Untitled

Background. Reducing immunosuppression not only reduces complications but also may lessen recurrent hepatitis C virus (HCV) infection after liver transplantation. Patients/Methods.
HCV-infected cirrhotic patients randomised to tacrolimus monother- apy (MT) or triple therapy (TT) using tacrolimus 0.1 mg/kg/day, azathioprine 1 mg/kg/day, and prednisolone 20 mg/day, tapering over We gratefully acknowledge ¢nancial support 3 months. Results. Twenty-seven patients (MT) and 29 (TT) ^ medi- involved in this investigator-led study. No an follow up 661 days (range, 1^1603). Rejection episodes (protocol/ funds were used for purchase of the drugs.
further biopsies) within ¢rst 3 months and use of empirical treatment 1Liver Transplantationand Hepatobiliary Unit, were evaluated. New rejection was diagnosed if repeat biopsy (5 -day interval) did not show improvement. Treated rejection episodes: 20 Royal Free Hospital,Hampstead, London, UK MT (15 biopsy-proven) vs. 24 TT (21 biopsy-proven), with 19 (MT) vs.
24 (TT) methylprednisolone boluses. Overall: 35 episodes (MT) and Correspondence to:Professor Andrew K.
46 (TT). Fewer MT patients had histological rejection (70%) than TT patients (86%), with fewer episodes of rejection (18.5% vs. 10%), and Hepatobiliary Unit,Academic Department of and more moderate rejection (22% vs. 41%).The MTgroup had higher early tacrolimus levels. Rates of renal dysfunction, retransplantation, Royal Free Hospital, PondStreet, Hampstead, and death were not significantly different. Conclusion. Tacrolimus monotherapy is a viable immunosuppressive strategy in HCV-infect- Tel: 0044 -207- 4726229Fax: 0044 -207- 4726226 e-mail: andrew.burroughs@royalfree.nhs.uk Optimal immunosuppression in orthotopic liver transplan- tation (OLT) should prevent rejection without serious complications. Liver allografts are considered ‘‘immunolog- Received 21 June 2005, revised 15 October2005, accepted for publication 26 October 2005 ically privileged,’ because of an absence of hyperacute re- Copyright & Blackwell Munksgaard 2006 jection despite a positiveT-cell cross-match, a low incidence Transplant Infectious Disease . ISSN 1398 -2273 *Current address: Histopathology Department, Ospedale Sacro Cuore Don Samonakis et al: Tacrolimus monotherapy versus triple therapy of graft loss from chronic rejection, and the capacity of he- HCV recurrence (15^18), and randomised them to groups patocytes to regenerate following tissue injury (1). Thus, receiving tacrolimus MT or TT consisting of tacrolimus, there might be a greater possibility to minimise immuno- azathioprine, and prednisolone in a prospective trial.
suppression in liver transplant recipients.
Tacrolimus is currently a ¢rst-line immunosuppressive A distinction is often made between biological rejection agent with better outcomes than micro-emulsi¢ed cyclo- (histological changes of cellular rejection in absence of sporine in our patient group (19), and has reliable action significant clinical or biochemical abnormalities) (2) and and acceptable side-effect pro¢le (20).
clinical rejection (histological changes accompanied by Our current report focuses on acute cellular rejection clinical signs of graft dysfunction). In liver transplantation rates in this ongoing trial during the ¢rst 3 months after liv- clinically significant cellular rejection is reported in ap- er transplantation, because during this period patients are proximately 50% of patients, whereas histological abnor- at greatest risk of rejection.We assessed whether tacrolimus malities can be seen in up to 80% of protocol biopsies MT is a clinically viable option to prevent important cellu- performed within the ¢rst week post OLT (3). Liver histolo- gy is the gold standard for the diagnosis of acute rejection (4, 5) and an international consensus on a common grading system has been achieved (6). In addition, eosinophilia in the graft is an independent diagnostic marker of cellular rejection as found in our centre (7 ).
Inclusion^exclusion criteria and randomisation The incidence of early clinical and biological cellular re- jection is in£uenced by the type of immunosuppression (8).
