Weekly High-Dose Cidofovir Is an Effective Treatment for Symptomatic BK Virus (BKV)-Associated Hemorrhagic Cystitis (HC) after Allogeneic Stem Cell Transplantation (Allo-SCT).
Authors: Baltathakis Ioannis , Michael Michael , Grispou Eirini , Kourti Georgia , Bouzani Maria , Anagnostopoulou Maria , Apostolidis John , Karakassis Dimitrios , Harhalakis Nicholas , Paniara Olga , Nikiforakis Emmanuel 
Published: October 2019

Abstract
A proportion of cases of HC after allo-SCT are associated with infection from BKV. Supportive treatment is not sufficient for the relief of symptoms in many patients with BKV-associated HC. Cidofovir is an antiviral agent active against BKV. Its use is limited, however, due to the reported risk of renal failure in patients with cytomegalovirus (CMV) infection. The experience with cidofovir in BKV-associated HC is anecdotal, and the optimal dose schedule of the drug has not been determined. We administered weekly high-dose cidofovir in 5 patients for the treatment of 6 episodes of symptomatic BKV-associated HC, which were refractory to first-line therapy with hydration and continuous bladder irrigation. One patient was treated twice with cidofovir for 2 temporally separated episodes of HC, combined with papillary necrosis and ureteritis respectively. All 5 patients were males, aged 21–44 years, and had received grafts from matched related (n=2), matched unrelated (n=1) or haploidentical (n=1) donors. The median time from transplantation to diagnosis of HC was 61.5 (range, 26–303) days. In all cases, the development of HC was associated with severe immunosuppression due to profound lymphopenia or treatment with steroids or antithymocyte globulin for GVHD. BKV-associated HC was confirmed by detection of BKV in the urine by real-time PCR (1.5 × 107–5.5 × 109 copies/ml). In 2 of the 6 episodes, the patients also developed BKV viremia (5.0–9.9 × 103 copies/ml). The median time from the manifestation of symptoms to initiation of cidofovir was 12 (range, 4–53) days. Cidofovir was started at a dose of 2.5 mg/kg/week intravenously over 1 hour. If renal function remained stable, subsequent doses of 5 mg/kg were given at weekly intervals for a total of 4–6 doses. Oral probenecid and intravenous hydration were administered in combination with cidofovir. No patient developed renal toxicity (a rise in serum creatinine of at least 1.5 × baseline or proteinuria). In 5 of the 6 cases, clinical improvement of patients was observed, with a median time to response of 5 (range, 3–8) days after the first dose of cidofovir. Complete resolution of symptoms of HC was achieved in these 5 cases after 4 to 6 doses of cidofovir. BKV viral load was monitored weekly in urine (and blood) during therapy. Clinical responses did not correlate with a reduction in viral load in urine. However, in the 2 cases with BKV viremia, real-time PCR became negative after treatment with cidofovir. Concomitant CMV infection was detected in 5 of the 6 episodes of BKV-associated HC, and in all but one, complete suppression of CMV reactivation was achieved by cidofovir. Four of the 5 patients are currently alive and free of symptoms of HC. In conclusion, treatment of BKV-associated HC with cidofovir at the dose of 5 mg/kg/week seems to be safe and may result in prompt and sustained relief of the debilitating symptoms of this condition. Additional manifestations of BKV-associated disease (papillary necrosis and ureteritis) and concurrent CMV infection can be managed successfully with this dose schedule. To our knowledge, these 6 cases comprise the largest reported experience of treatment of BKV-associated HC with cidofovir, albeit the encouraging results need to be substantiated by further trials.