Treatment of Renal Allograft Polyoma BK Virus Infection with Leflunomide

Josephson, Michelle A.; Gillen, Daniel L.; Javaid, Basit; Kadambi, Pradeep V.; Meehan, Shane A; Foster, Patricia L.; Harland, Robert C.; Thistlethwaite, Richard; Garfinkel, Marc R.; Atwood, Walter J.; Jordan, Joslynn A.; Sadhu, Molly; Millis, Michael; Williams, James W.

doi:10.1097/01.tp.0000181149.76113.50

Cited by 211 publications

(164 citation statements)

References 49 publications

Supporting

Mentioning

150

Contrasting

Unclassified

Order By: Relevance

“…There are also reports of efficacy studies in animal models with banzi virus, influenza B virus, and vaccinia virus (36) that showed either a lack of or very limited efficacy. Clinical trials in humans were also reported for HIV, CMV, and BK virus (38,(40)(41)(42)(43), with no conclusive results. It is reported that mean levels of circulating uridine in man are approximately 6 μM (44), spanning a range between 2.6 μM (45) and 21 μM (46).…”

Section: Discussionmentioning

confidence: 99%

Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV)

Bonavia¹,

Franti²,

Keaney³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The search for novel therapeutic interventions for viral disease is a challenging pursuit, hallmarked by the paucity of antiviral agents currently prescribed. Targeting of viral proteins has the inextricable challenge of rise of resistance. Safe and effective vaccines are not possible for many viral pathogens. New approaches are required to address the unmet medical need in this area. We undertook a cell-based high-throughput screen to identify leads for development of drugs to treat respiratory syncytial virus (RSV), a serious pediatric pathogen. We identified compounds that are potent (nanomolar) inhibitors of RSV in vitro in HEp-2 cells and in primary human bronchial epithelial cells and were shown to act postentry. Interestingly, two scaffolds exhibited broad-spectrum activity among multiple RNA viruses. Using the chemical matter as a probe, we identified the targets and identified a common cellular pathway: the de novo pyrimidine biosynthesis pathway. Both targets were validated in vitro and showed no significant cell cytotoxicity except for activity against proliferative B- and T-type lymphoid cells. Corollary to this finding was to understand the consequences of inhibition of the target to the host. An in vivo assessment for antiviral efficacy failed to demonstrate reduced viral load, but revealed microscopic changes and a trend toward reduced pyrimidine pools and findings in histopathology. We present here a discovery program that includes screen, target identification, validation, and druggability that can be broadly applied to identify and interrogate other host factors for antiviral effect starting from chemical matter of unknown target/mechanism of action.

show abstract

Section: Discussionmentioning

confidence: 99%

Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV)

Bonavia¹,

Franti²,

Keaney³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…In the largest trial using leflunomide therapy in 26 patients with BKVAN (14), leflunomide was initiated concurrent with MMF discontinuation and CNI reduction at the time of diagnosis. In the largest cidofovir intervention trial to date in 21 patients (12), the authors note that MMF may have been more systematically withdrawn in those who received cidofo- Neither intravenous Ig nor cidofovir was independently associated with graft survival (24).…”

Section: Discussionmentioning

confidence: 99%

Aggressive Immunosuppression Minimization Reduces Graft Loss Following Diagnosis of BK Virus-Associated Nephropathy

Weiss¹,

Gralla²,

Chan³

et al. 2008

Clinical Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Results: Of 910 kidney transplants, 35 (3.8%) cases of BKVAN were diagnosed at a median of 15 months after transplant (range, 5.5 to 90 months after transplant), 16 (46%) of which progressed to graft failure at a median of 11 months (range, 2 to 36 months) after diagnosis. Depleting antibody induction was a significant risk factor for graft loss on univariate analysis, whereas early drug withdrawal (<1 mo following diagnosis) protected against graft loss. On multivariate analysis, these findings were independent predictors of graft outcomes. Additionally, when patients were comanaged by referring nephrologists and the transplant center before the diagnosis of BKVAN, the risk of graft loss was 11-fold higher (P ‫؍‬ 0.03) than if patients were managed solely by the transplant center.Conclusions: Increased awareness and early diagnosis of BKVAN, with aggressive tapering of immunosuppression once established, is critical to preserve kidney graft function. Early drug withdrawal to low-dose two-drug therapy maintenance may be preferable to a general reduction of agents.

show abstract

“…Leflunomide has anti-viral properties against BK virus and is an attractive option for treatment of BKVN since it has minimal nephrotoxicity. It has been used successfully in adult and pediatric transplant recipients in combination with immunosuppression reduction [3,13]. Fluoroquinolones inhibits polyoma virus replication in vitro and has been shown to decrease BK viral load.…”

Section: Discussionmentioning

confidence: 99%

Intravenous Immunoglobulin in BK Virus Nephropathy

Anyaegbu¹,

Hmiel²

2014

TOUNJ

View full text Add to dashboard Cite

Abstract:The incidence of post transplant viral infections has increased with the use of more potent immunosuppressive regimens. Consequently, BK virus nephropathy (BKVN) has arisen as a significant cause of graft dysfunction and loss. Reduction of immunosuppression is the first line management of post-transplant viral infections. Other therapies such as intravenous immunoglobulin (IVIg), cidofovir, leflunomide and fluoroquinolones have been tried with varying degrees of success.We report our experience with IVIg in three pediatric renal transplant recipients who presented with allograft dysfunction. First, we describe two cases of biopsy proven BKVN, one diagnosed with undetectable viral titers in plasma, demonstrating that BKVN can occur even at low viral loads. We also present a pediatric renal transplant recipient with persistent BK viremia and allograft dysfunction who responded to therapy with recovery of renal function and clearance of viremia. Therefore we conclude that IVIg is efficacious in the treatment of persistent BK viremia and BKVN. The appropriate dose, frequency and duration of therapy require further study.

show abstract

Treatment of Renal Allograft Polyoma BK Virus Infection with Leflunomide

Abstract: Leflunomide inhibits Polyoma virus replication in vitro and closely monitored leflunomide therapy with specifically targeted blood levels appears to be a safe and effective treatment for Polyoma BK nephropathy.

Cited by 211 publications

References 49 publications

Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV)

Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV)

Aggressive Immunosuppression Minimization Reduces Graft Loss Following Diagnosis of BK Virus-Associated Nephropathy

Intravenous Immunoglobulin in BK Virus Nephropathy

Contact Info

Product

Resources

About