From January 2000 to January 2004, we randomised con- Severe rejection may affect graft and patient survival, pos- secutive transplant recipients with HCV cirrhosis (inde- sibly as a result of the use of more potent immunosuppres- pendently of whether they had concomitant alcoholic sion such as antilymphocytic preparations (9). Conversely, aetiology or hepatocellular carcinoma [HCC]) when they milder grades of rejection are associated with improved (a) were older than age 18 years, (b) gave informed written survival after liver transplantation, a situation different consent, (c) had a cadaveric liver transplant. Exclusion cri- from renal transplantation (9). Moreover, early cellular re- teria were (a) multi-organ transplants, (b) retransplanta- jection that responds promptly to treatment may be associ- tion, (c) split or auxiliary transplants, (d) patients with ated with a lower risk of immunological complications contraindications to tacrolimus or azathioprine, and (e) re- fusal to participate. We evaluated all patients up to May Complete steroid withdrawal is now common practice in 2004, i.e., had at least 3 -month follow up.
many centres as patient and graft loss are not increased, The study protocol conformed to the ethical guidelines of and long-term steroid complications are reduced (10). How- the Declaration of Helsinki and was approved by the Hos- ever few studies have avoided, from immediately after pital Ethics committee. Randomisation took place on arriv- transplant, the use of steroids in maintenance immunosup- al to the operating theatre. Sealed opaque envelopes were pression (11^14). When steroid use has been avoided, other used, opened in numbered sequence containing the allocat- agents have been substituted for the steroids so that ‘total’ ed treatment in a 1:1 proportion derived from a random immunosuppressive potency is not reduced. Our own expe- rience without steroids, using only calcineurin inhibitor monotherapy (MT), showed that it was safe and effective Thus, we evaluated calcineurin inhibitor MT vs. triple We evaluated 56 consecutive patients (26 females, 30 therapy (TT) in a clinical setting, where less potent males); 1 patient refused randomisation (given MT). Recip- immunosuppressive therapy might be more bene¢cial. We ient and donor characteristics and surgical details are chose recipients with hepatitis C virus (HCV) cirrhosis re- shown in Table 1. Typing of donor and recipient antigens ceiving a cadaveric liver transplant, because increased was performed with a standard assay using lymphotoxic immunosuppression has been one of the factors leading to antibodies. For each locus (-A, -B, -DR, -DQ) the number of Transplant Infectious Disease 2006: 8: 3^12 Samonakis et al: Tacrolimus monotherapy versus triple therapy Patient characteristics in the two randomised treatment arms 1Significant HLA DR mismatch: both HLA DR loci were different in donor compared with recipient.
2Significant total mismatch: a mismatch score 6 or more (from a maximum of 8) derived from HLA comparisons (2 HLA A locus, 2 HLA B locus, 2 HLADR locus, and 2 HLA DQ locus) where no mismatch 5 0, 1 mismatch 5 1, 2 Two consecutive CMV-DNA PCR with twice weekly sampling.
Monotherapy, tacrolimus alone; triple therapy, tacrolimus/azathioprine/ prednisolone therapy; OLT, orthotopic liver transplantation; HCC,hepatocellular carcinoma; HLA, human leukocyte antigens; DR, donor; BIL, bilirubin; GGT, g glutamyl transferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase; ALT, alanine transaminase; ALB, albumin;INR, International normalised ratio; CRE, creatinine; CMV, cytomegalovirus.
mismatches was scored as 0, 1, or 2. Total human leukocyte antigen (HLA) mismatch score (range: 0^8) was de¢ned as sum of the number of mismatches for the 4 loci ^ HLA-A, -B, -DR, or -DQ (21). Cold ischaemia time was de¢ned as the in- terval from donor cross-clamp to removal from cold storage.
Warm ischaemia time was de¢ned as the interval between removal from cold storage and venous reperfusion. Twenty- one patients had known HCC, 11 had concomitant alcoholic liver injury, and 2 patients were co-infected with hepatitis B or D virus. Median follow-up was 661 days (range: 1^1603).
Liver and renal biochemical parameters were documented at the ¢rst protocol biopsy. Renal dysfunction was de¢ned (for the purpose of the study) as an increase in creatinine value ! 130 mmol/L and was also evaluated at 6 weeks post OLT and at the end of follow up. No patient received HCVantiviral therapy within 3 months of transplantation.
Values at ¢rst protocol biopsy/(reference range) (median, range) Tacrolimus (Prograf , Fujisawa Ltd, Killorglin, County Kerry, Ireland) MT 0.1 mg/kg/day in 2 divided doses or TT of tacrolimus (same regimen), azathioprine ^ initially intravenously (IV) then orally ^ 1 mg/kg/day, and methyl- prednisolone (16 mg/day IV) until oral intake was estab- lished, when 20 mg/day prednisolone was used. The ¢rst doses of tacrolimus were administered initially via naso- Transplant Infectious Disease 2006: 8: 3^12 Samonakis et al: Tacrolimus monotherapy versus triple therapy gastric tube starting within 6 h after the transplant and and consent was not given for biopsy (empirical treatment).
