Spanish society of liver transplantation (SETH) consensus recommendations on hepatitis C virus and liver transplantation

Authors

  • Marina Berenguer,

    1. Hepatology Unit, Hospital La Fe, Valencia and Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd), Valencia, Spain
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    • All three authors contributed equally to the manuscript.
  • Ramón Charco,

    1. HBP Surgery and Transplant Department, Hospital Universitario Vall d'Hebron, Universidad Autónoma, Barcelona, Spain
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    • All three authors contributed equally to the manuscript.
  • Juan Manuel Pascasio,

    1. Department of Digestive Diseases, Hospital Virgen del Rocío, Sevilla, Spain
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    • All three authors contributed equally to the manuscript.
  • Jose Ignacio Herrero,

    Corresponding author
    • Liver Unit, Clínica Universidad de Navarra, Pamplona and Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd), Spain
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  • on behalf of the Sociedad Española de Trasplante Hepático

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    • Members of the Sociedad Española de Trasplante Hepático are listed in Appendix 1.

Correspondence

J. Ignacio Herrero, Liver Unit, Clínica Universidad de Navarra, Av. Pío XII, 36, 31008 Pamplona, Spain

Tel: +34-948-2255400

Fax: +34-948-296500

e-mail: iherrero@unav.es

Abstract

In November 2010, the Spanish Society of Liver Transplantation (Sociedad Española de Trasplante Hepático, SETH) held a consensus conference. One of the topics of debate was liver transplantation in patients with hepatitis C. This document reviews (i) the natural history of post-transplant hepatitis C, (ii) factors associated with post-transplant prognosis in patients with hepatitis C, (iii) the role of immunosuppression in the evolution of recurrent hepatitis C and response to antiviral therapy, (iv) antiviral therapy, both before and after transplantation, (v) follow-up of patients with recurrent hepatitis C and (vi) the role of retransplantation.

Abbreviations
CMV

cytomegalovirus

CYA

cyclosporine A

EPO

erythropoietin

EVR

early virological response

FCH

fibrosing cholestatic hepatitis

G-CSF

granulocyte colony-stimulating factor

HCV

hepatitis C virus

HVPG

hepatic venous pressure gradient

IFN

interferon

LT

liver transplantation

MMF

mycophenolate mofetil

mTOR

mammalian target of rapamycin

PCR

polymerase chain reaction

PEG-IFN

pegylated interferon

PPV

positive predictive value

RBV

ribavirin

RETH

Registro Español de Trasplante Hepático (spanish liver transplantation registry)

RVR

rapid virological response

SVR

sustained virological response

TAC

tacrolimus

VR

virological response

The Spanish Society of Liver Transplantation (Sociedad Española de Trasplante Hepático-SETH-) held a consensus conference in November 2010 about liver transplantation in patients with hepatitis C. The coordinators of this group (MB, RC and JMP) selected the bibliography before the meeting. The main points were discussed by the group (see Appendix 1). Finally, the three coordinators prepared the present manuscript that was reviewed by the rest of the group, the Scientific Committee and the Governing Board of the SETH.

The conclusions and recommendations were carried out to reflect the type (benefit versus risk) and level of evidence, according to Table 1.

Table 1. Grading system used for the allocation of the class and evidence level
 Description
Class
IConditions for which there is evidence and/or general agreement that a diagnostic evaluation, procedure or treatment is beneficial, useful and effective
IIConditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a diagnostic evaluation, procedure or treatment
IIaWeight of evidence/opinion in favour of usefulness/efficacy
IIbUsefulness/efficacy is not well established by evidence/opinion
IIIConditions for which there is evidence and/or general agreement that a diagnostic evaluation/procedure/treatment is not useful/effective and in some cases may be harmful
Level of evidence
AData derived from multiple randomized trials or meta-analysis
BData derived from a single randomized trial or non-randomized studies
COnly consensus opinion of experts, case studies or standard treatment

Natural history of infection by virus C after liver transplantation

Infection with hepatitis C virus (HCV), alone or associated with liver damage induced by alcohol, is the most common indication for liver transplantation (LT) in Western countries, now representing 30–50% of indications in adults [1]. In Spain, the Spanish Liver Transplant Registry (SLTR) shows that 35% of recipients of a first liver graft during the years 1984–2009 were infected with HCV [2]. The recurrence of viral infection occurs in practically all cases and takes place immediately after graft reperfusion [3]. The diagnosis of viral recurrence is purely virological and is established by the detection of serum HCV RNA by means of polymerase chain reaction (PCR) techniques. It is usually accompanied by a sharp increase in viral load, with levels 10–20 times higher than those detected pretransplantation [3].

The diagnosis of recurrent hepatitis or disease on the graft is based on histological findings and the evolution is variable; while in some cases the histological recurrence is mild and non-progressive, in many, it follows a faster rate than that observed in immunocompetent hosts, with frequent progression to cirrhosis and graft loss [4-6]. From a physiological point of view, there are two recurrent patterns with clinical and prognostic differences: (i) a pattern of chronic hepatitis C, similar to that observed in non-transplanted patients, but with a greater fibrosis progression rate (0.3–0.8 fibrosis unit increase per year compared to 0.2 units/year) and therefore a shorter time for the establishment of advanced fibrosis or cirrhosis (9–12 years as opposed to 20–50 years) [4, 6], (ii) a second pattern, possibly mediated by an HCV direct effect, termed ‘fibrosing cholestatic hepatitis’ (FCH), infrequent (less than 10%), but very severe, which usually occurs in a state of intense immunosuppression [6, 7]. It can develop as the initial manifestation of recurrent disease or, less frequently, as chronic hepatitis. It is characterized by biochemical cholestasis, marked jaundice, very high titres of viraemia and distinctive histological features, which include extensive hepatocyte swelling and degeneration, cholestasis, spotty acidophilic hepatocyte necrosis and Kupffer's cell hypertrophy in combination with portal expansion due to prominent ductular-type and fibrotic-type interface activity and mild mixed or even neutrophil-predominant portal inflammation [8]. Accurate histological confirmation and the exclusion of biliary and/or arterial problems are needed for diagnosis. Regardless of the relapse pattern, prospective studies have shown that approximately 25–30% of patients develop cirrhosis in the graft after 5 years of follow-up (8–44% at 5–10 years) [4, 6]. The natural history of cirrhosis is also more aggressive than that observed in non-transplanted patients [5]. The first episode of decompensation, normally in the form of ascites, usually occurs after a median of 8 months from diagnosis of cirrhosis in the graft, with a cumulative rate of 42% and 63% in the first and third year since compensated cirrhosis respectively. Factors that predict decompensation include a Child-Pugh > A class, a serum albumin level < 3.4 g/dL and a period from transplantation to diagnosis of compensated cirrhosis of less than 1 year. Survival of decompensated cirrhosis is less than 10% at 3 years compared to 60% in non-transplanted patients [5]. In another study, a MELD score higher than 16 was the main risk factor for decompensation and mortality after the development of post-transplant HCV cirrhosis [9].

