NUDT15 Genetic Polymorphism as a Risk Factor for Early Neutropenia During Valganciclovir Prophylaxis in Lung...

Valganciclovir (VGCV) prophylaxis effectively prevents cytomegalovirus infection in lung transplant patients. However, VGCV-induced neutropenia causes early cessation. Nucleoside diphosphate-linked moiety X-type motif (NUDT) 15 degrades the ganciclovir (GCV) triphosphate, an active metabolite. We assessed the effects of NUDT15 variants on neutropenia and VGCV cessation in recipients of lung transplants.

We recruited 28 patients who had received lung transplants and VGCV prophylaxis and genotyped NUDT15 exons 1-3 using Sanger sequencing. Neutrophil counts were monitored from 1 month to 1 year in the wild-type and NUDT15 reduced-function variant groups. Cumulative incidences of neutropenia (< 1500/mm³) and neutropenia-related cessation within 1 year, including late-onset neutropenia, were assessed using Kaplan-Meier analysis. A subgroup analysis was conducted focusing on patients with stable renal function, the primary route of excretion for GCV.

Of the 28 patients, nine carried NUDT15 variants (Arg139Cys, Val18Ile, Val18_Val19insGlyVal, Arg139Cys/Val18Ile). The neutrophil count nadir within 1 month of treatment was lower in the NUDT15-variant group than in the wild-type group. A higher incidence of neutropenia and VGCV cessation was observed in the NUDT15-variant group, but without statistical significance. Among 13 patients with stable renal function, all four in the NUDT15-variant group developed neutropenia and cessation within 60 days, compared with two of nine in the wild-type group. Covariance analysis showed that NUDT15 variants were associated with decreased neutrophil counts, independent of GCV trough concentration.

NUDT15 variants increase the risk of early neutropenia during VGCV prophylaxis in lung transplant recipients.