then orally. If poor renal and/or poor graft function was Mycophenolate mofetil was used if there were more than 2 present, a suitable adjustment in initial and subsequent episodes of moderate/severe rejection not responding to doses was made. Oral tacrolimus doses were adjusted ac- methylprednisolone boluses or as a tacrolimus-sparing cording to the clinical progress and the occurrence of ad- agent if there was chronic renal impairment. A new episode verse effects, to maintain a whole blood level of 5^14 ng/ of rejection was considered as one diagnosed by biopsy 5 mL (aiming for 5^10) by microparticle enzyme immunoas- days or more after the histological diagnosis of the preced- say (Imx Tacrolimus II, Abbot Laboratories, Illinois, USA).
ing episode only if it showed the same or worse grade than In patients randomised to TT, the tacrolimus adjustment the initial one or if after 5 days from the start of empirical was the same as for the MT group. Azathioprine was con- therapy there was moderate or severe rejection. Chronic tinued at the same dose unchanged unless neutropenia de- ductopenic rejection was de¢ned according to the criteria veloped. Prednisolone was gradually tapered from 3 weeks and then stopped between 3 and 4 months.
Serum samples before transplant and then at 1 and 3 Protocol liver biopsies were planned between the 5th and months post transplant, were collected, stored at À 701C, 7th days after transplantation, and thereafter if clinically and analysed for quantitation of serum HCV-RNA by a sec- indicated, performed transjugularly for those with contra- ond-generation branched DNA assay (bDNA 2.0, Quanti- indications to the percutaneous route (22). If rejection was plex, Chiron, Emeryville, California, USA). Determination treated (1 g/day for 3 days of methylprednisolone IV) a re- of HCV genotype was performed by reverse transcription peat biopsy was performed 5 days after the initial methyl- polymerase chain reaction (PCR) and reverse hybridisation prednisolone bolus to assess histological response to assay of the ampli¢ed sequence (InnoLipa HCV II, Innoge- netics, Zwijnaarde, Belgium). Cytomegalovirus (CMV) vir- The liver biopsy samples were formalin ¢xed, paraf¢n aemia was screened for by PCR assay twice weekly (24).
embedded, and stained with haematoxylin and eosin. A Two consecutive positive CMV DNA samples were an indi- separate set of 20 biopsies from transplanted livers show- cation to treat with ganciclovir or valgancyclovir for 14 ing different degrees of rejection or other post-transplanta- tion pathology (e.g., cholangitis, ischaemia) were reviewed by all 3 histopathologists before the start of the study, using a multi-head microscope in order to develop ‘ a similar atti- tude and threshold to each feature’ as described before (7 ).
F|sher exact test was used for frequency tables and Mann^ All biopsies of this study were reviewed by 3 histopatholo- Whitney rank-sum test was used for means. Bio-Medical gists (A.P., A.Q., and A.P.D.), using the grading of cellular Data Processing (BMDP Dynamic version 7, University of rejection according to the Royal Free Hospital (RFH) scor- California, Los Angeles, California, USA) was used for all ing system as follows: mixed portal in£ammation, endo- calculations. A P value less than 0.05 was considered statis- thelialitis, bile duct damage, eosinophils in the portal tract, giving a maximum score of 12 (score 4^6, mild rejection; score 7^9, moderate rejection; score 10^12, severe rejection) (7 ). Disconcordant cases were discussed using a multi-head microscope to achieve a ¢nal consensus. The criteria for grading into mild, moderate, or severe cellular rejection are similar, with the exception of eosinophils in the graft, By randomisation 27 patients received tacrolimus MT and to the international Ban¡ criteria (6).
29 TT. The groups were well matched at randomisation Acute cellular rejection was treated if the RFH score was with no significant differences except for ascites, which ! 7 or if there was strong clinical suspicion of rejection Transplant Infectious Disease 2006: 8: 3^12 Samonakis et al: Tacrolimus monotherapy versus triple therapy Frequency of rejection episodes in the two randomised treatment armsusing protocol biopsies during the ¢rst 3 months from transplantation From the 56 patients, 51 had 1 biopsy or more (median 3, range: 1^7 ). Of the 5 without biopsy, 4 (3 MT, 1 TT) were clinically very sick and died within 1^20 days, and 1 (MT) refused consent. No histological rejection was diagnosed in 14 (MT: 8^30%; TT: 6^21%), mild in 25 (MT: 11^41%; TT: 14^50%), moderate in 11 (MT: 3^11%; TT: 8^28%), and se- vere rejection in 2 (MT: 2^7.5%; TT: 0^0%) patients. Medi- an time to protocol biopsy was 6 days (MT) and 7 days (TT).
