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Abbreviations
ALC

absolute lymphocyte count

ATP

adenosine triphosphate

HCV

hepatitis C virus

HR

hazard ratio

IFN-γ

interferon-gamma

LT

liver transplantation

RATG

rabbit antithymocyte globulin

SVR

sustained virologic response.

End-stage liver disease and hepatocellular carcinoma from chronic hepatitis C (HCV) remain as the most common indications for liver transplantation (LT) in the Western world. Unfortunately, HCV infection universally persists into the post-transplant period, threatening graft and patient survival. Unlike chronic HCV in the immunocompetent population, the natural history of chronic HCV in the LT population has a more accelerated course, with 10%-30% of LT recipients progressing to cirrhosis within 5 years of transplantation and more than 40% within 10 years. The median interval of developing cirrhosis is 9.5 years from transplantation, as compared to 30 years from infection in immunocompetent persons.[1] Undoubtedly, recipients with recurrent HCV have a lower graft and patient survival than their noninfected counterparts.[2]

Various factors associated with aggressive HCV recurrence after LT have been identified (Fig. 1). Donor age >40 years,[3] higher HCV RNA levels at time of transplantation and in the early posttransplant period,[1, 3] and use of corticosteroid pulses or antilymphocyte antibody preparations, such as OKT3, for treatment of acute cellular rejection have predicted fibrosis progression and, consequently, graft and patient survival.[1, 3, 4] Underlying all these factors is the recipient's immune response, which exerts its actions through both innate and adaptive mechanisms.

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Figure 1. Predictors of accelerated progression in recurrent hepatitis C.[1, 3, 4]

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In acute HCV infection, clearance of the virus has been associated with rapid expansion of CD4+ and CD8+ T cells, whereas maintenance of viral clearance has correlated with persistence of HCV-specific CD4+ T cells with the production of memory Cd8+ T cells and interferon-gamma (IFN-γ).[5] In spite of immunosuppression after LT, stronger HCV-specific, major histocompatibility complex class II–restricted CD4(+) T-cell responses targeting nonstructural proteins are still detected in recipients with mild histological recurrence, but not in those with more severe recurrence.[6, 7] This finding suggests that the recipient's capacity to generate HCV-specific T-cell responses plays a role in the pathogenesis and evolution of HCV graft reinfection after LT. A similar pattern has been observed with the host-adaptive immune system, wherein increased natural killer cell number and function in response to antiviral therapy has been associated with HCV clearance, acting by the production of IFN-γ and tumor-necrosis factor-alpha.[5]

In their article published in this issue of Hepatology, Nagai et al. identified low absolute lymphocyte counts (ALCs) during the peritransplantation period to be predictive of early advanced fibrosis (F3-F4) from HCV recurrence within 2 years of transplantation.[8] In addition, severe pretransplant lymphopenia (ALC <500/µL) was an independent prognostic factor for overall survival, although HCV was not a dominant cause of death. The researchers retrospectively analyzed data from 289 patients who received LT at their institution from 2005 to 2011 for HCV. These patients were followed for a median of 2.8 years (range, 1 month to 7.7 years). Half (49.5%) of the patients developed F2-F4 fibrosis at a median time of 10.8 months (range, 1.1-86.9), with 15.6% developing advance fibrosis (F3-F4) within 2 years. On a multivariate analysis, persistent lymphopenia (ALC <500 µL), as compared to improving ALC levels, was independently associated with the development of early advanced fibrosis (P = 0.02; hazard ratio [HR] = 3.16), along with steroid therapy for acute cellular rejection (P = 001; HR = 4.87) and donor age (P = 0.01; HR = 1.03/year). Overall, patient survival was significantly lower in patients with pretransplant ALC <500/µL, as compared with ALC >1,000 µL (P = 0.01; HR = 3.01), and in those with longer cold ischemia time (P = 0.03; HR = 1.19/hour) and older donor age (P < 0.001; HR = 1.04/year). Approximately 43% of patients treated with antiviral therapy in the study had sustained virologic response (SVR). Interestingly, these patients were noted to have a higher pretreatment mean ALC of 1,387/µL than those without SVR at 749/µL (P < 0.001).

The identification of ALC as a predictor of the histologic severity of recurrent HCV and its response to IFN-based therapy provide additional support for the vital role of the lymphocyte in virologic control. This finding also concords with reports that highlight the relationship between the potency of HCV-specific immune response and progression of fibrosis from recurrent HCV. The Cyclex ImmunoKnow assay has been utilized to quantify cellular-mediated immunity by measuring the amount of adenosine triphosphate (ATP) released by CD4+ T cells in response to mitogenic stimulation by phytohemagglutinin-L in vitro.[9] Lower blood ATP levels have been consistently reported in patients with recurrent HCV, when compared to noninfected LT recipients,[10, 11] and have correlated with progression of fibrosis as well.[12] A pilot study demonstrated the potential value of blood ATP levels in guiding immunosuppression management to result in less biopsies and hospitalizations, but did not address its effect on HCV recurrence.[13] The current article then raises the following question: Can the ALC be utilized as an adequate surrogate measure of cellular-medicated immunity? Would a representation of the quantity (though not quality) of T-cell lymphocyctes adequately reflect the host's immune response to HCV? Will it be useful in guiding immunosuppression management to allow a deceleration in fibrosis from recurrent HCV?

In the study of Nagai et al., patients routinely received tacrolimus, mycophenolate mofetil, and corticosteroids for maintenance immunosuppression, but some patients also received rabbit antithymocyte globulin (RATG) for induction. Despite its ability to cause lymphopenia, RATG induction was associated with a lower rate of HCV F2-F4 recurrence, particularly in those with posttransplant lymphopenia (P = 0.01). This is a rather unexpected finding, considering that RATG depletes lymphocyte counts and would intuitively weaken immune response to the virus. Its paradoxical effect on HCV recurrence was attributed by the researchers to its protective effect against rejection and thus avoidance of steroid boluses. However, it is highly likely that lower dosages of maintenance immunosuppression were initiated concomitant with RATG administration in the early posttransplant period. It is also conceivable that these lower dosages may have been carried out further into the posttransplant course, particularly if graft function had remained stable. Unfortunately, no immunosuppressive doses or serum levels were reported at any follow-up point of the study. If such is indeed the case, then the benefit from RATG may simply be a reflection of lower overall immunosuppression after its lymphopenic effects dissipated.

Although Nagai et al. identified a potential tool, readily available and inexpensive, in the clinical management of recurrent HCV, its utility in changing the course of recurrent HCV remains to be proven. Future studies should evaluate its ability to guide reduction of immunosuppression that would, in turn, effectively retard the progression of recurrent HCV while keeping the graft safe from rejection. Nonetheless, the liver transplant community is hopeful that patient and graft survival will soon shift toward a more favorable curve for HCV-infected recipients. The new era of direct antiviral therapy that promises higher efficacy rates and an excellent safety profile is expected to greatly ease the bane of recurrent HCV both at the front and back ends.

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