BK viral infection: A review of management and treatment

Table 1 Summary table of studies on management of BK infection

Ref.	Study type/period	Subjects	Key findings (include P value if available)
Alterations in immunosuppression
Vela et al[7], 2022	Retrospective study; Mar 2013-Oct 2020	43 kidney transplant recipients with BK DNAemia; 26 received mTORi + IVIg; 17 had immunosuppression reduction	BK DNAemia and viral clearance reduced faster and more significantly in subjects with reduced immunosuppression (P < 0.001 and P = 0.033 respectively). Death-censored graft loss, rejection rates, and kidney graft function at 12 mo did not differ significantly
Halim et al[6], 2016	Cohort study	55 kidney transplant recipients with BK viremia and/or BKVAN nephropathy; 22 received leflunomide + IVIg + ciprofloxaci; 33 had immunosuppression reduction alone	Administration of leflunomide, IVIg, and ciprofloxacin added no benefit to the long-term outcome of patients with established BKVAN. Treatment of BKVAN by reduction of immunosuppression alone appears to be more effective
Huang et al[4], 2015	Prospective study; Mar 2006-Oct 2008	229 kidney transplant recipients with BK viremia and BKVAN 30%-50% reduction in FK and/or MPA	BK viremia resolved in 100% of patients without increased acute rejection. All patients with BKVAN had viral clearance and showed no decline in GFR
Saad et al[3], 2008	Retrospective, single center study; Sept 2001-Dec 2003	24 kidney transplant recipients: 16 with BKVAN; 8 with BK viremia	Reduction in immunosuppression alone results in clearance of the BK viremia with good long-term outcome
Leflunomide
Krisl et al[9], 2012	Retrospective, single center study; Jun 2001-Dec 2009	76 kidney transplant recipients with BK viremia with or without BKVAN; 52 received leflunomide; 24 did not receive leflunomide	No difference in BK viral clearance. Multivariate analysis demonstrated that mycophenolate mofetil discontinuation, BK viremia without nephropathy, and mean BK viral load were significantly associated with BK viral clearance. Leflunomide use lacked this association
Canivet et al[11], 2009	Prospective study; Jan 2006-May 2008	12 kidney transplant recipients with BKVAN; MMF switched to leflunomide	Not statistically significant T cell markers, BK DNAemia clearance in 41.6%, creatinine clearance stable or improved in 50%, no significant adverse events
Teschner et al[12], 2009	Prospective study	13 kidney transplant recipients with BKVAN; MMF switched to leflunomide	12 had viral clearance at a mean of 109 d. Graft function stabilized or improved (mean [median] creatinine concentration at diagnosis, 2.39 [2.5] mg/mL, vs 2.27 [2.0] mg/dL at follow-up). 1 graft loss due to refractory rejection. Leflunomide concentration did not correlate with treatment efficiency
Faguer et al[10], 2007	Prospective study; Jul 2002-Apr 2006	12 kidney transplant recipients with BKVAN; MMF switched to leflunomide	42% had BK clearance. 66.6% had stable or improved renal allograft function
Josephson et al[13], 2006	Prospective study; Apr 2001-Apr 2004	26 kidney transplant recipients with BKVAN; 17 received leflunomide alone; 9 received leflunomide + cidofovir	84% of cases blood and urine viral load levels uniformly decreased over time (P < 0.001). Mean serum creatinine levels stabilized over the first 6 months of treatment, and with 12 mo or more of follow-up. 16 patients had fairly unchanged serum creatinine
Fluoroquinolones
Patel et al[19], 2019	Prospective, randomized, placebo-controlled trial; Jan 2013 -Oct 2016	200 adult solitary kidney transplant recipients; 133 received ciprofloxacin as BK prophylaxis; 67 did not receive ciprofloxacin	BK viremia at 6 mo post-transplant occurred in 25 (18.8%) patients in the ciprofloxacin group and 5 (7.5%) in the placebo group (P = 0.03). Increased risk of fluoroquinolone-resistant infections in those who received ciprofloxacin
Knoll et al[18], 2014	Prospective, double-blind, placebo-controlled randomized trial; Dec 2011 -Jun 2013	154 adult kidney transplant recipients; 76 received a 3-mo course of levofloxacin; 78 received placebo	BK viruria occurred in 22 (29%) in the levofloxacin group vs 26 (33.3%) in the placebo group (HR 0.91, 95%CI: P = 0.58). Increased risk of resistant infection among isolates usually sensitive to quinolones in the levofloxacin group vs placebo (58.3% vs 33.3%, respectively); (RR 1.75; 95%CI: 1.01-2.98) as well as a nonsignificant increased risk of suspected tendinitis (7.9% vs 1.3%; RR 6.16; 95%CI: 0.76-49.95)