Following the ¢rst biopsy, 43% TTand 46% MT were treat- Patients with at least 1 rejection episode Rejection during 3 months after transplant Patients with no more than mild rejection During the ¢rst 3 months, following and including the ¢rst Patients with no more than moderate rejection biopsy, 19 MT patients (70%) had 35 rejection episodes and received 19 courses of methylprednisolone (5 empirical therapy, in 5 patients). In comparison, 25 TT patients (86%) had 46 rejection episodes and received 24 courses of methylprednisolone (3 empirical therapy, in 3 patients).
Thus, over the course of 3 months, 15 MT patients (10 biop- Monotherapy, tacrolimus alone, triple therapy, tacrolimus/azathioprine/ sy-proven episodes) and 17 TT patients (21 biopsy-proven episodes) were treated for rejection. Details of rejection ep- isodes are shown in Table 2. The TT group had more rejec- tion episodes and more moderate rejection episodes than the MT group, but neither difference was statistically sig- Other immunosuppression and virology evaluation In 3 cases (2 MT, 1 TT) rejection was treated without me- thylprednisolone boluses but with an increase in ta- Patients without rejection or mild rejection in the ¢rstprotocol biopsy crolimus dosage, and in 2 patients (1 MT at 3rd week post- OLT; 1 TTat 2nd week) mycophenolate mofetil was used to The TT patients, who did not have rejection in their ¢rst potentiate the immunosuppressive regimen. Overall myco- protocol biopsy, did not develop any episode of severe rejec- phenolate mofetil was used in 10 patients in the MTgroup (8 tion thereafter and only 2 subsequently had moderate rejec- for renal dysfunction, 1 for additional immunosuppression, tion. However, if mild rejection was present, moderate or 1 after tacrolimus toxicity) commenced within the ¢rst severe rejection subsequently occurred (F|g. 1). One patient month of OLT (days 4^25), and in 7 patients in TTgroup (3 had mild rejection on ¢rst biopsy and subsequently moder- for renal dysfunction, 3 for toxicity, 1 for ongoing rejection ate rejection and then (responding fully to treatment) devel- despite adequate tacrolimus levels) commenced within the oped chronic ductopenic rejection, and was re-grafted 6 ¢rst month of OLT (days 4^19). No antilymphocytic prepa- In the MTgroup, of those who had no rejection in the ¢rst HCVgenotypes were similarly distributed: genotype 1/1b protocol biopsy, only 1 developed moderate rejection subse- MT 41% vs. TT 41%, genotype 2/3 MT 36% vs. TT 38%, quently; some who had histological rejection did subse- genotype 4 MT 7% vs. TT 13%. Median HCV RNA levels quently develop severe rejection (F|g. 2). No patient pre-transplant were not significantly different 150,000 IU/ mL (MT) vs. 252,000 IU/mL (TT) (P 5 0.7 ), and nor at Transplant Infectious Disease 2006: 8: 3^12 Samonakis et al: Tacrolimus monotherapy versus triple therapy TRIPLE THERAPY
1st PROTOCOL BIOPSY
28 patients- 1 died
REJECTION
NO REJECTION
6 patients
Moderate
Moderate 1
Moderate 3
Moderate
Fig. 1. Patients with tacrolimus/azathioprine/prednisolone triple therapy: rejection episodes.
1 month (MT) 1.5 Â 106 IU/mL vs. 860,000 IU/mL (TT) 3^20) (P 5 0.006). Median levels at 1 month (MT: 8.5 vs.
(P 5 0.98), nor at 3 months (MT) 4 Â 106 IU/mL vs.
TT: 8.5 ng/mL), 2 months (MT: 7 vs. 7.5 ng/mL), and 1.5 Â 106 IU/mL (TT) (P 5 0.52) in keeping with the previ- 3 months (MT: 7 vs. 6.7 ng/mL) were not significantly dif- ous study from our group (25). CMV viraemia was not dif- ferent (P40.05). Thus, within 3 months of transplantation ferent in the 2 groups (5 MT, 6 TT).
