Numerous pre- and post-transplant variables have been linked to progressive disease and increased mortality. There is robust evidence pointing to a negative effect of old donor age, over-immunosuppression as a result of rejection treatment, post-transplant diabetes or metabolic syndrome and HIV coinfection [5, 10, 27–31].

Old donor age is independently linked to greater disease severity and progression in addition to poorer graft and patient survival [10, 28, 32], both when using deceased and living donors and when using anti-HCV-positive donors. In the Spanish Liver Transplant Registry, the 5-year survival was only 41 and 52 % for HCV patients using grafts from donors older than 74 or 50 to 74 compared to 63 % in those transplanted with grafts from younger donors (www.​ont.​es). The effect is nonlinear, with donor age greater than 65 years linked to the poorest results. In a retrospective analysis of more than 20,000 transplants performed between 1998 and 2000 in the USA, donor age >40 years (and particularly over 60 years) was significantly associated with high risk of graft failure [33]. More recent data has further suggested that the use of allografts from old donors is also a risk factor for the development of FCH. Applying the more rigorous diagnostic of FCH from Verna et al., donor age (OR = 1.37, 95 % CI: 1.02–1.84, P = 0.04) and previous history of acute cellular rejection (OR = 4.19, 95 % CI: 1.69–10.4, P = 0.002) were the most reliable predictors of developing FCH on multivariate analysis. In summary, the transplantation of older allografts into HCV recipients results in worse outcomes due to recurrent HCV in the short as in the long-term [12], and hence the recommendation to avoid the allocation of “elderly donors” to HCV(+) recipients. Unfortunately, donor age has increased dramatically in recent years so that allocating only young donors to HCV(+) recipients remains a near impossible task in most centers. Reasons that explain the negative effect of increased donor age are incompletely understood. Telomere shortening, impaired proliferative response to insults, increased fibrogenesis, and reduced fibrinolysis, in conjunction with immunological changes, may contribute to the “lower quality” of advanced donor-aged grafts. It’s likely that the increased use of elderly donors might explain the worse outcomes observed in some centers in recent years, as well as the discrepant results in terms of fibrosis progression post-transplantation between centers. Importantly, the donor age effect can be heightened by other cofactors such as diabetes, ischemic time, preservation injury, recipient age, or over-immunosuppression. Decreasing ischemic times, using donor-recipient models such as the D-MELD (donor age × MELD score) for organ allocation, promoting immunosuppressive protocols that avoid over-immunosuppression and also diabetes, should always be tried, but particularly when using old donors.

Donor liver steatosis has also been described as a risk factor for increased disease severity. The degree of steatosis that would define a specific risk is however still unclear [28, 34].

Anti-HCV(+) donors can be an additional source of organ donors in an era of organ scarcity. These grafts can be safely used if extracted from young donors <46 years of age when fibrosis is absent or minimal and only slight inflammation is present. In the era before new direct antiviral agents were available, these grafts could only be used in genotype 1 HCV recipients [10, 27, 35]. This restriction is likely to disappear with the advent of highly effective anti-HCV therapies [36].

While IL28B polymorphism, particularly that of the donor, was found to have a substantial impact on IFN responsiveness to post-transplant IFN-based therapy, the effect of both donor and recipient IL28B genotype on the natural history of recurrent hepatitis C is less evident [37, 38].

High pre-transplantation levels of viremia have been described in those with severe recurrent hepatitis C and high mortality [10, 27]. An association between post-transplant levels of viremia and long-term outcome has also been shown in some but not all studies. In one interesting retrospective analysis of 118 HCV LT recipients, a peak viral load ≥10⁷ IU/mL post-transplantation was found to be an independent predictor of reduced patient and graft survival and HCV-allograft failure. A peak viral load in the first year after transplant of >10⁸, 10⁷ to 10⁸, and <10⁷ IU/mL was associated with a mean survival of 11.8, 70.6, and 89.1 months, respectively (P ≤ 0.03) [39]. In turn, the impact of HCV genotype on outcome is controversial [5, 40–46].

While early studies suggested that living donor LT was a risk factor for developing aggressive recurrent disease, more recent and larger studies have proven otherwise. In the large retrospective study of HCV-infected transplant recipients from the 9-center Adult to Adult Living Donor Liver Transplantation Cohort Study, patient and graft survival as well as incidence of advanced fibrosis were compared between 195 living donor liver transplant (LDLT) recipients and 180 deceased donor liver transplant (DDLT) recipients, monitored for a median of 4.7 years. The 5-year cumulative risk of advanced fibrosis (Ishak stage ≥ 3) was 44 and 37 % in LDLT and DDLT patients (p = 0.16), respectively. The 5-year unadjusted patient and graft survival probabilities were 79 and 78 % in LDLT, and 77 and 75 % in DDLT (p = 0.43 and 0.32), with 27 and 20 % of LDLT and DDLT graft losses due to HCV (p = 0.45). Biliary strictures (HR = 2.25, p = 0.0006), creatinine at LT (HR = 1.74 for doubling of creatinine, p = 0.0004), and AST at LT (HR = 1.36 for doubling of AST, p = 0.004) were found to be independent predictors of graft loss, but LDLT was not (HR = 0.76, 95 % CI: 0.49–1.18, p = 0.23). Importantly, first analyses of these series demonstrated lower graft and patient survival among the first 20 LDLT cases at each center (LDLT ≤ 20) compared to later cases (LDLT ≥ 20; P = 0.002 and P = 0.002, respectively) and DDLT recipients (P < 0.001 and P = 0.008, respectively) [47]^. Therefore a learning curve is necessary to avoid worst results in LDLT recipients with HCV [48].

Given the expansion in the use of organs retrieved from cardiac death donors (DCD), there has been a significant interest in assessing whether HCV is more aggressive in that setting. While initial studies showed conflicting results, more recent data suggest that the severity of HCV disease over the first 3–5 years following LT is comparable to that seen following DDLT [49, 50]. In a recent meta-analysis the authors evaluated the clinical outcomes of DCD vs. DBD organs in HCV(+) patients (n = 324). The use of DCD livers was associated with a significantly higher risk of primary nonfunction but not with a significantly different patient or graft survival, rate of recurrence of severe HCV infection, retransplantation or liver disease-related death, and biliary complications [51].

Whether outcome differs based on gender is a matter of debate. An Italian study highlighted that women were at greater risk of developing severe recurrent HCV disease [52]. A recent multicenter study (CRUSH-C), involving 1264 patients (24 % women), reported similar findings. In their multivariate analysis, female sex was found to be an independent predictor of advanced disease (HR = 1.31, 95 % CI: 1.02–1.70, P = 0.04), death (HR = 1.30, 95 % CI: 1.01–1.67, P = 0.04), and graft loss (HR = 1.31; 95 % CI: 1.02–1.67; p = 0.04) [53]. Interestingly, a large retrospective study of the UNOS/OPTN cohort , including 18,159 HCV(−) LT recipients and 9,403 HCV(+) recipients, found an increased risk of graft loss only among HCV(+) recipients transplanted with organs from male donors with an HR of 1.23 (1.10–1,38). In contrast, this increased gender mismatch-related risk was not observed in the HCV(−) recipients [54]^.

Metabolic syndrome (MS) post-LT is associated with worse HCV outcomes after LT, similar to that observed in the non-transplant setting, and could represent a significant modifiable risk factor [55–57].

Afro-American HCV+ recipients of a racially mismatched allograft are at risk of graft failure and mortality. Two recently published investigations added further weight to the survival data by establishing that racial mismatch was a significant independent predictor of advanced fibrosis [58, 59].