatment with alpha-interferon starting very early after transplant was found to decrease the incidence of recurrent HCV hepatitis after transplant (66). However, in another study using a 6-month prophylactic course of interferon, there was only a delay in the occurrence of hepatitis C but no reduction in its incidence or severity (85). Whether prophylactic treatment with combination of alpha-interferon and ribavirin could be beneficial is currently unknown.

On the other hand, initial immunosuppressive regimens have not changed significantly in most centres during the last decade. In most of the published studies, initial immunosuppressive regimens with triple, or more rarely double, but sometimes quadruple therapy, have been used. We have recently suggested that initial immunosuppression with only cyclosporin or tacrolimus may be safely used in liver transplant patients (86). If this strategy is confirmed to be safe, then treatment with a single selective immunosuppressant may be beneficial for patients transplanted for HCV cirrhosis. Since liver transplant patients with recurrent hepatitis C may experience a higher incidence of serious infections compared to other liver transplant groups (87), less initial immunosuppression may not only improve the outcome of HCV infection but decrease the infectious or other immunosuppression related complications as well.

Apart from these suggestions for therapeutic trials of recurrent hepatitis C after liver transplantation, more experimental studies are needed to understand the immune response to HCV. This may allow the choice of a more favourable immunosuppressive regimen, which not only prevents rejection but also minimises the risk of severe recurrent hepatitis C and cirrhosis.

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Acknowledgements 

George V. Papatheodoridis is in receipt of a scholarship from the Hellenic Gastroenterology Association.

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PII: S0168-8278(99)80208-6

Journal of Hepatology
Volume 30, Issue 4 , Pages 731-738, April 1999

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