among the 22 patients with moderate or severe rejection, more had subtherapeutic concentrations of tacrolimus (12 patients ^ 4 MTand 8 TT), compared to those with mild rejection (5^2 MT and 3 TT of 22 patients), or no rejection Tacrolimus levels just before or on the day of ¢rst protocol biopsy were significantly higher in the MTgroup: median 7.3 (range: 3.5^26.2 ng/mL) vs. TT median 5.1 (range: 2.8^ 12.2 ng/mL) (P 5 0.015), as also on day 3 (MT: 10 ng/mL,2.9^28.2 vs. TT: 6 ng/mL, 2.9^14) (P 5 0.011), day 5 (MT: The median follow up was 661 days (1^1603). In both 9 ng/mL, 2.9^22.7 vs. TT: 6.3 ng/mL, 2.7^11.8) (P 5 0.045), groups, 3 received a second transplant: 2 MT patients for and day 21 (MT: 9.6 ng/mL, 3.3^17.7 vs. TT: 6.1 ng/mL, hepatic artery thrombosis (8^12 days after ¢rst OLT) and Transplant Infectious Disease 2006: 8: 3^12 Samonakis et al: Tacrolimus monotherapy versus triple therapy MONOTHERAPY
PROTOCOL BIOPSY
(3died- 1 no biopsy-empirical treatment- REJECTION
16 patients
NO REJECTION
8 patients
Moderate
Moderate 2
2 Treated
Moderate
Fig. 2. Patients with tacrolimus monotherapy: rejection episodes. MP, methylprednisolone boluses; MMF, mycophenolate mofetil.
1 for primary non-function (at 2 days), while in the 3 TT pa- 1 because of neurotoxicity ^ converted to cyclosporine), tients: 1 for hepatic artery thrombosis (42 days), 1 for chron- and in 3 TT patients all because of neurotoxicity (2 convert- ic rejection (6 months), and 1 for recurrent HCVcirrhosis (31 ed to cyclosporine and 1 to mycophenolate mofetil substi- months). In the MT group 6 patients died; 4 from sepsis- multiple organ failure (8, 8, 20, and 123 days), 1 from graft proportion of patients whose serum creatinine was failure (14 days), and 1 from pulmonary hypertension (6 ! 130 mmol/L during the ¢rst 3 months was similar in days). In the TT group 1 patient died after re-transplant the 2 groups, 63% vs. 62%. At 6 weeks, median creatinine (sepsis ^ 2 days) and 1 at 44 days from sepsis and multiple was 100.5 mmol/L in the MT group vs. 115.5 mmol/L in the TT group (not significant), and at 3 months both groups had same median creatinine value (110 mmol/L, range MT: 78^222 and TT: 76^281 mmol/L). Antibiotics given after the¢rst 5 days were similar, 20 in MT and 20 in TT group During the ¢rst 3 months tacrolimus was discontinued in patients. No significant difference was found in the inci- 6 MT patients (5 because of severe renal impairment dence of diabetes pre- and post-OLTaccording to treatment with multiple organ failure shortly before death, and in Transplant Infectious Disease 2006: 8: 3^12 Samonakis et al: Tacrolimus monotherapy versus triple therapy who subsequently developed cirrhosis post OLTcompared with those without, but another study (27 ) showed that cu- We evaluated 2 different immunosuppressive regimens in mulative frequency of acute cellular rejection was not sig- liver transplant recipients with HCVcirrhosis, with respect nificantly different in HCV and non-HCV recipients within to the frequency and severity of cellular rejection, using a the ¢rst 6 weeks post OLT. A further study reported no dif- schedule of protocol liver biopsies, which is the gold stand- ference in the incidence and timing of acute cellular rejec- ard for the diagnosis of cellular rejection (26). The ¢rst 3 tion in HCV vs. a control group (38). In contrast, a recent months after transplant, rather than just the ¢rst 6 weeks study (without protocol biopsies) showed that HCVaetiolo- were evaluated, because this longer period usually encom- gy was strongly associated with acute rejection (49% with- passes most acute rejection episodes (9, 27 ) and during this in 6 months and 42% receiving treatment) (29). It was time there should be far less histological confusion with re- unclear whether this ¢nding was the result of either an im- current HCV (28). Protocol biopsies of HCV-infected recipi- munologic environment associated with HCV infection, or ents are particularly useful to minimise empirical because rejection episodes were over-diagnosed in the treatment of rejection, which might otherwise be given if setting of recurrent HCV (29). The question could not be an- liver dysfunction occurs, but it is not clear if some biopsies swered, as protocol biopsies were not used.The interactions are not performed because of poor clotting or other reasons, between HCV, allograft rejection, and immunosuppression and what severity of rejection warrants treatment.