As a result of primary disease recurrence on the graft, long-term survival is lower than that observed in recipients uninfected by HCV [10, 11]. Data from the Spanish LT Registry, based on adult recipients of a first elective graft between 1991 and 2009, showed a 10% patient and graft survival difference at 3 years when comparing patients transplanted for HCV-cirrhosis (without hepatocellular carcinoma) with non-HCV patients. Patient and graft survival in HCV (+) was 73% and 66% at 3 years, 67% and 59% at 5 years, and 54% and 45% at 10 years in comparison with 82% and 76% at 3 years, 78% and 71% at 5 years, and 66% and 59% at 10 years in non-HCV recipients [12]. All this has meant that while LT survival, in other indications, has improved over time, survival has diminished or at least has not improved in HCV-recipients in recent years [13, 14].

Indications for liver transplantation in HCV-infected recipients – pretransplant recipient factors

The indications for LT are the same as in cirrhosis or hepatocellular carcinoma due to other causes. However, when assessing this indication, it is important to evaluate in the potential recipient the presence of pretransplant factors associated with poor post-LT prognosis, such as older age [15-17], hepatocellular carcinoma [9, 13, 15, 18-24], diabetes [25] and metabolic syndrome [26]. Higher pretransplant HCV-RNA level, a more impaired liver function at the time of transplantation (Child-Pugh score > 10) or non-white races have also been associated with poorer survival after transplantation [27]. Recent studies suggest that polymorphisms close to the IL28B gene both in the recipient and in the donor can affect not only the response to antiviral therapy but also the course of recurrent HCV hepatitis after LT with a poorer outcome in the CT and TT genotypes (rs12979860 polymorphism) in relation to genotype CC [28, 29]. If these data are confirmed, IL28B genotype could be used when selecting a suitable donor for an HCV-infected recipient.

Recommendations:

  • Given its poor prognosis, we recommend following strict selection criteria (Milan criteria) for LT in patients with hepatocellular carcinoma associated with HCV (Class I, Level B).

Factors associated with higher severity of recurrent hepatitis C and poorer graft and patient survival in HCV-positive recipients

Donor and transplant surgery factors

Several researchers have studied potential donor factors that may negatively impact post-transplantation outcome of HCV-positive patients [30, 31]. Donor age [11, 17, 32-37], steatosis [30, 31, 38, 39] ischaemia time [40-46], HLA-DR donor–recipient matching [31, 39], preservation injury [30, 31], the use of non-heart-beating donors [30, 31], the use of grafts from living donors [30, 31], partial graft split [30, 31] and anti-HCV (+) donors, amongst others, are donor and perioperative factors that can influence the severity and progression of recurrent hepatitis C after transplantation [47, 48].

Donor age

Among all factors, donor age is the most widely studied. There are numerous articles showing that advanced donor age is a negative independent factor of HCV-disease severity as well as graft and patient survival [11, 17, 32-37]. The mechanisms that might explain these associations are not completely understood.

The problem is to determine above which donor age cut-off the expected graft and patient survival will be seriously compromised. Strategies that may be put into place by LT groups include the use of these grafts in other recipients on the waiting list in whom the expected survival is not compromised. In short, finding ways to optimize the scarcity of donors. To determine this donor age limit, the National Transplant Organization was requested to analyse using the Spanish LT Registry (SLTR), the survival of HCV(+) and HCV(−) recipients according to donor age stratified into 5-year periods. The results of the SLTR analysis over the historical series of 25 years (1984–2009), with nearly 10 000 LT recipients (excluding hepatocellular carcinoma) are shown in Tables 2 and 3. The differential impact of increased donor age on survival of HCV (+) and (−) recipients is shown on these Tables. Survival at 5 years in HCV (+) recipients falls below 50% when donor age is over or equal to 65–69 years. Based on data from the literature and the SLTR, with its limitations in performing only a univariate analysis in a series spanning many years, LT teams should properly assess the advantages and disadvantages of implanting the liver from a 65-year-old donor into an HCV-positive host.

Table 2. Survival of first graft according to donor age in HCV-negative adult patients with cirrhosis (excluding hepatocellular carcinoma) in Spain. Elective transplants 1984–2009
Donor age (number)1 month (%)1 year (%)3 years (%)5 years (%)10 years (%)15 years (%)
  1. Source: Registro Español de Trasplante Hepático. http://www.ont.es/infesp/Registros/MEMORIA RETH 2009.pdf

    .
16–19 years (546)92.382.476.072.662.355.0
20–24 years (618)92.482.277.072.462.049.5
25–29 years (485)89.579.072.769.059.852.3
30–34 years (390)90.279.271.766.254.050.2
35–39 years (421)90.579.074.369.257.247.0
40–44 years (481)89.078.471.568.857.946.8
45–49 years (567)90.678.472.067.856.144.0
50–54 years (594)90.679.971.567.757.044.5
55–59 years (581)90.780.874.968.555.540.3
60–64 years (536)91.883.075.669.854.843.9
65–69 years (497)92.582.675.271.857.044.9
70–74 years (437)94.979.271.766.254.050.2
75–79 years (289)95.581.372.265.750.6
≥ 80 years (72)89.083.274.369.569.5
Table 3. Survival of first graft according to donor age in HCV-positive adult patients with cirrhosis (excluding hepatocellular carcinoma) in Spain. Elective transplants 1984–2009
Donor age (number)1 month (%)1 year (%)3 years (%)5 years (%)10 years (%)15 years (%)
  1. Source: Registro Español de Trasplante Hepático. http://www.ont.es/infesp/Registros/MEMORIA RETH 2009.pdf

    .
16–19 years (286)92.883.778.670.360.148.0
20–24 years (283)87.975.469.065.256.043.5
25–29 years (201)90.079.073.165.456.045.8
30–34 years (231)93.982.577.270.158.452.1
35–39 years (235)91.583.273.169.257.343.2
40–44 years (236)92.376.563.258.844.029.9
45–49 years (336)90.177.665.753.738.134.2
50–54 years (307)93.176.765.058.241.227.3
55–59 years (315)93.375.362.557.043.533.8
60–64 years (319)90.675.261.750.527.4
65–69 years (261)90.471.555.045.925.1
70–74 years (206)87.370.757.343.733.4
75–79 years (126)90.569.348.042.829.3
≥ 80 years (40)75.058.734.334.325.7

Recommendations:

  • The preferential allocation of young donors to HCV-infected recipients may be detrimental to other HCV (−) patients, and particularly, taking into account the advanced age of a large proportion of the donor population, this strategy could lead to an increase in mortality in the waiting list of HCV (+) patients.
  • Taking into account these factors, we recommend using livers of donors aged less than 65 years for HCV-recipients. Each transplant group should consider the impact of donor age on HCV+ and HCV− recipients’ survival (Level B).

Ischaemia time

Ischaemia time is another factor, although less studied, which impacts negatively on the severity of HCV recurrence and graft and patient survival [40-43]. The same as with age, it is difficult to mark a limit from which the negative impact will be significant. In published studies, cold ischaemia time exceeding 12 h has a significant negative impact on survival, although the best results are obtained with ischaemic times shorter than 8 h [42, 44]. Registration studies such as the one based on the United Network for Organ Sharing database showed that a warm ischaemia time exceeding 90 min is associated with decreased graft survival in HCV patients [43].

