TreatmentThe goal in treating BKV infection is to eliminate the virus while preserving renal function and preventing acute or chronic rejection. The treatment of BKV infection has centered on alterations in immunosuppressive therapy with or without antiviral therapies. Several regimens for altering immunosuppressive therapy have been attempted to treat this infection. These include discontinuation of an agent, decreasing an agent, switching immunosuppressant within the same class or to another class, and steroid avoidance. As a proof of this strategy, patients who had BKV infection and were inadvertently treated with an antilymphocyte agent or pulse corticosteroids for presumptive acute rejection had rapid progression toward graft failure (6,49). Discontinuation of a single immunosuppression agent, antimetabolite (MMF or azathioprine), upon recognition of viremia has been used successfully to clear viremia (49). Reduction in immunosuppression by halving both antimetabolites and calcineurin inhibitors has also been successful in eliminating viremia and preserving renal function (50). Steroid avoidance has been suggested to decrease the prevalence of BKV infection (51). Antiviral therapy with leflunomide or cidofovir has been used in conjunction with decreasing immunosuppression in some cases. Leflunomide is an immunosuppressant medication developed for use in treatment of rheumatoid arthritis. A metabolite of leflunomide (A77 1726) has been shown to have antiviral properties (52,53). Treatment with this agent is associated with decreasing circulating viral copies (53–55); however, introduction of leflunomide has been attempted only with concomitant discontinuation of the antiproliferative agent MMF and decreased dosages of tacrolimus (53,54). Hence, it is unclear whether viral clearance is secondary to leflunomide or the decrease in immunosuppression. Leflunomide treatment is limited because of the requirement of large doses of drug, necessity for liver function monitoring to detect liver toxicity, and need for therapeutic monitoring of trough A77 1726 levels for effectively treating this infection (53–55). In their successful report of 17 patients with BKVN, Williams et al. (53) showed viral clearance or reduction in viral load when A77 1726 levels persisted above 40 μg/ml. This requirement for a target therapeutic level of leflunomide was confirmed by the same investigators in their subsequent study of 26 patients with BKVN (54). A short-acting leflunomide, FK778, has been compared with reduction in immunosuppression alone in a prospective, randomized study to treat BKVN. This study did not show any beneficial effect of FK778 in clearing the virus as opposed to reduction in immunosuppression alone (A. Guasch, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, personal communication (May 9, 2007 at the American Transplant Congress), presented for Astella Study Group ATC 2007). Cidofovir, a nucleoside analogue used in the treatment of cytomegalovirus retinitis, has shown activity against BKV. Unfortunately, cidofovir is nephrotoxic, and its use must be weighed against the possible risk for further worsening of renal function (56–58). Cidofovir has also been used in conjunction with lowering immunosuppression, making comments regarding its efficacy difficult. A prospective, randomized, controlled trial is under way to evaluate the efficacy and safety of cidofovir for patients with BKVN (http://www.clinicaltrials.gov/ct2/show/NCT00138424). Cidofovir is administered when patients fail to respond to reduction in immunosuppressive therapy and is administered typically 10 to 20% of that needed in the treatment of cytomegalovirus retinitis in patients with HIV infection (0.25 to 1 versus 3 to 5 mg/kg) (57,58). Therapy with the anti-CD20 mAb rituximab was recently reported with promising results. Patients who had BKVN and were treated with rituximab and followed for 17 mo had no graft failure compared with 46% graft loss in the control group (59). The administration of intravenous Ig (IVIG) with concomitant reduction in immunosuppressive therapy has been successful; however, efficacy of IVIG is unclear, because it has been administered with concomitant reduction in immunosuppressive therapy (54,60). Wadei et al. (61) recently reported on their experience with treatment of BKVN with cidofovir and IVIG in patients whose immunosuppression was generally reduced in all and converted to cyclosporine therapy in some. Their findings suggested no benefit with conversion to cyclosporine from tacrolimus, use of cidofovir, or IVIG therapies. Close monitoring for BKV DNA and renal function with any therapy is critical to improving outcome for patients with BKV infection. Elimination of BKV DNA occurs during a period of 6 mo with either an antiviral agent or reduction in immunosuppressive therapy (50,53). At our center, we follow quantitative plasma BKV DNA and renal function every 2 wk for 8 wk then monthly thereafter until clearance of BK viremia and stabilization of renal function. We have been successful in eliminating circulating virus and preventing further renal dysfunction with low rates of acute rejection (50). Thus, close follow-up is of paramount importance in effectively treating patients with BKVN.
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