are complex and the diagnostic dilemma between recurrent We arbitrarily de¢ned episodes of rejection as separate, HCVand cellular rejection can only be minimised with his- if a protocol biopsy 5 days after histological diagnosis showed the same degree or worse rejection, and if a biopsy In our randomised trial, tacrolimus MT was not associat- 5 days after the start of empirical therapy for rejection ed with an increased number or severity of cellular rejec- showed moderate or severe rejection. This evaluation ac- tion episodes. The trend for more moderate rejection counts for the apparent high rate of cellular rejection over episodes in theTTgroup was probably associated with low- the 3 -month period. If solely the ¢rst protocol biopsy data er tacrolimus levels similar to another cohort of HCV-infect- are evaluated (common to many reports on rejection rates ed transplant recipients (29). Less likely, but also possible, in liver transplantation) then only 18.5% of the MT group is that ascites is associated with increased rejection (9), and and 27.5% of theTTgroup had moderate or severe rejection.
there was more ascites in the TT group. Lower tacrolimus Overall 56% of our cohort (4/5 of these following the ¢rst levels in either group were associated with moderate or se- protocol biopsy) received treatment for rejection which ap- vere rejection in a similar fashion so the added azathiopr- proximates to the rate of 42% in a recent study of HCV pa- ine, prednisolone, and mycophenolate mofetil as a renal- tients with transplants, in which protocol biopsies were not sparing agent (39) or to potentiate immunosuppression (used similarly in both groups) did not ‘ compensate’ for Currently, management of patients with HCV cirrhosis the lower tacrolimus levels. Neither immunosuppressive who are transplanted is a major challenge. These patients regimen resulted in unusual rates of retransplantation constitute the leading indication for transplantation, but (11% in TT and 10% in MT) or of chronic rejection (1/56 ^ HCV recurrence reduces survival (30). Early management, 1.8%). Interestingly, in our cohort, patients in either trial including modi¢cation of immunosuppression, may in£u- group who did not have any rejection in the ¢rst protocol ence severity of recurrent HCV infection (15, 17, 27, 31). Re- biopsy did not have severe rejection during follow up (F|gs.
ducing immunosuppression has become more common (32, 33) and, in addition, avoidance of steroids in HCV recipients In conclusion, MT with tacrolimus is comparable to TT is increasingly popular using substitution with interleu- with tacrolimus, azathioprine, and prednisolone in terms kin-2 receptor blockers. Methylprednisolone boluses and of the frequency and severity of cellular rejection and its antilymphocytic preparations are associated with a worse treatment, in HCV recipients transplanted with cadaveric evolution of recurrent HCV infection (17, 18, 34^36), with livers, so that this trial continues. Whether the absence of few exceptions (11). In one study (37 ), rejection was signi¢- maintenance azathioprine or steroids will be bene¢cial in cantly more common among HCV recipients (genotype 1b) terms of recurrence of HCVcan only be evaluated with pro- Transplant Infectious Disease 2006: 8: 3^12 Samonakis et al: Tacrolimus monotherapy versus triple therapy longed follow up. Our preliminary data, mainly with cy- 10. RAIMONDO ML, BURROUGHS AK. Single-agent immunosuppression closporine as MT (ab initio), was associated with less severe after liver transplantation: what is possible? Drugs 2002: 62: ¢brosis (21). In a randomised study of microemulsi¢ed cy- 11. EASON JD, NAIR S, COHEN AJ, BLAZEK JL, LOSS GE Jr. Steroid-free liver closporine (C2 monitoring) vs. tacrolimus (40), there was no transplantation using rabbit antithymocyte globulin and early difference in cellular rejection rates diagnosed by non-pro- tacrolimus monotherapy. Transplantation 2003: 75: 1396^1399.
tocol biopsies, but graft and patient survival was signi¢- 12. LANGREHR JM, NEUMANN UP, LANG M, et al. First results from a prospective randomized trial comparing steroid-free induction cantly better in liver transplant patients with HCV therapy with tacrolimus and MMF versus tacrolimus and steroids in cirrhosis given cyclosporine. This is in contrast to another patients after liver transplantation for HCV. Transplant Proc 2002: 34: randomised study (41) in which graft and patient survival was no different between the 2 drugs, but HCV RNA con- 13. PIRENNE J, AERTS R, KOSHIBA T, et al. Steroid-free immunosuppression during and after liver transplantation ^ a 3 -yr centrations rose far more in the cyclosporine group. On the follow-up report. Clin Transplant 2003: 17: 177^182.
other hand, azathioprine-containing regimens have been 14. ROLLES K, DAVIDSON BR, BURROUGHS AK. A pilot study of documented as reducing histological recurrence and pro- immunosuppressive monotherapy in liver transplantation: gression of HCV (16, 42), and while an antiviral effect tacrolimus versus microemulsi¢ed cyclosporin. Transplantation against HCV has been proposed (43), we found no substan- 15. BERENGUER M, PRIETO M, CORDOBA J, et al. Early development of tial difference in viral loads between trial groups before or chronic active hepatitis in recurrent hepatitis C virus infection after after transplantation. In addition, maintenance steroids in liver transplantation: association with treatment of rejection.