Recommendations:

  • We recommend to avoid cold ischaemia time over 8 h and/or warm ischaemia time exceeding 90 min (Level B).

Anti-HCV (+) donors

Although there are few studies in the literature, in none there is evidence that the use of HCV donors impacts negatively on the severity of recurrence or on survival [30, 31, 47-51]. There is no consensus, however, regarding the need to perform a biopsy in the donor. Indeed, the applicability of the biopsy is sometimes difficult. Its assessment in freeze-fixation is limited and the possibility of another type of fixation may prolong ischaemia time. In addition, as genotype 1 recipients respond less to antiviral therapy than non-1 genotypes, and superinfection with the donor genotype has been shown to occur, anti-HCV (+) donors should be used only in HCV genotype 1 recipients.

In one study, recipients of HCV+ graft from older donors (age > 50 years) were shown to have higher rates of death and graft failure, and develop more extensive fibrosis than recipients of HCV− grafts of the same age [49]. On the basis of these preliminary data and taking into account that the probability of capsular fibrosis is low under 50 years, we believe that while HCV+ liver donors do not subject the HCV+ recipient to an increased risk of death over the HCV− donor, careful donor selection is critical for the proper use of extended criteria donors

Recommendations:

  • HCV (+) donors can be used in HCV (+) recipients under the following conditions: donor age not exceeding 50 years, normal liver biochemistry, normal ultrasound and visual inspection of the liver and genotype 1 recipient (Level C).
  • Ischaemic time should be minimized.
  • Although the practice of a liver biopsy is recommended, in no case this practice should translate into ischaemia times over 8 h.

Viral factors

Some, but not all, studies have suggested that infection with HCV genotype 1b [15, 19, 35, 49, 52] or 4 [53] is associated with poorer outcomes. High viral titres at 7 days [54], 4 months [55, 56] and 12 months [57, 58] post-LT have also been associated with lower patient and graft survival. In this regard, a recent study has shown a clear relationship between viral load peak in the first 12 months and the patient's median survival: > 108 IU/mL (12 months), 107–108 (71 months) and < 107 (89 months) [58]. The association of higher pretransplant viraemia with a poorer outcome after transplantation is less clear [55, 59]. The lesser amount of HCV quasispecies is associated with FCH [59].

Cytomegalovirus (CMV) infection has been associated in most studies with a higher severity of HCV disease [15, 48, 60-62], greater progression to cirrhosis (50% vs. 11%) [60] and a higher rate of graft failure (45% vs. 16%) [17] in comparison with those without CMV infection, although this association has not been observed in other studies [62-65]. Recommendations regarding prevention and treatment of CMV infection in solid organ transplant recipients have been recently published as a Consensus Guidelines of the Group of Study of Infections in Transplantation (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology [66]. Screening of pp65 antigenemia or viral load is suggested, but there is no enough evidence to recommend a test or a frequency of testing.

Recommendations:

  • CMV infection should be monitored closely for early detection and treatment (Class IIa, Level B).

Recipient factors: metabolic syndrome/diabetes/insulin resistance (post-transplant)

Metabolic syndrome occurs in 50% of HCV-infected recipients within the first 12 months after transplantation and is associated with a greater progression of fibrosis [56]. In one study, post-transplant diabetes in HCV-infected recipients multiplied the risk of developing bridging fibrosis/cirrhosis at 6 years by 3.3 times, with an additive effect if it was associated with a donor > 55 years (risk multiplied by 8.4) [25]. The presence of diabetes was associated with higher mortality (56% vs. 14%) in HCV-infected individuals [67], although no differences in survival were observed in another study [68]. In one study, increased insulin resistance (HOMA > 2.5) measured at 4 months after transplantation was associated with a greater progression of fibrosis, with a rate of development of advanced fibrosis/cirrhosis at 5 years of 43% in comparison to 21% in those without increased insulin resistance [69].

Recommendations:

  • Effective treatment of diabetes and other metabolic syndrome components should be carried out in an attempt to improve the outcome of recurrent hepatitis C after transplantation (Class I, Level B).

Biochemical and histological recurrence pattern and early histological findings (first 12 months after transplantation)

The AST serum peak [61] and bilirubin levels [61, 70], as well as the presence of biochemical cholestasis [61] at the time of recurrence of hepatitis, are associated with a higher rate of progression to graft cirrhosis. In one study, having levels of bilirubin in serum > 3.5 mg/dL was the only independent predictor of cirrhosis development [70]. The ALT serum level 1 year after transplantation was also associated with the risk of progression to cirrhosis at 5 years: ALT > 100 IU/L, 35% (vs. 6%) and ALT > 70 IU/L, 29% (vs. 3%) [4].

The presence of histological recurrence [24], especially with histological cholestasis or the presence of hepatocellular ballooning [70], is associated with higher rates of progression to cirrhosis. The severity of progression is greater when the time of recurrence is shorter, resulting in a lower patient and graft survival when this occurs in the first 12 months after transplantation [71].

Histological findings in liver biopsies performed within the first 12 months after transplantation are also predictive of progression to cirrhosis. For instance, 28–36% of those with moderate-to-severe inflammation in the first year biopsy progressed to cirrhosis within 5 years in two studies compared to 0.10% in patients with no/mild inflammation [4, 16]. In another study, the finding of confluent necrosis in early biopsies (6–12 months) multiplied the risk of developing cirrhosis by 123, while the presence of moderate/severe portal inflammation multiplied it by 39 [72]. Similarly, the finding of fibrosis and its severity in the first year biopsy was associated with the development of cirrhosis (in the absence of fibrosis: 9–11% versus fibrosis ≥ 1: 21–27%) [4, 14], patient mortality (risk multiplied by 10 in the case of fibrosis ≥ 2) [19] and graft loss [53].

Conclusions:

  • The greatest risk of progression to cirrhosis can be predicted by the biochemical and histological recurrence pattern (Class I, Level B).
  • Jaundice and/or biochemical cholestasis at the time of recurrence is associated with increased risk of developing cirrhosis (Class I, Level B).
  • Histological findings in the biopsies performed in the first 12 months after transplantation are useful for predicting the risk of developing cirrhosis (Class I, Level B).
  • The presence of moderate/severe inflammation and/or fibrosis involves high risk of progression to cirrhosis and the need to introduce antiviral therapy (Class I, Level B).

Biliary complications

Recently, a higher proportion of biliary stenosis has been observed in some studies in HCV-infected recipients, both late (> 1 month after transplantation) [73], and diffuse non-anastomotic stenosis [74]. Likewise, a higher rate of severe fibrosis associated with the presence of biliary complications [23, 74] has been found, with a rate of severe fibrosis (fibrosis 3–4) in 75% of those who developed biliary complications compared with 26% in those who did not [74]. In another study, however, there was no association between the presence of biliary complications and HCV-related disease severity [23].

Recommendations:

  • Although controversy exists about the possible influence of biliary complications in the progression of recurrent hepatitis C, we recommend an active approach to detect and treat biliary stenosis as early as possible to minimize the possible detrimental effect (Class IIb, Level B).

