**5. Treatment**

In non-transplant setting, the combination therapy with interferon (IFN) and Ribavirin is the standard of care for treatment of initial as well as relapse of HCV infection. Clearance of Ribavirin is impaired in patients with renal dysfunction as the drug itself and its metabolites cannot be removed by Hemodialysis. Therefore, Ribavirin is not recommended in patients with creatinine clearance of less than 50mL/min. IFN therapy is however recommended in dialysis patients. The goal of pretranslant HCV treatment is to attempt to eradicate HCV before transplant subsequently leading to decrease in the risk of progression of HCV-associated liver disease, reduced risk of posttransplant renal dysfunction, and possible reduction in HCV disease progression. The optimal treatment of HCV in dialysis patients is regarded as IFN therapy but it is not known whether there is any added advantage on the use of pegylated IFN over nonpegylated standard IFN. Dialysis patients are not considered candidates of combi‐ nation therapy owing to concerns regarding development of Ribavirin-induced anemia as the clearance of the drug is impaired in patients with renal dysfunction. A safer but less costeffective approach is to use IFN therapy to treat HCV positive patients on dialysis who are potential transplant candidates. This strategy seems to have a beneficial effect on the course of liver disease posttransplant, shows higher rates of sustained biochemical and virological response, and seems to have reduced risk of HCV disease progression. At present data on relapse rate on HCV positive patients treated pretransplant is limited and controversial. 2008 KDIGO guidelines suggest HCV positive transplant candidates to be considered for IFN therapy before transplant. Ribavirin is not recommended because of its impaired clearance. Similar concerns apply to pegylated IFN because of its longer half-life and is also not recom‐ mended for pretransplant HCV therapy.

Posttransplant HCV treatment is generally not recommended. A major limitation to the use of IFN posttransplant is the potential of developing acute rejection. In addition to antiviral activity, IFN also has pleiotropic effects including antiproliferative and immunomodulatory functions. The National Institute of Health (NIH) Consensus Statement on management of HCV infection lists renal transplant as one of the contraindications to IFN therapy. Most authorities are in line with this approach because of the increased risk of acute rejection, high cost, limited efficacy, and significant side effects that are reported with IFN treatment after transplant. Treatment may be recommended in exceptional and life-threatening cases of HCV complications such as fibrosing cholestatic hepatitis, life-threatening vasculitis, recurrent and progressive HCV-associated glomerulopathy in the transplanted kidney, and advanced histologic stages of liver fibrosis.

2008 KDIGO guidelines recommend monotherapy with standard IFN only to be considered in HCV positive kidney transplant recipients (Terraut & Adey, 2007; Kim et al., 2011; Carbone et al., 2011; Natov & Periera, 2012. Data on efficacy of Ribavirin treatment alone after transplant is limited. Combination therapy is the most likely regimen to achieve a sustained virologic response (SVR), however Ribavirin dosage must be adjusted based on the renal function to minimize the complication of anemia.

Large scale, multicenter clinical trials are needed to determine the optimal treatment approach in these populations. New therapies may offer specific advantages and show decreased incidence of treatment-related side effects than the currently available drugs.

In addition SVR to antiviral therapy in patients with HCV associated renal disease has been associated with improvement in renal histology with reduced inflammation and immune deposits. Recently, five HCV positive renal transplant patients who developed type III cryoglobulinemic MPGN were successfully treated by Rituximab (anti-CD 20) chimeric monoclonal antibody (Basse et al., 2005, 2006).

Transplantation after adequate antiviral therapy followed by minimal immunosuppression can be a good option. Recently, Shah and colleagues evaluated graft function and graft as well as patient survival in retrospective analyses of 132 HCV-positive renal transplant patients who received tolerance induction protocol (TIP) with minimal immunosuppression and compared them with 79 controls transplanted using standard triple immunosuppression drugs. TIP consisted of 1 donor-specific transfusion, peripheral blood stem cell infusion, portal infusion of bone marrow, and target-specific irradiation. In the TIP group patient survival at 1, 5, and 10 years was 92.4%, 70.4%, and 63.7%, respectively, versus 75.6%, 71.7%, and 55.7% in the control group. The graft survival was 92.9%, 81.5%, and 79.1% versus 91.7%, 75.7%, and 67.7%, respectively. Rejection episodes were less frequent in the former group. Abnormal liver enzymes were seen in 22% patients in the TIP group versus 31% of the control group (Shah et al., 2011).
