Living-Donor Liver Transplantation and Hepatitis C

Hepatitis-C-virus- (HCV-) related end-stage cirrhosis is the primary indication for liver transplantation in many countries. Unfortunately, however, HCV is not eliminated by transplantation and graft reinfection is universal, resulting in fibrosis, cirrhosis, and finally graft decompression. In areas with low deceased-donor organ availability like Japan, living-donor liver transplantation (LDLT) is similarly indicated for HCV cirrhosis as deceased-donor liver transplantation (DDLT) in Western countries and accepted as an established treatment for HCV-cirrhosis, and the results are equivalent to those of DDLT. To prevent graft failure due to recurrent hepatitis C, antiviral treatment with pegylated-interferon and ribavirin is currently considered the most promising regimen with a sustained viral response rate of around 30% to 35%, although the survival benefit of this regimen remains to be investigated. In contrast to DDLT, many Japanese LDLT centers have reported modified treatment regimens as best efforts to secure first graft, such as aggressive preemptive antiviral treatment, escalation of dosages, and elongation of treatment duration.


Introduction
Since the �rst successful application of living donor liver transplantation (LDLT) in 1990 [1] and subsequent successful LDLT for adult recipient in 1994 [2], the use of live donors for liver transplantation has been widely applied to adult recipients where the availability of deceased-donors is severely restricted, like in Japan [3], and also accepted as a solution to the cadaveric donor shortage in Western countries [4].
End-stage liver disease caused by chronic hepatitis C virus (HCV) infection is the leading cause of liver transplantation in developed countries [5,6], including Japan [7]. Unfortunately, liver transplantation does not cure HCV-infected recipients, but re-infection of HCV universally occurs and disease progression is accelerated compared with that in the nontransplant population, resulting in poor outcomes for HCV-infected recipients [8].
e aim of this paper was to overview the current trends and controversies in LDLT for patients with HCV in relation to the perspectives from deceased-donor liver transplantation (DDLT).

Natural History of Hepatitis C after Orthotopic Liver Transplantation
Accumulating perspectives of disease recurrence in HCVinfected recipients have been obtained in DDLT within the last two decades. HCV reinfection occurs just aer reperfusion followed by a rapid increase in HCV ribonucleic acid (RNA) levels within 4 postoperative months [9]. e histologic features of liver injury usually resemble those of nontransplant HCV hepatitis typically developing aer 3 months, but the clinical presentation, severity, and outcome are extremely heterogeneous and more profound compared to those in immune competent patients [10]. Progression to cirrhosis usually takes 9 to 12 years aer liver transplantation with a linear progression of histologic �brosis [10, 11]. A less common, but well-documented, form of recurrence is called �brosing cholestatic hepatitis (<10%), possibly mediated by a direct cytopathic mechanism under an extremely high viral load and immune-compromised condition. Gra failure occurs in 50% of recipients within a few months aer �brosing cholestatic hepatitis develops [12]. Some HCV-reinfected recipients, however, show no apparent disease progression for at least the �rst decade and their gra injury remains mild or even absent despite a high vira burden.
Overall, cirrhosis develops in approximately 25% of liver transplant recipients (range 8%−44%) aer 5 to 10 years and this percentage is likely to increase with an increase in the follow-up period [10,11]. Once cirrhosis is complete, survival time is severely decreased and decompression is encountered with cumulative rates at 1 and 3 years of 40% and 60%, respectively, which �nally results in gra failure [11,13].
e development of decompensated cirrhosis due to recurrent hepatitis C is now the most frequent cause of gra failure, patient death, and the need for retransplantation in HCV-infected recipients [11,[13][14][15][16][17]. As a result, survival is signi�cantly decreased compared with other indications, an overall 10% difference at 3 years [18]. In the most recent United Network for Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) study from the United States, 3-year survival is 78% among 7459 HCVpositive recipients compared with 82% among 20734 HCVnegative recipients ( < ; http://www.unos.org) [19]. e poor outcome of HCV-positive recipients has resulted in the divergence in transplant outcomes between HCV-positive recipients and HCV-negative recipients. Improvements in organ preservation, surgical techniques, and postoperative care have dramatically improved the survival of HCV-negative recipients over the last two decades, whereas this has not been the case in HCV-positive recipients for whom outcome has remained unchanged or even worsened over time [19][20][21][22].