Role of immunosuppression in the evolution of recurrent HCV hepatitis after liver transplantation and its response to antiviral therapy

Role of immunosuppression in the natural history of recurrent hepatitis C

There is consensus that immunosuppression plays a relevant role in the natural history of recurrent hepatitis C [31, 33, 48, 75-77]. The role of each immunosuppressive agent on HCV replication and course of hepatitis C graft is more controversial.

Calcineurin inhibitors

In vitro modelling studies (replicon and cultured hepatocytes) have shown that cyclosporine (CYA) inhibits HCV replication, while this effect is not produced with tacrolimus (TAC). There are few prospective studies that have examined this effect in vivo. A study by Martin et al. [78] evaluated the effect of CYA and TAC on viral replication. They randomly distributed CYA or TAC to 79 patients. An increase in viral load was observed, which was significantly higher in patients receiving CYA when compared with those receiving TAC, but it was not clear whether this effect was due to the former patients receiving higher steroid cumulative doses.

In a systematic review [79], the effect of calcineurin inhibitors on the prognosis of patients transplanted for HCV cirrhosis was studied. Only five studies fulfilled the criteria for inclusion in the analysis. A total of 366 patients were included and divided into two treatment arms, one based on CYA and another on TAC, without any significant differences in patient mortality and graft loss; in two of the five studies, no differences were found in the rate of FCH.

A study by Levy et al. [80] followed 495 patients for 12 months, of whom 173 were HCV (+), divided into two treatment groups: CYA (n = 88) and TAC (n = 85) + steroids + azathioprine. Mortality and graft loss were lower in the group receiving CYA. When evaluating only HCV (+) patients, mortality due to HCV, percentage of patients with mild fibrosis and viraemia were found to be similar in both groups; the only difference between the groups was the time to recurrence of hepatitis, which was shorter in the TAC group.

In another study with similar design [81], patients were randomized into two treatment groups: 250 TAC (46 HCV+) vs. 233 CYA (58 HCV+) with concomitant immunosuppression (azathioprine and prednisone which was discontinued after 3 months). The primary aim was patient death ± retransplantation ± immunological failure (need for change in immunosuppression due to rejection). The overall results of patients were favourable to the TAC group. However, detailed analysis of the HCV+ subgroup of patients found no differences between HCV (+) patients treated with CYA when compared with those treated with TAC.

In terms of disease progression, Berenguer et al. [82] studied the relationship between the calcineurin inhibitors and the development of acute hepatitis, FCH and severe recurrence by means of protocol biopsies. Ninety patients were randomly allocated (44 CYA and 46 TAC) and were followed-up prospectively for 2 years by protocol biopsies with no significant differences in the three parameters evaluated. The time to recurrence was shorter in the TAC group when compared with the CYA group (59 days vs. 92 days). This study has been enlarged to include 136 CYA and 117 TAC patients and no differences were observed regarding all evaluated variables nor in survival [83].

Recommendations:

  • To date, the use a specific calcineurin inhibitors cannot be recommended with the existing data, as no differences in graft or patient survival nor progression of recurrent hepatitis C (Class I, Level A) have been found.

Steroid boluses

Numerous studies have clearly demonstrated that steroids administered for graft rejection in HCV-positive patients worsen the prognosis of recurrent hepatitis C. Rejection treatment with steroid boluses leads to increased viral replication, more aggressive recurrence (increased incidence of acute hepatitis, less time to recurrence, greater risk of progression to cirrhosis or developing cholestatic hepatitis) and increased early post-transplant mortality [4, 24, 31, 33, 48, 75-77, 83-86].

Steroid maintenance

To avoid the negative effects of steroids, two different strategies have been adopted: (i) use of steroid-free immunosuppressive regimens, and (ii) use of steroid regimes that are rapidly withdrawn. The benefit of these two regimens on the curse of hepatitis C remains unclear.

Regarding early withdrawal, the first retrospective studies [24, 35, 87], many of which had protocol biopsies, did not show any benefit and even hinted that disease progression (fibrosis 3 or 4) was higher in patients in whom steroids had been withdrawn at earlier time points post-transplantation. A single prospective study [88] seems to confirm the results of retrospective studies. In this study, with a very small number of patients, the group of patients in which steroids were withdrawn early (n = 21) had a significantly lower fibrosis-free survival than that of those who continued with steroids (n = 16). The maintenance duration is a term that, however, has not been clearly defined. A short model would be at least 3–6 months, while a longer one generally refers to continuing with steroids until a year after transplantation.

Regarding steroid-free protocols, several studies with biopsies and using different IS protocols, some with steroids and others without, generally show no differences in viraemia, survival or fibrosis progression [89-95]. The meta-analysis of Segev et al. showed that steroid-free patients are accompanied by less relapses, although the definition of this varies according to surveys, which hampers the interpretation of the data [95]. In another meta-analysis of Sgourakis, the authors also show fewer relapses, lower acute graft hepatitis and fewer treatment failures in patients immunosuppressed with steroid-free regimens [94].

Recommendations:

  • To avoid the use of steroid boluses in mild rejection (Class IIa, Level B).
  • Steroid-free regimens are safe in HCV- infected patients (Class IIa, Level B).
  • If steroids are used, we recommend a progressive withdrawal with complete discontinuation not before the sixth month (Class IIa, Level B).

Role of other immunosuppressive agents: mycophenolate, azathioprine, mammalian target of rapamycin (mTOR) inhibitors, IL-2 receptor antibodies

There are very few published studies on the specific role of these drugs in the natural history of recurrent hepatitis C.

In a study in which the role of mycophenolate (MMF) was evaluated [96], an increase in viral load in patients who changed azathioprine for MMF was observed, although whether this increase was associated with any histological change was not analysed. In one trial comparing MMF with azathioprine, no differences were observed regarding the rate of recurrent hepatitis C or survival [97]. In the study with the highest number of patients to date, with randomization of patients into three treatment arms, two with and one without MMF [TAC, steroids (n = 80), TAC, MMF, steroids (n = 79); daclizumab, TAC, MMF (n = 153)], no differences in time to progression to advanced fibrosis or survival free of HCV recurrence [98] were found.

Regarding azathioprine, in a randomized prospective study [99] with two treatment groups, TAC monotherapy (n = 54) versus triple therapy based on TAC + azathioprine + prednisone (n = 49), the probability of reaching fibrosis or portal hypertension was lower in the group assigned to triple therapy, in which azathioprine was continued for over a year and steroids for 3–6 months. In this study, the authors were unable to establish if the benefit was due to the slow withdrawal of steroids or the potential protective role of azathioprine. In this regard, when reviewing the studies published to date, there is none that shows poorer results in patients receiving azathioprine; on the contrary, a recent review points out that almost all studies show that the azathioprine groups obtain better results [100]. Azathioprine is also a drug with potential antiviral effect [101].

