Safe and effective antiviral treatment of BKPyV diseases is still lacking . In the management of kidney transplant patients with BKPyV viremia, regardless of the presence or absence of BKPyV-positive cells in a kidney biopsy, it is recommended to reduce, change or discontinue immunosuppressive drugs to allow for a BKPyV-specific antiviral immune response [reviewed by [65, 82]]. If the disease is detected at an early stage, a reduction in the immunosuppression is often enough to clear the BKPyV viremia and stop the progression of disease [129-131]. In a recent histopathological study of 35 patients with PyVAN treated by reduction in immunosuppression alone, 83% of the patients showed stable or improved allograft function 2 years later, while 2 patients (6%) experienced clinical rejection . Interestingly, the morphological pattern of resolving PyVAN could not be distinguished from rejection and revealed intraepithelial lymphocytes and interstitial inflammation. However, as the majority of patients resolved their PyVAN, the inflammation was apparently beneficial.
A systematic analysis of all published treatments for PyVAN concluded with no graft survival benefit of treatment with cidofovir or leflunomide combined with reduction in immunosuppression compared to the reduction in immunosuppression alone . There is no clinical evidence to support the use of any other drugs either. Nevertheless, cidofovir, leflunomide, fluroquinolones and intravenous immunoglobulins are sometimes given as adjunctive therapies.
Cidofovir, trade name Vistide (Gilead, Foster City, CA, USA), is an intravenously administered nucleoside analogue of deoxy cytidine monophosphate that is licenced by the U.S. Food & Drug Administration for the treatment of cytomegalovirus retinitis in AIDS patients. In 2000, a patient with PyVHC and simultaneous cytomegalovirus (CMV) infection was successfully treated with cidofovir  and shortly after it was reported to be useful in the treatment of one patient with PyVAN . The drug is taken up via the organic anion transporters (OAT1), which are mainly expressed on the basolateral side of renal tubular epithelial cells. The drug becomes active after two phosphorylation steps performed by cellular enzymes [136, 137]. In vitro studies on cidofovir and CMV replication suggest that incorporation of a single molecule of cidofovir in the viral DNA results in reduced replication, while incorporation of two consecutive molecules efficiently terminates elongation . In agreement with this, in vitro studies on cidofovir and BKPyV replication showed decreased intracellular and extracellular BKPyV loads but also reduced cellular DNA replication and metabolic activity [139, 140]. As BKPyV does not encode a viral polymerase, unlike CMV, the results suggest that the antiviral activity is caused by the cytostatic and cytotoxic effects of the drug. The cytostatic and cytotoxic effects found in vitro were not completely unexpected since cidofovir is known to be nephrotoxic . While some studies report that cidofovir treatment stabilizes kidney function, others report no benefit [reviewed in ]. However, as immunosuppression is usually decreased simultaneously with cidofovir treatment, the effect is difficult to evaluate. A lipid conjugate of cidofovir, 1-O-hexadecyloxypropyl cidofovir (CMX001), was found to have a longer lasting, less toxic and 400 times stronger inhibitory effect on BKPyV replication in primary human kidney epithelial cells . It has also been well tolerated in healthy volunteers  and is therefore a potential drug candidate for treatment of BKPyV infections. Currently clinical trials with CMX001 treatment of infections with double-stranded DNA viruses in immunocompromised patients are under way.