Lee et al[17], 2014	Prospective, multicenter, double-blinded, placebo-controlled trial; Jul 2009 -Mar 2012	43 adult kidney transplant recipients with documented BK viremia; 22 received levofloxacin for 30 d; 21 received placebo	At the 3-mo follow up, there was no significant difference in BK viral load reduction between the levofloxacin and placebo group (70.3% vs 69.1%, respectively, P = 0.93). The percentage reductions in BK viral load were also equivalent at 1 mo (58% vs 67.1%, P = 0.47), and 6 months (82.1% vs 90.5%, P = 0.38)
Wojciechowski et al[16], 2012	Retrospective study; First cohort (group 1): Jul-Dec 2009 Second cohort (group 2): Jan-Jun 2010	236 adult renal transplant recipients; Group 1: 106 did not receive BK virus prophylaxis; Group 2: 130 received ciprofloxacin as BK virus prophylaxis	At 3 mo post-transplant, the group that did not receive ciprofloxacin (group 1) had a higher risk of developing BK viremia than the group that received ciprofloxacin (group 2) (0.161 vs 0.065, P = 0.0378) and viruria (0.303 vs 0.146, P = 0.0067), but this difference progressively narrowed until there was no significant difference anymore at 12 mo for both viremia ( 0.297 vs 0.261, P = 0.6061) and viruria (0.437 vs 0.389, P = 0.5363)
Gabardi et al[15], 2010	Retrospective analysis; Jan 2004-Dec 2008	185 adult kidney transplant recipients; 25 received a 30-d course of ciprofloxacin; 160 did not receive a fluoroquinolone	Higher rate of BK viremia in those who did not receive a 1-mo course of levofloxacin 36 (22.5%) vs 1 (4%) who received levofloxacin; P = 0.03
Cidofovir
Schneidewind et al[29], 2018	Systematic review	189 adult patients with BK virus associated hemorrhagic cystitis after allogenic stem cell transplant; 172 received intravenous cidofovir; 17 patients received intravesical cidofovir (2 patients received both routes of administration)	Complete response: 68% in intravenous cidofovir group, 88.2% in intravesical cidofovir. Kidney toxicity: 9.3% in intravenous cidofovir group, none in intravesical cidofovir group
Papanicolaou et al[30], 2015	Case report	58 yr old male post hematopoietic stem cell transplant; developed biopsy-proven polyomavirus associated nephropathy; received brincidofovir 100 mg twice weekly for 6 mo; no immunosuppression reduction	4-log decrease in BK virus viremia. No drug-related adverse events. Stable kidney function, and did not require dialysis
Caruso Brown et al[28], 2015	Open-label, non-randomized, single-dose, pilot study	12 pediatric patients (ages 6-18) with a hematopoietic stem cell transplant within 2 yr, with symptomatic infection of adenovirus, nucleoside-resistant CMV, human polyomavirus (BK or JC virus), and/or nucleoside-resistant HSV diagnosed by viral culture or PCR; all patients received cidofovir	2/12 acute kidney injury after the first dose 2/12 developed nephrotoxicity. Mean drug half-life 9.5 h (longer than documented half-life for adults based on other studies). No correlation between nephrotoxicity and plasma maximum concentration, clearance, or half-life. Cidofovir was well- tolerated in majority of patients
Kuten et al[27], 2014	Single-center, retrospective review; Jan 2007 to Jun 2012	75 kidney and kidney-pancreas transplant recipients who received cidofovir combined with reduced immunosuppression	32 (43%) had short-term BK (≤ 6 mo); 43 (57%) had long-term BK. 53 (71%) eventually cleared BK at a median of 4.2 mo (interquartile range 2.1-9.3 mo). Factors associated with long-term BK: older age (OR 1.1, P = 0.02), Delayed graft function (OR 31.4, P = 0.01); higher peak BK (OR 12.8, P = 0.02. This group was associated with a 15% decline in estimated glomerular filtration rate. Factor associated with short-term BK: BK reduction by at least 1 log10copies/mL at 1 mo of treatment (OR 49.3, P < 0.01). This group maintained stable graft function and no graft loss was noted
Reisman, et al[31], 2014	Case report	pediatric patient who received kidney transplant for bilateral dysplastic kidneys, developed BKVAN; did not respond to decreased immunosuppression, ciprofloxacin, leflunomide; given brincidofovir	BK viral load decreased, but still detectable. Urine viral load declined but still elevated. Creatinine declined to baseline level and was stable for 2 yr. No drug-related adverse events