With regard to antibodies against the receptor of IL-2, there are very few prospective studies assessing the effect of these immunosuppressive agents on the progression of hepatitis C. In three randomized controlled studies, the use of these immunosuppressive agents was not associated with lower survival [102-104]. On the other hand, in an uncontrolled study in which the results of transplantation in a cohort of patients treated with antibodies against the receptor of IL-2 together with MMF were compared with a historical cohort of patients treated with standard therapy based on TAC and steroids, the authors found poorer results in those in which induction immunosuppression had been used [105]. In the comparative study of the aforementioned three arms, one arm included induction with antibodies against the receptor of IL-2 without finding differences in comparison with the other two groups [98].

Regarding mTOR inhibitors, currently, there are few studies that have evaluated the effect of these drugs on the course of recurrent hepatitis C. While overall, the findings from retrospective studies suggest a beneficial effect [106, 107], there are to date no prospective studies.

Overall, there are no clear guidelines regarding each immunosuppressive agent and hepatitis C recurrence. Avoiding overimmunosuppression is probably the only way to improve outcome as it was shown in a retrospective study [108]; in addition, complete withdrawal of immunosuppression in immune tolerant patients may be beneficial for disease progression, but more data are needed [109].

Conclusions:

  • The use of protocols that include MMF, steroid-free regimens or antibodies against the receptor of IL-2 does not influence the severity of recurrent hepatitis C in the medium-term (Class IIa, Level B).
  • There is no ideal immunosuppression protocol for HCV-infected patients. The only strong recommendation is to avoid a state of over-immunosuppression. To this end, we recommend avoiding steroid boluses, and triple or quadruple regimens at full doses. (Class I, Level B).

Role of immunosuppression in the response to antiviral treatment

Overall, sustained virological response (SVR) in transplant patients is around 30%. There are diverse variables associated with SVR, such as a low fibrosis on baseline biopsy, infection due to genotypes other than 1, a young age of both donor and patient, and good therapeutic adherence. Furthermore, the viral response kinetics significantly predict SVR (see post-transplant antiviral treatment section). Regarding the influence of calcineurin inhibitors on antiviral treatment response, the data are controversial. Although there are many retrospective studies which have included calcineurin inhibitors in the analysis of potential factors associated with SVR, only one was a well-designed prospective randomized study [110]. Overall, it appears that SVR is higher when baseline immunosuppression is CYA. However, there is great variability between studies with a wide range of results, suggesting that apart from differences in study design and study population, there are other factors, not only the calcineurin inhibitors, which affect antiviral response. In the only prospective study whose preliminary results have been published to date, there were no differences in SVR rates according to the calcineurin inhibitors used.

Recommendations:

  • Changing the IS treatment has shown no impact on SVR, and should be modified according to the toxicity profile of each IS (Class IIa, Level B).

Pretransplant antiviral treatment

The aim of antiviral therapy before transplantation is to obtain the negativity of viraemia at the time of transplantation and to prevent HCV re-infection after transplantation. It remains unclear whether reduction in viral load before transplantation without becoming negative can be beneficial in terms of disease progression after transplantation [27].

Antiviral treatment in the pretransplant period has substantial limitations resulting from poor liver function as well as hypersplenism and cytopenias that the patient can present; in addition, a high proportion of patients are non-responders to previous treatments reducing the applicability to less than 50% [111, 112]. Two antiviral treatment strategies have been used: a long-term approach to achieve SVR before transplantation [111] and a short-term approach beginning 3–4 months before the possible estimated date of transplantation, with the aim of achieving HCV-RNA negativity before transplantation and to prevent graft re-infection [113, 114]. Regardless of the approach used, the results are similar, resulting in prevention of HCV re-infection in about 20% of treated patients [113, 114].

To date, five antiviral treatment studies have been published in this phase. In the first study [112], different treatments were used with standard interferon (IFN) in monotherapy or combined with Ribavirin (RBV), with a mean treatment duration of 8 weeks, including patients with poor performance status (average score Child-Pugh = 12); the results were very disappointing: 5/15 (33%) had virological response (VR) and HCV infection recurred in two patients who were transplanted. Side effects were frequent (87%) and generally severe, and the study had to be interrupted before completion. On the other hand, Everson et al. [111] included 124 patients with better functional status (mean score Child-Pugh score of 7.4, class A, 45% B, 36%, C, 18%; MELD mean = 11) in a combination therapy with IFN-alpha 2b and RBV starting at low doses with gradual increases as tolerated, maintaining the treatment for the standard duration (24 weeks for genotypes 2–3 and 48 weeks for genotypes 1–4). The results in this trial were better, achieving a 24% of SVR (13% in genotype 1, 50% in genotypes 2-3) and prevention of HCV reinfection after transplantation in patients who achieved SVR. Thomas et al. [115] used IFN-alfa 2b (5 MU/d) in 20 patients on the transplant list (mean score Child-Pugh = 10) until transplantation (mean treatment duration of 14 months): 12 (60%) had on-treatment VR and 4 (20%) did not have re-infection after transplantation. In Spain, two studies have been performed on patients on the transplant waiting list, using the short-term approach, one with standard IFN [113] and another with pegylated IFN (PEG-IFN) [114]. In the first study, 30 patients (83% genotype 1, Child-Pugh A, 50&, B, 43%, C, 7%) were included. They received IFN-alfa 2b (3 MU/d) and RBV (800 mg/d) with a median treatment of 12 weeks. Nine (33%) achieved an on-treatment VR (genotype 1, 24%; genotypes 2–3, 60%). Of these, 6 (20%) remained HCV RNA negative after transplantation [113]. In the second study, 51 patients (80% genotype 1, 12 MELD, Child Pugh A, 45%; B, 43%; C, 6%) were treated with PEG IFN alfa-2a (180 mcg/wk) and RBV (800–1000 mg/d) with an average treatment duration of 15 weeks. A group of 51 patients on the transplant waiting list with similar baseline characteristics but without treatment was used as a control group. Efficacy was similar to that obtained with daily administration of standard IFN: 15 patients (29%) reached transplantation with a negative viral load and 10 (20%) remained negative after the procedure. Predictive factors associated with VR were non-1 genotype (VR 67% versus 21% in genotype 1) and rapid decline in viral load (≥ 2 log10 at week 4) (93% vs. 28 VR%). In addition, no patient with poor liver function (Child Pugh C or MELD > 18) had a VR [114].

The most common side effects of antiviral therapy are asthenia/fatigue and haematological effects that prompted the premature discontinuation in 13–43% [111-115], reduction in the dose in 0–60% [111-115] in spite of the use of erythropoietin (EPO) in 5–67% [105, 107, 108] and granulocyte colony-stimulating factor (G-CSF) in 33–45% [111-115]. Another possible complication, potentially severe, to take into account with antiviral treatment are bacterial infections. In the study by Carrion [114] the likelihood of bacterial infections was higher in the treated group than in the control group; almost all episodes occurred in Child-Pugh B-C class patients. Poor liver function (Child-Pugh ≥ 7 or MELD ≥ 14) and antiviral treatment were independent variables associated with the risk of infection. Prophylaxis with norfloxacin prevented this complication in the antiviral treatment group [114].