HCV-infected recipients have been recently associated with 16. BERENGUER M, CRIPPIN J, GISH R, et al. A model to predict severe HCV- favourable histological outcomes (16, 44^46). The long-term related disease following liver transplantation. Hepatology 2003: 38: histological outcomes in this randomised study will help determine whether minimising initial immunosuppression 17. SHEINER PA, SCHWARTZ ME, MOR E, et al. Severe or multiple rejection episodes are associated with early recurrence of hepatitis C after and avoiding maintenance azathioprine and steroids is of orthotopic liver transplantation. Hepatology 1995: 21: 30^34.
bene¢t or not in minimising the severity of recurrence of 18. SINGH N, GAYOWSKI T, NDIMBIE OK, NEDJAR S,WAGENER MM,YU VL.
Recurrent hepatitis C virus hepatitis in liver transplant recipients receiving tacrolimus: association with rejection and increased immunosuppression after transplantation. Surgery 1996: 119: 19. O’GRADY JG, BURROUGHS A, HARDY P, ELBOURNE D,TRUESDALE A.
Tacrolimus versus microemulsi¢ed ciclosporin in liver 1. RIORDAN SM,WILLIAMS R. Tolerance after liver transplantation: does transplantation: the TMC randomised controlled trial. Lancet 2002: it exist and can immunosuppression be withdrawn? J Hepatol 1999: 20. SCOTT LJ, MCKEAGE K, KEAM SJ, PLOSKER GL. Tacrolimus: a further 2. International Working Party. Terminology for hepatic allograft update of its use in the management of organ transplantation. Drugs rejection. Hepatology 1995: 22: 648^654.
3. HUBSCHER S. Diagnosis and grading of liver allograft rejection: a 21. PAPATHEODORIDIS GV, DAVIES S, DHILLON AP, et al. The role of European perspective. Transplant Proc 1996: 28: 504^507.
different immunosuppression in the long-term histological outcome 4. NEUBERGER J,WILSON P, ADAMS D. Protocol liver biopsies: the case in of HCV reinfection after liver transplantation for HCVcirrhosis.
favour. Transplant Proc 1998: 30: 1497^1499.
5. WIESNER RH. Is hepatic histology the true gold standard in 22. PAPATHEODORIDIS GV, PATCH D,WATKINSON A,TIBBALLS J, diagnosing acute hepatic allograft rejection? LiverTranspl Surg 1996: BURROUGHS AK. Transjugular liver biopsy in the 1990s: a 2-year audit. Aliment Pharmacol Ther 1999: 13: 603^608.
6. Ban¡ schema for grading liver allograft rejection: an international 23. DEMETRIS A, ADAMS D, BELLAMY C, et al. Update of the International consensus document. Hepatology 1997: 25: 658^663.
Ban¡ schema for liver allograft rejection: working recommendations 7. DATTA GS, HUDSON M, BURROUGHS AK, et al. Grading of cellular for the histopathologic staging and reporting of chronic rejection. An rejection after orthotopic liver transplantation. Hepatology 1995: 21: International Panel. Hepatology 2000: 31: 792^799.
24. KIDD IM, FOX JC, PILLAY D, CHARMAN H, GRIFFITHS PD, EMERY VC.
8. TIPPNER C, NASHAN B, HOSHINO K, et al. Clinical and subclinical acute Provision of prognostic information in immunocompromised patients rejection early after liver transplantation: contributing factors and by routine application of the polymerase chain reaction for relevance for the long-term course.Transplantation 2001: 72: 1122^1128.
cytomegalovirus. Transplantation 1993: 56: 867^871.
9. WIESNER RH, DEMETRIS AJ, BELLE SH, et al. Acute hepatic allograft 25. PAPATHEODORIDIS GV, BARTON SG, ANDREW D, et al. Longitudinal rejection: incidence, risk factors, and impact on outcome. Hepatology variation in hepatitis C virus (HCV) viraemia and early course of HCV infection after liver transplantation for HCVcirrhosis: the role Transplant Infectious Disease 2006: 8: 3^12 Samonakis et al: Tacrolimus monotherapy versus triple therapy of different immunosuppressive regimens. Gut 1999: 45: 37. PRIETO M, BERENGUER M, RAYON JM, et al. High incidence of allograft cirrhosis in hepatitis C virus genotype 1b infection following 26. BURROUGHS AK, PATCH DW, STIGLIANO R, CECILIONI L. Protocol transplantation: relationship with rejection episodes. Hepatology biopsies in liver transplantation. Liver Transpl 2003: 9: 780^781.
