Cytomegalovirus DNAemia Requiring (Val)Ganciclovir Treatment for More Than 8 Weeks Is a Key Factor in the Development of Antiviral Drug Resistance

Abstract

Background Prolonged (val)ganciclovir [(V)GCV] exposure for ≥ 6 weeks is a known predisposing factor for cytomegalovirus (CMV) drug resistance. However, the selection of this threshold was based on limited data. Here, we sought to reappraise the risk factors for the development of (V)GCV resistance through a specific focus on kidney transplant recipients (KTRs). Methods This single-center retrospective study included 313 consecutive KTRs treated for a first CMV episode. Adjusted Cox multivariate regression analysis was used for identifying independent risk factors. Results Antiviral drug resistance was identified in 20 (6%) KTRs. A cumulative (V)GCV exposure for more than 6 weeks (regardless of the viral load) was not associated with antiviral drug resistance (hazard ratio [HR] = 2.45, 95% confidence interval [CI] = 0.33−18.30, p = 0.38). On the opposite, persistent CMV DNAemia requiring (V)GCV treatment for more than 8 weeks was the main independent risk factor for antiviral drug resistance (HR = 11.68, 95% CI = 2.62−52.01, p = 0.001). (V)GCV treatment for more than 8 weeks was given to 9% and 18% of patients who had persistent or recurrent CMV DNAemia, respectively. These scenarios were associated with the occurrence of drug resistance in 39% and 12% of cases, respectively. Conclusions Cumulative (V)GCV exposure ≥ 6 weeks regardless of the viral load is not associated with antiviral drug resistance. On the opposite, prolonged exposure to (V)GCV during CMV replication (with a cutoff ³ 8 weeks) appears to be a key factor.

Factors Associated With Genotypic Resistance and Outcome Among Solid Organ Transplant Recipients With Refractory Cytomegalovirus Infection

“…We found that both being on VGCV prophylaxis at infection onset and the exposure to low levels of VGCV were associated with CMV resistance: patients presenting refractory infection in this particular setting should be considered as more at risk of genotypically resistant infection. We also found significantly more patients with a history of VGCV prophylaxis in the R group: pre-emptive strategy could reduce resistance development through reduced GCV exposure [ 5 , 6 , 11 ], but CMV prophylaxis strategy did not result significative in multivariate analysis accordingly with the recent findings of Acquier et al [ 29 ] in a cohort of kidney transplant recipients. It has been known for a few years that VGCV exposure per se is not a risk factor for infection but that a longer exposure is associated with resistance development [ 29 , 30 ].…”

“…We also found significantly more patients with a history of VGCV prophylaxis in the R group: pre-emptive strategy could reduce resistance development through reduced GCV exposure [ 5 , 6 , 11 ], but CMV prophylaxis strategy did not result significative in multivariate analysis accordingly with the recent findings of Acquier et al [ 29 ] in a cohort of kidney transplant recipients. It has been known for a few years that VGCV exposure per se is not a risk factor for infection but that a longer exposure is associated with resistance development [ 29 , 30 ]. The threshold of exposure is usually recognized as 6 weeks [ 1 ] but a recent study found a threshold of 8 weeks of treatment with active replication as a risk factor [ 29 ] rather than prophylaxis itself or the cumulated time on prophylaxis and curative treatment Finally, the potential effect of VGCV exposure on resistance development should be balanced with the effects of more episodes of CMV replication in patients with pre-emptive strategies (immune exhaustion and opportunistic infections for instance).…”

“…It has been known for a few years that VGCV exposure per se is not a risk factor for infection but that a longer exposure is associated with resistance development [ 29 , 30 ]. The threshold of exposure is usually recognized as 6 weeks [ 1 ] but a recent study found a threshold of 8 weeks of treatment with active replication as a risk factor [ 29 ] rather than prophylaxis itself or the cumulated time on prophylaxis and curative treatment Finally, the potential effect of VGCV exposure on resistance development should be balanced with the effects of more episodes of CMV replication in patients with pre-emptive strategies (immune exhaustion and opportunistic infections for instance).…”

Cytomegalovirus Disease as a Risk Factor for Invasive Fungal Infections in Liver Transplant Recipients under Targeted Antiviral and Antimycotic Prophylaxis

“…To assess the dose–response relationship, CMV viral load was divided into three categories: (1) 125–500 IU/mL, (2) 501–1000 IU/mL, and (3) more than 1000 IU/mL. The lowest threshold of 125 IU/mL arises from the lower limit of quantification of the assay used; the upper threshold of 1000 IU/mL was chosen based on the earlier cut-off for pre-emptive therapy initiation [ 26 , 27 ]. The pre-emptive antiviral therapy was applied once DNAemia exceeded 125 IU/mL and was continued until CMV DNA was undetectable in two consecutive samples taken within two weeks.…”

Human Cytomegalovirus (HCMV) Genetic Diversity, Drug Resistance Testing and Prevalence of the Resistance Mutations: A Literature Review

“…CDV is a cytidine monophosphate analogue and a competitive inhibitor of the viral DNA polymerase that undergoes phosphorylation using cell kinase so that the resistance mutations can be detected in the UL54 gene. It is also reserved for second-line treatments due to its considerable toxicity [ 27 , 28 ].…”