New antiviral agents such as the protease inhibitors, telaprevir and boceprevir, recently approved in USA and Europe, might be useful in compensated cirrhotic patients infected by HCV genotype 1 awaiting liver transplantation, but the indication needs to be tested in this population. In addition, in the studies published to date, the SVR obtained by cirrhotic patients was lower than in non-cirrhotics, and this was particularly true for prior non-responders with advanced fibrosis, where SVR rates were about 10–15% [116-121].

Recommendations:

  • Antiviral therapy is recommended in all patients on the transplant list, who are in a compensated situation and Child-Pugh A class, regardless of genotype and viral load, provided that they do not present contraindications and have not been non-responders to a previous combined antiviral therapy (Class I, Level B).
  • The treatment is also recommended for patients in functional status class B Child-Pugh and MELD < 18 who have a good virological response profile (naïve, genotype 2–3 or genotypes 1–4 and low viral load) (Class I- Level B).
  • The treatment should be contraindicated in all patients in functional status Child-Pugh C class or MELD ≥ 18 (Class I, Level B).
  • The treatment of choice is the combination of Peg-IFN and RBV at standard doses (Class I, Level C).
  • The use of growth factors (erythropoietin and colony-stimulating factor granulocyte) is recommended if needed (Class IIa, Level C).

Post-transplant antiviral treatment

The reasons that justify the use of antiviral treatment in transplant patients are: (i) the decrease in survival as a consequence of hepatitis C recurrence in the graft [33, 48, 122, 123], (ii) improved prognosis (histological and clinical with decrease in portal pressure, fibrosis progression, hepatic decompensation rate, graft loss and increased survival) when an SVR is achieved [124-129].

The main goal of subjecting these patients to antiviral treatment is therefore the permanent eradication of HCV. Secondary objectives include stabilizing disease progression and avoiding graft loss due to the recurrence of hepatitis C even in the absence of a VR.

Therapeutic strategies to achieve these goals depend on the time of intervention:

  • Preventive treatment (preemptive): To begin antiviral therapy during the first weeks after transplantation, when there is a recurrence of the infection, but there are no changes compatible with graft injury secondary to HCV infection (normal transaminases and histology in case of a biopsy).
  • Established hepatitis C treatment: Start antiviral treatment when there is evidence of lesion in the graft histology; treatment may be started in the early stage (acute hepatitis), or during the chronic phase.

Preemptive treatment

It is a ‘prophylactic’ treatment that is usually started during the first 2–8 weeks after transplantation [33, 48, 122, 123, 130-138]. Viral kinetic studies have shown that viraemia is minimal in the anhepatic phase and immediately after surgery, but as early as the second post-transplant week, the viral load increases, reaching its maximum level between the 1st and 3rd post-transplant months, with even higher levels than those observed before transplantation. Acute graft hepatitis usually becomes apparent between the 1st and 6th post-transplant months. Therefore, many authors believe that the time window to start a strictly ‘prophylactic’ treatment is practically inexistent.

With the combination of PEG IFN and RBV, SVR rates range between 18% and 39% (5–33% in G1 and 14–100% in G2/3). One of the main problems of this strategy is the poor tolerability. In published studies, antiviral treatment was withdrawn prematurely because of adverse events in 33–40% of patients and dose reduction was required in up to 80% of cases. Most likely, the low efficacy obtained with this strategy is due to the difficulty of maintaining full doses of antivirals. Furthermore, although the incidence of rejection in treated groups does not appear to be higher than in control groups, the severity of the episodes appears to be higher in the groups receiving treatment. Another limitation is the low applicability as antiviral treatment cannot be started in a high percentage of transplants (up to 58% of patients newly transplanted in one series) at such an early stage because of the existence of cytopenias, clinical instability, rejection or extrahepatic complications [136]. Patients who are transplanted in better conditions (MELD and Child-Pugh score low) are more likely to tolerate the treatment. With the introduction of the MELD system, it is more difficult to have patients in adequate conditions to initiate antiviral therapy in the first weeks after transplantation. Furthermore, this treatment strategy is not targeted to patients who really need it, but rather to those who tolerate it. This therapeutic alternative would be a good strategy for patients in whom we predict an aggressive recurrence, such as (i) patients undergoing liver retransplantation for recurrent aggressive hepatitis C in the first graft; (ii) suboptimal donors (especially elderly donors); (iii) or patients co-infected with human immunodeficiency virus (HIV). In all these subgroups, the applicability is unfortunately extremely low.

Neither the dose nor the optimal duration has been established. Whether growth factors (EPO and G-CSF) improve the results remains unknown.

Treatment of established recurrent hepatitis C

The questions are: (i) type of treatment, (ii) need to treat all patients and (iii) the ideal moment to start treatment, which may be in the acute or chronic phase of hepatitis.

Efficacy depending on the type of treatment

The treatment consists of PEG-IFN and RBV for 48–52 weeks. Most available data come from uncontrolled studies with different designs regarding time to start treatment, regime used and follow-up. Therefore, the results are also very different, with SVR rates ranging between 20% and 50% with an average around 30% [124-129, 139-172]. These results are lower than those obtained in non-transplanted patients, possibly because of the immunosuppressive status, the high prevalence of HCV genotype 1-infected patients, the typical high viral load and the difficulty in maintaining adequate antiviral doses, especially RBV, and maintaining therapy for the ideal duration.

An SVR can be obtained by re-treated patients after an initial treatment failure, especially if pre-existing non-response factors present in the first attempt are modified.

Protease inhibitors (telaprevir and boceprevir) are potent inhibitors of cytochrome P450 3A4, the enzyme responsible for the metabolism of CYA and TAC [173, 174]. They have not been tested and should not be used in liver transplant recipients, with the possible exception of clinical trials.

Therapeutic regimen

There are no controlled studies comparing different treatment regimens, so it is not possible to define whether it is preferable to begin treatment with full or reduced doses and increase as tolerated, or whether individualized treatment is beneficial according to viral response kinetics. It is therefore recommended to follow the rules set out in the non-transplanted population. RBV dose should be adjusted to renal function [175-177].

Adverse effects

They represent the main cause of dose reduction (50%), mostly RBV and premature discontinuation of treatment (25%). The most common adverse effects include blood disorders, especially anaemia (60–80%), neuropsychiatric disorders (about 10–15%), thyroid abnormalities, poor clinical tolerance and infections (15–25%).

To avoid dose reduction, and thus the possibility of obtaining an SVR, many groups use adjunctive therapy with EPO and G-CSF. While these drugs improve tolerability to antiviral treatment, there are no data to confirm that they result in higher efficacy.

One possible complication is the development of cellular rejection, with an incidence of around 6% (0–35%) [177-180].The risk of rejection depends on the intensity of immunosuppression, the time since transplantation, the concomitant use of RBV and the use of PEG-IFN (as opposed to conventional IFN). Recommendations are not to reduce immunosuppression excessively during and after treatment, and to perform a liver biopsy whenever there is a biochemical alteration that is not attributable to other causes.