Current Status of LDLT
In areas with low deceased-donor organ availability like Japan, the indication of LDLT for HCV cirrhosis is similar to that of DDLT [7], whereas in Western countries, LDLT is conducted in an attempt to alleviate the shortage of donor organs and decrease the mortality among patients awaiting transplants, accounting for only 3% to 4% of all liver transplants [23].
According to the Japan Liver Transplantation Society [24], a total of 6097 LDLTs, comprising 98% of all liver transplants, have been performed till the end of 2010 in Japan. Among those, 3796 were adult cases including 1200 (32%) cases of HCV-related disease as a leading indication for adult LDLT. e 1, 3, 5, and 10 year survival rates of all adult LDLT and those of HCV-positive adults were 81%, 75%, 72%, and 66%, and 78%, 72%, 68%, and 59%, respectively, without difference.
In Early studies raised some negative concerns regarding the outcomes of LDLT in HCV patients, such as a poorer gra outcome and earlier and more aggressive HCV recurrence aer LDLT compared with DDLT [144][145][146]. Several theories have been proposed to explain the differences in HCV recurrence between LDLT and DDLT recipients. One possible explanation is that the intense hepatocyte proliferation that occurs in partial liver gras may lead to increased viral translation and replication [145,[147][148][149]. Genetic donorrecipient similarity is another proposed mechanism for more severe HCV recurrence [150,151]. Recent studies, however, comparing outcomes of LDLT and DDLT in HCV-infected patients have not only failed to identify LDLT as a risk factor for more intense viral recurrence with impaired outcome, but also revealed improved results in LDLT recipients [39, [84][85][86][87][88][89][90][91][92][93][94][95], which do not support the aforementioned speculations. Alternatively, recent studies favored the theory that outcomes of LDLT for HCV cirrhosis could be better than those of DDLT due to the younger donor age and shorter ischemic time of LDLT gras. e studies comparing outcomes between LDLT and DDLT in HCV-infected recipients are summarized in Table 2.
ese data should be interpreted with caution, however, because of the important clinical distinction between LDLT and DDLT. At the time of transplantation, DDLT recipients are far sicker than LDLT recipients as represented by a signi�cantly higher MELD score, donor age is higher, and gra ischemic time is longer. Indeed, signi�cantly poorer preoperative condition and older donor age in DDLT recipients were indicated in 7 and 6 studies, respectively, among 16 studies listed in Table 2. Additionally, cold ischemia time is signi�cantly longer in DDLT than that in LDLT in all studies. All these factors, as presented in Table 1, are considered independent prognostic factors for severe HCV recurrence and impaired patient/gra outcome. Actually, Jain et al. [95], who recently reported that both patient/gra survival and histologic �ndings are better in LDLT, found in a subanalysis of the study that adjusting for MELD score (<25) and donor age (<50) resulted in similar outcomes.
Based on accumulating reports demonstrating comparable outcome of LDLT and DDLT for HCV cirrhosis, and re�nement of surgical techniques and management in LDLT, hepatitis C recurrence by itself does not seem to explain the differences in patient/gra survival between LDLT and DDLT, and even improved outcomes could be achieved in LDLT due to the better quality of the gra, younger donors, and less sick recipient condition at the time of transplantation. Furthermore, based on these bene�ts of LDLT, donor selection to improve outcome of LDLT for HCV positive recipients could be assumed. Selecting younger donors [17] or donors with favorable IL-28B genotype [108,109] could be possible future issues; however, with the severe lack of live donors, it seems impractical in clinical setting at present. Anyway, LDLT could be strongly recommended for HCVpositive patients whenever it is available.   [152], and to date, only six studies [153][154][155][156][157][158] have been published in this phase with differences in the treatment duration (6-14 months versus 2-3 months) and in regimens used (INF only, INF/RBV, or PEG-INF/RBV). Regardless of the approach used, the results are similar, resulting in the prevention of HCV re-infection in about 20% of treated patients with high discontinuation rate and high dose reduction rate [152]. Considering the less severe disease of LDLT recipients as discussed earlier, pretransplant antiviral treatment seems more preferable for LDLT recipients to improve outcome; however, no such trial has been published so far in LDLT setting. is issue also seems remain to be investigated in future studies as with the case in live donor selection issues.

Antiviral Treatment
Prophylactic or preemptive antiviral treatment generally means antiviral treatment with INF/PEG-INF and RBV started early posttransplant, without requiring evidence of recurrent hepatitis C. In published studies [159][160][161][162][163][164] of preemptive antiviral therapy, SVR rates are reported to range from 8% to 34% (5% to 43% for genotype 1 and 14% to 100% for genotypes 2 or 3), with the rates of dose reduction and drug discontinuation are approximately 70% and 30%, respectively, due to the existence of cytopenia, renal dysfunction, rejection, or extrahepatic complications, and high levels of immunosuppression in this time window. e most recently published prospective, multicenter, randomized study (PHOENIX study) by Bzowej et al. [165] was designed to compare the efficacy, tolerability, and safety of an escalating dose regimen of PEG-INF alpha 2a/RBV for 48 weeks for preemptive antiviral treatment versus no treatment, which showed only 22% SVR in the prophylaxis patients with the rate of marked HCV recurrence at 120 weeks (62% in prophylaxis patients versus 65% in observation patients), and comparable �brosis progression 120 weeks as well as similar patient/gra survival in both study arms. Dose reduction and discontinuation were required in 70% and 28%, respectively. Based on these results, European and United States transplant societies do not support the routine use of preemptive antiviral therapy.
Consequently, initiating antiviral therapy with PEG-INF/RBV aer the con�rmation of recurrent hepatitis C in the gra by liver biopsies is the mainstay for the treatment of recurrent disease in Western countries [35, . Most of the data come from uncontrolled studies with different designs regarding time to start treatment, regimen used, and follow-up, but treatment duration is generally 48 to 52 weeks. erefore, the results were also very different, with SVR rates ranging 0% to 56% (median: 33%), discontinuation rates ranging 4% to 58%, and dose reduction rate ranging 28% to 100%. In addition, the survival bene�t of the treatment has not been con�rmed in most studies so far, and it is compelling to conclude that there is currently no evidence to support the antiviral treatment for recurrent gra hepatitis C due to the lack of clinical bene�t and frequent adverse effects, as concluded by the recent Cochrane meta-analysis [191]. On the other hand, recent retrospective cohort studies with a considerable follow-up duration found improved patient/gra survival in patients who obtained an SVR aer antiviral treatment [35,[192][193][194]. Further randomized clinical trials with appropriate trial methodology and adequate follow-up duration are necessary to con�rm an actual survival bene�t of antiviral treatment.