Leflunomide, trade name Arava (Sanofi, Bridgewater, NJ, USA) is an orally administered drug that was approved by the U.S. Food & Drug Administration in 1998 for the treatment of rheumatoid arthritis. Leflunomide is converted to the active metabolite, A771726, presumably within the mucosal interstitia and liver. A771726 inhibits the mitochondrial enzyme dihydroorotate dehydrogenase, which is responsible for de novo pyrimidine synthesis. The lack of pyrimidines affects proliferation of T- and B-lymphoytes in particular, thereby causing an immunosuppressive effect. Leflunomide is therefore administered to kidney and liver transplant patients when existing immunosuppression is inadequate . Moreover, it has been used as an antiviral treatment against CMV and herpes simplex virus type 1 infections. The suggested mechanism for this antiviral effect is prevention of tegumentation and thereby, virion assembly [145, 146]. Despite the fact that BKPyV is a non-enveloped virus without tegument, leflunomide was used for the first time in 2003 to treat PyVAN in a kidney transplant patient [147, 148] and is still in use for this indication. Leflunomide is often preferred over cidofovir as it is not nephrotoxic. It may, however, cause other severe side effects such as hemolysis, thrombotic microangiopathy, bone marrow suppression and hepatitis . In vitro studies examining BKPyV replication found that A771726 inhibited BKPyV replication, but that this was closely connected to the significant cytostatic effects triggered by pyrimidine depletion [139, 150]. There are several case reports presenting favourable outcomes in both adult [151-154] and paediatric kidney transplant patients , but also reports where some patients experienced graft function deterioration [156, 157]. Of note, no difference in clearance of viremia was found between patients maintained at a high (>40 μg/mL) or low dose (<40 μg/mL) . Similar to the clinical studies of cidofovir, immunosuppression is usually simultaneously decreased, making evaluation of the effect difficult.
Fluoroquinolones are synthetic broad-spectrum antimicrobial agents targeting the bacterial enzymes topoisomerase II and IV  and are also suggested to interfere with the helicase activity of BKPyV LTag as described for SV40 LTag . A modest inhibition of BKPyV replication in vitro has been observed in several studies [160-163]. One study on BKPyV replication in primary renal tubular epithelial cells supported that fluoroquinolones might interfere with LTag but also suggested inhibition of the cellular topoisomerase II enzyme as an explanation of the reduced cellular DNA replication found . A prophylactic effect has been reported in some non-randomized studies of HSCT and kidney transplant patients [162, 165, 166], but the effect was either short lived  or not observed in all patients .
The known immunomodulatory activity  and potential anti-BKPyV effect of intravenous immunoglobulin (IVIG) has given rise to empiric use in patients with PyVAN. Commercial IVIG contains pooled immunoglobulin G (IgG) from the plasma of approximately 1000 blood donors. The IVIG is found to contain neutralizing antibodies against BKPyV, reducing in vitro infections by 90% . While some report favourable responses in patients receiving IVIG [171-174], others find no response  or even an increased viral load after IVIG administration . The fact that some kidney transplant patients with PyVAN already have high titres of BKPyV IgG raises the question if antibodies really give any protection . As for the other adjunctive therapies, the evaluation of an effect is complicated by the simultaneous reduction in immunosuppression. Although most of the adverse effects of IVIG are mild and transient , IVIG is in short supply and is an expensive treatment.
Therapy for PyVHC is purely supportive, involving symptom relief by analgesia, hyperhydration to increase diuresis and continuous bladder irrigation to prevent clot formation and urinary tract obstruction . Moreover, lost platelets and erythrocytes are substituted.
The same adjuvant treatments have been tried for PyVHC as for PyVAN again without any documented benefit. In a recent study of five paediatric allogenic HSCT patients treated with intravenous ciofovir, intravesical cidofovir or both, only patients mounting BKPyV-specific IgM and IgG responses showed clinical resolution . The authors speculated that the patients with increasing BKPyV antibody titres also had residual cellular immune competence which facilitated the resolution of PyVHC under cidofovir treatment. They also discussed the possibility of neutralization or clearing effect, which would suggest a limited to non-existent effect of cidofovir. If intravenous cidofovir is given as treatment for PyVHC, it should be given together with probenecid which prevents the uptake of cidofovir into renal tubular epithelial cells and thereby prevents nephrotoxicity .
Hyperbaric oxygen is frequently used for radiation induced haemorrhagic cystitis and has also been reported to be of benefit for patients with PyVHC . Apparently the hyperbaric oxygen stimulates mucosal repair in the urinary bladder. In a retrospective study, 16 patients with PyVHC received 100% oxygen in a hyperbaric chamber at 2.1 atmospheres for 90 min, 5 days per week for between 4 and 84 times and 15 patients showed complete resolution of hematuria . There are also reports on intravesicular instillation of formalin and aluminium to stop bleeding [182, 183], but formalin is known to give different side effects like ureteric stenosis and renal parenchymal damage while aluminium can cause intoxication especially in children .