Reports of chronic rejection (< 1%) have been described, especially in patients who obtain a virological and biochemical response. A change in the metabolism of immunosuppressive drugs with the improvement in liver function and subsequent reduction in immunosuppression levels in blood might be the cause [177-180]. Close monitoring of immunosuppressive therapy during treatment (at least monthly) and after antiviral treatment is warranted. A liver biopsy is recommended in patients with SVR without biochemical response; the differential diagnosis should include late rejection induced by the treatment, toxic hepatitis, de novo autoimmunity [181-184] and biliary problems.

Time to start antiviral therapy

Treatment in the acute phase of recurrent hepatitis C is a poorly studied strategy. In a study by Castells et al., PEG-IFN and RBV was evaluated in 24 patients with biochemical and histological evidence of acute hepatitis and the outcome was compared with that of 24 untreated control patients. An SVR rate of 35% was obtained with adverse events no higher than expected with this therapy [158]. These results have not been confirmed in other series. In the series of Zimmerman et al., 26 consecutive LT recipients with acute hepatitis C were treated with peg-IFN alfa 2a and RBV with increased doses as tolerated, and results were compared with those from a historical series of untreated patients in the acute phase. The SVR was 19% as opposed to 0% in the historical series [160]. Side effects were equally common and in three cases resulted in discontinuation of therapy. It is therefore a strategy to consider, especially in patients with a generally acceptable state who can tolerate the treatment, but further studies are needed to be able to generally recommend it.

In daily practice, treatment is generally started in the chronic phase, especially when progression of fibrosis is observed. This strategy is the most frequent because the patient is usually in a more stable clinical situation, with less need of immunosuppression, lower risk of acute rejection and better tolerability. Long-term close monitoring is required (see monitoring of hepatitis C in liver graft).

Predictive factors of treatment response

Taking into account the high frequency of side effects and early discontinuation of treatment, it is important to find predictors of response to continue the treatment at the expense of poor tolerability in those with high chances of response or, on the contrary, to stop therapy at an early time point if the likelihood of response is practically nil. Baseline predictors of response are similar to those described in the immunocompetent population, including infection with genotype non-1, low initial viral load, absence of metabolic syndrome and presence of low fibrosis. Several series have reported very poor results, in terms of both efficacy and tolerability in patients treated at the stage of cirrhosis. The role of immunosuppression is described in the section on immunosuppression and HCV. Donor age has been associated with treatment outcome in several series, with older donor age predicting poorer results. Polymorphisms in the IL28B gene are also involved in the SVR, with similar results to those described in immunocompetent patients [28, 185-187]. Notably, in transplantation, the genetic profile of both the recipient and the donor plays a role. Thus, cases have been described in which patients who had not responded before LT, achieved an SVR after transplantation using livers from patients with favourable genetic profiles.

On-treatment variables predicting treatment response are also similar to those described in the non-transplanted population. Rapid viral response (RVR) evaluated 1 month after starting treatment and early virological response (EVR) assessed after 3 months, are the best SVR predictors. Thus, patients who achieve an RVR have high chances of obtaining an SVR (positive predictive value 88–100%). On the contrary, not obtaining EVR, i.e. a decrease of at least 2 log at 12 weeks, has a negative predictive value of 100% and a positive predicitive value ranging between 52% and 64%.

Other factors associated with SVR include the absence of previous treatment and treatment adherence.

Re-treatment or maintenance therapy

In the LT field, data are very scarce [33, 48, 122-124, 127-131, 164, 188] and therefore recommendations rely on published studies based on immunocompetent patients. A first concept is that the response profile to antiviral therapy may change after transplantation in the new immunological environment. It has been demonstrated that unresponsive patients may become, at least partially, responsive to IFN after transplant [189].

On the other hand, there are also data that suggest a beneficial effect even in the absence of SVR. In some cases of lack of VR but normalization of liver biochemistry, histology appears to remain stable [124-129, 139-143, 190, 191] and even portal pressure is reduced. Therefore, maintenance therapy can only be recommended to (i) patients included in controlled studies, (ii) patients with significant baseline fibrosis (F3–F4), (iii) patients in whom clinical or histological benefit by means of a haemodynamic study, liver biopsy or elastrography has been demonstrated (iv) patients whose transaminases are normalized. As for the type of maintenance therapy, there are insufficient data on whether it should be carried out with low-dose IFN alone or in combination with low doses of RBV.

Fibrosing cholestatic hepatitis due to its aggressiveness and poor prognosis may benefit from maintenance antiviral therapy [189].

Recommendations:

  • Antiviral treatment in liver transplantation should be carried out by dedicated transplant physicians, or physicians in close contact with the transplant centre (Class I, Level C).
  • The post-LT antiviral treatment is performed with the same drugs as those used in immunocompetent individuals. However, to optimize results, the treatment may not be the same in duration, doses, early stopping rules and/or use of growth factors. (Class I, Level A).
  • In Genotypes 2–3, there are no data indicating that treatment duration should be reduced (Class I, Level C).
  • The lack of early virological response predicts no response to 12-month therapies (Class I, Level B).
  • The prolongation of treatment may be beneficial in some situations. Therefore:
  • In patients with low stages of fibrosis and absence of EVR, it is recommended that antiviral treatment is stopped. (Class I, Level C).
  • In patients with advanced histological lesions and/or predictors of poor prognosis, with clinical and/or biochemical response and who tolerate treatment, the continuation/maintenance treatment may be justified (Class II, Level C).
  • The modification of immunosuppressive therapy has shown no impact on SVR, and it should be modified according to the toxicity profile of each immunosuppressive agent (Class II, level A).
  • Close monitoring of immunosuppression levels is recommended (Class I, level C).
  • Antiviral treatment does not imply a modification of the immunosuppressive therapeutic range (Class I, level C).
  • A liver biopsy before starting antiviral treatment should be performed (Class I, level B).
  • Treatment is recommended in severe acute hepatitis and cholestatic forms (Class I, level B).

Post-transplant follow-up and monitoring of HCV hepatitis

Two types of diagnostic methods are used in the follow-up of recurrent hepatitis C after transplantation: invasive (liver biopsy and measurement of portal pressure gradient) and non-invasive (elastography, biochemical serum and fibrogenesis markers and predictive mathematical models of fibrosis).

Invasive methods

Liver biopsy

We have already discussed the prognostic value of histological findings at the time of recurrence and the biopsy performed within the first 12 months. In addition, the performance of sequential follow-up protocol liver biopsies has been widely accepted and recommended by different transplant teams [48, 53, 192-194]. Its justification is based, on one hand, on the poor correlation between the analysis and histology. On the other hand, the development of fibrosis throughout time is not linear and can have a late start [53, 192-194]. Besides, several lesions can coexist [192]. Finally, when antiviral therapy is planned, a biopsy is essential not only to assess the severity of hepatitis but also to rule out rejection. Liver biopsy remains the gold standard and the technique against which the different tests are compared to assess fibrosis.

Measurement of hepatic venous pressure gradient

The measurement of hepatic venous pressure gradient (HVPG) at 12 months shows a very good correlation with the fibrosis stage, appraised by percutaneous [195] as well as transyugular biopsies [196]. An HVPG ≥ 6 mmHg at 12 months is an excellent predictor of future development of hepatic decompensation (sensitivity, 92%, specificity 88%), even better than the discovery of significant fibrosis (F ≥ 2) in the biopsy (sensitivity, 69% specificity, 88%) [195].