Kuypers et al[26], 2009	Single-center study	41 adult renal transplant recipients with biopsy-proven BKVIN; 26 received cidofovir at 1 mg/kg for a maximum duration of 10 wk and without probenecid; 15 did not receive cidofovir; All patients had immunosuppression reduction	Graft loss: 4/26 (15.4%) in cidofovir group, 11/15 (73.3%) in no cidofovir group (P = 0.0002). Percentage of patients who completely cleared the virus from the blood was not different between the 2 groups. 3 patients in the cidofovir group developed severe anterior uveitis at 6, 7 and 8 doses, respectively (later switched to leflunomide). No BM or renal toxicity was observed in the cidofovir group. One patient developed a skin rash during infusion of cidofovir
IVIg
Naef et al[39], 2021	Retrospective analysis; Jan 2009-Mar 2019	Kidney transplant recipients with high level BK viremia; 79 transplanted before 2014 and had immunosuppression reduction alone; 52 transplanted after 2014 and had immunosuppression reduction + IVIg	IVIg group showed lower eGFR (44 mL/min vs 52 mL/min). IVIg did not shorten duration of BK viremia
Kable et al[38], 2017	Retrospective, single-center cohort study	50 BKVAN patients received IVIg 1 g/kg	Better clearance of BK viremia and fewer graft loss (not statistically significant)
Vu et al[37], 2015	Retrospective analysis; 2008-2012	30 kidney transplant recipients with BKVAN received IVIg 2 g/kg	90% of patients showed positive response in clearing viremia. Graft survival rate was 96.7% at 12 mo follow-up
Sener et al[34], 2006	Case series; Jul 2000-Jul 2003	8 kidney transplant recipients with IVIg 2 g/kg	88% of patients showed functioning graft at 15 mo follow-up
Monoclonal antibodies
In the study	Ongoing RCT (NCT 04294472)	30 kidney transplant recipients with BK viremia; 22 received MAU868; 8 received placebo	Better BK viral clearance in MAU group
Virus-specific T-cell therapy
Pfeiffer et al[44], 2023	Open-label, phase II trial; Apr 2014-Jul 2021	27 pediatric and adult HSCT recipients with BK infection; 25 with hemorrhagic cystitis; 2 with nephritis	100% had partial response at 6 weeks of treatment. 74% of patients who developed hemorrhagic cystitis had symptom resolution. 9/24 (37.5%) had increase in IFN-γ ELISpot counts
Koldehoff et al[1], 2023	Sequential analysis	17 HSCT recipients with BK hemorrhagic cystitis; 7 received VST; 10 did not receive VST (immunosuppression reduction or cidofovir)	6/7 from the VST group vs 6/10 from the non-VST group had T-specific cellular response, in most cases parallel to decrease in BK viral load
Olson et al[43], 2021	Single-arm, phase II clinical trial; Oct 2015-Sept 2019	59 HSCT recipients with BK hemorrhagic cystitis; received single IV infusion of partially HLA-matched BKV-CTL	Response rate and clinical improvement following the off-the-shelf BK-specific cytotoxic T-cells: 67.7% at day 14; 81.6% at day 45
Nelson et al[51], 2020	Phase II study; Jun 2017-Dec 2019	38 HSCT recipients; 3 solid organ transplant recipients: 1 kidney transplant recipient; 1 heart transplant recipient; 1 heart-kidney transplant recipient	Response rates: 86% in patients with BK viremia, 100% in patients with hemorrhagic cystitis, 87% in patients with BK viremia and hemorrhagic cystitis. Of the 3 solid organ transplant recipients, 1 had complete response and 2 had partial response
Tzannou et al[42], 2017	Phase II study	16 HSCT recipients; 14 with BK hemorrhagic cystitis; 2 with BKVAN	Decrease in urine BK viral load following VST: 85.5% at week 6, 96% at week 12. 13/14 with hemorrhagic cystitis had resolution of hematuria. 1/2 with BKVAN had improved renal function
Jahan et al[50], 2020	Case report; Sept 2018	1 kidney transplant recipient with BKVAN who failed other treatments	BK viral load decreased significantly following T-cell therapy, but allograft eventually failed due to interstitial fibrosis and tubular atrophy

BKVAN: BK virus-associated nephropathy; BKVIN: BK virus interstitial nephritis; CMV: Cytomegalovirus; eGFR: Estimated glomerular filtration rate; FK: Tacrolimus; GFR: Glomerular filtration rate; HLA: Human leukocyte antigen; HSCT: Hematopoietic stem cell transplant; IVIg: Intravenous immunoglobulin; MMF: Mycophenolate mofetil; MPA: Mycophenolic acid; mTOR: Mechanistic target of rapamycin; PCR: Polymerase chain reaction; RCT: Randomized controlled trial; VST: Virus-specific T-cell therapy.