Abstract
BACKGROUND: 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. METHODS: 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/mm(3)) 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. RESULTS: 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. CONCLUSION: NUDT15 variants increase the risk of early neutropenia during VGCV prophylaxis in lung transplant recipients.