Non-invasive methods

Transient elastography

The estimation of liver tissue stiffness (measured in kilopascals, kPa) correlates well with the fibrosis stage and HVPG [197]. Its value in estimating the fibrosis stage has been confirmed in studies of transplants from both cadavers [198, 199] and living donors. The best cut-off values for detection of patients with fibrosis ≥ 2 have varied in different studies between 7.9 and 10.1 kPa, all of them with high positive predictive values (65–86%) and negative predictive values (88–94%) [197-200]. For cirrhosis diagnosis, the cut-off values used in cadaver donor transplants have ranged from 12 to 12.5 kPa with 50–74% positive predictive values and 99–100% negative predictive [197, 198] while in living donors, these values have been 26.5 kPa with 83% PPV and 100% negative predictive [200]. The cut-off value to estimate the existence of portal hypertension (HVPG > 6 mmHg) was 8.7 kPa with a PPV of 81% and NPV of 90% [197].

Performing repeated elastographies has shown its ability to identify patients with significant fibrosis (F ≥ 2) or patients with HVPG > 6 mmHg as soon as 6 months after transplantation, reaching an excellent diagnostic ability at 12 months. A mathematical model, adding the serum bilirubin level and donor age to the value of liver elastography, significantly improved the diagnostic capability of elastography alone at 6 months to identify the aforementioned patients [201].

Other non-invasive tools

Other non-invasive methods have been investigated to identify patients with significant fibrosis, such as the ALT/AST ratio index, AST/platelets (APRI), Forns index, Fibrotest [199], or serum markers of fibrogenesis (hyaluronic acid, procollagen type 4, YKL-40) [200, 201]. Prospective studies have shown the superiority of transient elastography over these methods to detect significant fibrosis [199, 200].

Mathematical predictive models of fibrosis have also been investigated [202-206], such as the Hospital Universitario La Fe or Benlloch index, developed in the retrospective model [203] with parameters such as AST, prothrombin time, total albumin/protein and time from transplant and simplified in the prospective model [204] with only the AST and prothrombin time, the London Transplant Centers index, based on AST, INR, platelet count and time since transplant [205]. An algorithm with the combination of three serum biomarkers of fibrosis (hyaluronic acid, aminoterminal pro-peptide of procollagen type III and tissue inhibitor of metalloproteinase type 1) was recently published with good predictive capability at 6 months post-transplant (better at 12 months) to identify fibrosis, portal hypertension and risk of decompensation and death, better than other methods such as AST/ALT ratio, APRI or Benlloch indices [206]. None of these models appears to improve the diagnostic efficacy of elastography, although they have not been compared amongst themselves.

Conclusions:

  • It is essential to sequentially assess the severity of hepatitis C (Class I, Level B).
  • Liver biopsy is the gold standard technique for assessing the severity of recurrent hepatitis C after transplantation (Class I, Level B).
  • Transient elastography has proven to be the non-invasive method with a greater ability to identify significant fibrosis and portal hypertension in this context and may be an appropriate alternative to biopsies for monitoring the evolution of hepatitis C after transplantation (Class I, level A).

Liver retransplantation

Graft re-infection due to HCV is universal [3] with a faster progression to fibrosis and cirrhosis in comparison with non-transplanted patients [5]. In patients with decompensated cirrhosis, retransplantation is the only potentially curative option, although, in general, liver retransplantation has a poorer survival rate than the first transplant [5, 207].

It is widely accepted that severe recurrence (hepatitis cholestatic) and the forms that quickly evolve into fibrosis have a worse prognosis after retransplantation [208, 209]. However, it is not well established whether this rapid evolution to fibrosis will also occur in retransplantation [210, 211].

Several considerations may directly or indirectly influence the indication of retransplantation in patients with HCV recurrence: a shortage of donors, resources and efforts made in the first transplant and, in many cases, the emotional relationship established between the doctor and the patient. To maintain maximum equity and to optimize the few organs that we have, it seems reasonable that the opportunity of retransplantation should be offered to patients who have a minimal chance of survival at 1 year of 50–60% [210, 211].

There are many variables that can influence patient survival after retransplantation: bilirubin level, serum creatinine, age, experience of the centre or the time between the first transplantation and recurrence of HCV, among others [33, 212].

The use of predictive models of survival after retransplantation helps in predicting the prognosis of these patients [213-219]. Among the various existing models, the model of Rosen [218] (Table 4) is one of the most widely used and validated. The most widely accepted variables that have been shown to impact retransplantation outcome, such as renal function and bilirubin are included in this model.

Table 4. Rosen score for retransplantation [218]
  1. a

    Primary non-function: 0; other causes: 1.

  2. b

    UNOS 1: −0.261; UNOS 2: −0.463; UNOS 3: −1.070.

R = 
0.224 × age (years)
+ 0.112 × (√bilirubin (mg/dL))
+0.230 × logecreatinine (mg/dL)
−0.974 × cause of graft failurea
+UNOS coefficientb

Besides all the ethical debates the indication for retransplantation in a scenario of organ shortage might cause, three recommendations were agreed on.

Recommendations:

  • Liver retransplantation is not contraindicated in HCV-infected patients.
  • We recommend using the ‘Rosen score’ to determine the indication of retransplantation in these patients.
  • In patients with a value of ≥ 20.5 Rosen, retransplantation should be contraindicated as the expected 1-year survival is less than 50%.

Acknowledgements

The third Consensus Meeting of the Spanish Society of Liver Transplantation was supported by Astellas, Novartis and Roche.

Financial support: Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd) is financed by the Instituto de Salud Carlos III.

Appendix

Other members of the working group on hepatitis C of the SETH

Rafael Bañares. Hospital Gregorio Marañón (Madrid)

Fernando Casafont. Hospital Marqués de Valdecilla (Santander)

Lluis Castells. Hospital Vall d′Hebron (Barcelona)

Valentín Cuervas-Mons. Clínica Puerta de Hierro (Madrid)

Manuel Delgado. Hospital Juan Canalejo (La Coruña)

Inmaculada Fernández. Hospital Doce de Octubre (Madrid)

Félix García. Hospital Río Hortega (Valladolid)

Antonio González. Hospital Nuestra Señora de la Candelaria (Santa Cruz de Tenerife)

Sara Lorente. Hospital Lozano Blesa (Zaragoza)

Esther Molina. Hospital Clínico Universitario (Santiago)

Miquel Navasa. Hospital Clinic (Barcelona)

María Flor Nogueras. Hospital Virgen de las Nieves (Granada)

José Antonio Pons. Hospital Virgen de la Arrixaca (Murcia)

Juan Miguel Rodrigo. Hospital Carlos Haya (Málaga)

Manuel Rodríguez. Hospital Central de Asturias (Oviedo).

Milagros Testillano. Hospital de Cruces (Bilbao)

Xavier Xiol. Hospital de Bellvitge (Barcelona)

Ancillary