Reports from Japanese LDLT Centers
Although retransplantation is the only potentially curative option for those with decompressed cirrhosis due to recurrent hepatitis C, in contrast to Western countries where re-DDLT is spared as a last resort [195,196], it is extremely unlikely in Japan to perform retransplantation for patients with recurrent end-stage hepatitis C, if not absolutely impossible. ese backgrounds might have led to various modi�ed strategies for the treatment of recurrent disease as best efforts to secure �rst gra, such as aggressive preemptive antiviral treatment, escalation of dosages, and elongation of treatment duration.
We have reported preemptive INF/RBV treatment for HCV-positive LDLT recipients [161,[197][198][199]. Preemptive treatment was started just aer recipient's condition had become stable (approximately one month aer LDLT) with low-dose INF alpha 2b and RBV (400 mg/day) followed by escalation to PEG-INF (1.5 g/kg per week) and RBV (800 mg/day) depending on patient's tolerance. e treatment duration was not settled, and was continued for additional 12 months aer the serum HCV-RNA became negative. e response was considered to be SVR provided negative serologic results for another 6 months aer discontinuation of therapy. at is, nonstopping peg-INF/RBV approach was applied for non-responders. Among 122 HCV-positive LDLT recipients, 42 (34%) achieved SVR and those with SVR showed signi�cantly improved survival when compared to those without SVR (cumulative 5-year survival rate; 97% versus 66%) [199].
�yoto group also reported modi�ed PEG-INF/RBV treatment with individualized extension, while they started antiviral treatment for cases with biopsy-proven recurrent disease [200][201][202]. ey started with PEG-INF (1.5 g/kg per week) and RBV (400-800 mg/day) for 12 months for all patients with recurrent hepatitis. en, full dose treatment was continued for additional 8-22 months for those whose serum HCV-RNA became negative within 12 months, while patients who did not become negative for serum HCV RNA within 12 months continued to receive a low-dose PEG-INF (0.5-0.75 g/kg per week) with or without reduced RBV (200 mg/day) as maintenance treatment. Among 80 patients with recurrent hepatitis C aer LDLT, SVR was achieved in 31 (39%), while remaining 49 (61%) received maintenance therapy among those 26 (53%) discontinued. In comparison to �brosis progression, no difference was observed between SVR group and maintenance treatment group with improved or stable �brosis in both groups, while those who withdrew from maintenance showed signi�cantly deteriorated �brosis [202].
Kyushu group performed antiviral treatment for 80 patients among 106 consecutive HCV-positive recipients, excluding 26 cases of early death, negative HCV RNA, and refusal for treatment [203]. Basically, they started with PEG-INF (0.5 g/kg per week) and RBV (200 mg/day), then escalated to PEG-INF (1.5 g/kg per week) and RBV (800 mg/day), with the treatment duration of 48 weeks and over 72 weeks for those with early viral response and for those without it, respectively. ey reported overall SVR rate of 35%. ey found both signi�cantly severe �brosis and impaired gra survival in those who did not show viral nor biochemical response.
Other Japanese centers [204][205][206][207] have also reported similar modi�ed antiviral treatment with PEG-INF and RBV including dose escalation, treatment for all HCV-positive cases, and extension of treatment. Additionally, simultaneous splenectomy during LDLT operation in an attempt to improve tolerance to antiviral treatment, SVR rate and further gra survival should be noticed [198,208,209].

Conclusion
Hepatitis C is here to stay and will remain the most common indication for liver transplantation. In the areas where cadaveric organs are extremely limited like in Japan, indication of LDLT is same as that of DDLT, and recent studies have proved that LDLT can be performed as safely and effectively as DDLT for HCV-infected patients in experienced centers. Further investigation for more effective and tolerable antiviral treatment is warranted to secure the �rst live donor gra to the possible extent.