27. CHARLTON M, SEABERG E. Impact of immunosuppression and acute 38. CASAVILLA FA, RAKELA J, KAPUR S, et al. Clinical outcome of patients rejection on recurrence of hepatitis C: results of the national institute infected with hepatitis C virus infection on survival after primary of diabetes and digestive and kidney diseases liver transplantation liver transplantation under tacrolimus. Liver Transpl Surg 1998: 4: database. Liver Transpl Surg 1999: 5: S107^S114.
28. REGEVA, MOLINA E, MOURA R, et al. Reliability of histopathologic 39. RAIMONDO ML, DAGHER L, PAPATHEODORIDIS GV, et al. Long-term assessment for the differentiation of recurrent hepatitis C from mycophenolate mofetil monotherapy in combination with calcineurin acute rejection after liver transplantation. Liver Transpl 2004: inhibitors for chronic renal dysfunction after liver transplantation.
29. MCTAGGART RA,TERRAULT NA,VARDANIAN AJ, BOSTROM A, FENG S.
40. LEVY G,VILLAMIL F, SAMUEL D, et al. Results of lis2t, a multicenter, Hepatitis C etiology of liver disease is strongly associated with early randomized study comparing cyclosporine microemulsion with C2 acute rejection following liver transplantation. Liver Transpl 2004: monitoring and tacrolimus with C0 monitoring in de novo liver transplantation. Transplantation 2004: 77: 1632^1638.
30. FORMAN LM, LEWIS JD, BERLIN JA, FELDMAN HI, LUCEY MR. The 41. MARTIN P, BUSUTTIL RW, GOLDSTEIN RM, et al. Impact of tacrolimus association between hepatitis C infection and survival after versus cyclosporine in hepatitis C virus-infected liver transplant orthotopic liver transplantation. Gastroenterology 2002: 122: recipients on recurrent hepatitis: a prospective, randomized trial.
31. TESTA G, CRIPPIN JS, NETTO GJ, et al. Liver transplantation for 42. HUNT J, GORDON FD, LEWIS WD, et al. Histological recurrence and hepatitis C: recurrence and disease progression in 300 patients. Liver progression of hepatitis C after orthotopic liver transplantation: in£uence of immunosuppressive regimens. Liver Transpl 2001: 7: 32. BURROUGHS AK. Induction immunosuppression for patients who underwent transplantation for cirrhosis caused by hepatitis C? The 43. STANGL JR, CARROLL KL, ILLICHMANN M, STRIKER R. Effect of answer is no!. Liver Transpl 2002: 8: S47^S49.
antimetabolite immunosuppressants on Flaviviridae, including 33. MCCAUGHAN GW, ZEKRYA. Mechanisms of HCV reinfection and hepatitis C virus. Transplantation 2004: 77: 562^567.
allograft damage after liver transplantation. J Hepatol 2004: 40: 44. BRILLANTI S,VIVARELLI M, DE RUVO N, et al. Slowly tapering o¡ steroids protects the graft against hepatitis C recurrence after liver 34. GANE EJ, PORTMANN BC, NAOUMOV NV, et al. Long-term outcome of transplantation. Liver Transpl 2002: 8: 884^888.
hepatitis C infection after liver transplantation. N Engl J Med 1996: 45. FASOLA C, NETTO G, ONACA N, et al. A more severe hepatitis C recurrence (HCVR) post liver transplantation (OLT) observed in 35. LAKE JR. The role of immunosuppression in recurrence of hepatitis C.
recent years may be explained by the use of lower-dose corticosteroid (CS) maintenance protocols. Hepatology 2003: 38 (Suppl 1): 226A.
36. NEUMANN UP, BERG T, BAHRA M, et al. Long-term outcome of liver 46. SAMONAKIS D,TRIANTOS C,THALHEIMER U, et al. Immunosuppression transplants for chronic hepatitis C: a 10 -year follow-up.
and donor age with respect to severity of HCV recurrence after liver transplantation. Liver Transpl 2005: 11: 386^395.
Transplant Infectious Disease 2006: 8: 3^12

Source: http://www.theliverunit.com/downloads/830471218_16623815.pdf