Onset of valganciclovir resistance in two infants with congenital cytomegalovirus infection

Abstract

Ganciclovir and its prodrug valganciclovir are elective treatments for cCMV. Neonates with important symptoms undergo 6 months of therapy to ameliorate/prevent symptoms and late sequelae, but evidence of resistance is emerging. Over the last 5 years, we took care of 59 cCMV infants and experienced two cases of resistance among nine cCMV infants receiving long-term valganciclovir therapy. In the first case, valganciclovir therapy was prolonged beyond 6 months due to severity of symptoms, control of viral load, and absence of adverse events. Resistance was detected in the 8th month of therapy. In the second case, after a significant reduction following valganciclovir administration and no adverse events, CMV viral load suddenly increased in the 6th month of therapy due to resistance. Both events were associated with UL97 gene mutation. The cCMV infants, affected by severe symptoms, remained in a steady state during treatment, and their later neurological development was coherent with initial seriousness of diagnosis. Prolonged therapeutic exposure may therefore be a risk for resistance, suggesting that constant dosage/ weight adjustments, monthly surveillance of viral load, and therapeutic drug monitoring could be proposed to monitor resistance onset and optimize the therapy regime. The risk-benefit ratio for longterm therapy, including the possibility of resistance onset, alongside SNHL and neurodevelopmental improvement, should also be evaluated.

The Effect of (Val)ganciclovir on Hearing in Congenital Cytomegalovirus: A Systematic Review

“…In contrast with short‐term, long‐term side effects are poorly known and may cause concern. Animal models showed impaired fertility and carcinogenic toxicity but similar findings have not been found in humans 5,37,39–44 . Today, it is generally only recommended to treat children with moderately to severely symptomatic cCMV because their symptom severity exceeds the risk for side effects 10 .…”

Detection of antiviral drug resistance in patients with congenital cytomegalovirus infection using long-read sequencing: a retrospective observational study

“…A treatment period longer than 3 months appears to be a risk factor for antiviral drug resistance [ 30 ] in immunocompromised patients. Recently, antiviral drug resistance has been reported in patients with cCMV infection [ 8 , 31 – 35 ]. It was observed that GCV resistance emerged after 3 months in patients with cCMV infection [ 8 ].…”

“…Recently, antiviral drug resistance has been reported in patients with cCMV infection [ 8 , 31 – 35 ]. It was observed that GCV resistance emerged after 3 months in patients with cCMV infection [ 8 ]. A 6-month GCV/VGCV treatment is the recommendation for cCMV therapy [ 6 ]; therefore, careful CMV blood load monitoring is needed.…”

“…CMV antiviral drug resistance has been primarily reported in patients with immunosuppression, such as transplant recipients or those with AIDS [ 7 ]. Recently, antiviral drug resistance has also been reported in several cases of cCMV receiving GCV/VGCV treatment [ 8 ]. Mutations in the viral thymidine kinase gene ( UL97 ) and the DNA polymerase gene ( UL54 ) confer resistance to GCV/VGCV [ 9 ].…”

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“…The aim is to prevent the onset of deafness or to prevent it from getting worse, in cases where it is already present. Although this is the recommended therapy, cases of resistance to treatment (approximately 4%) are also reported [6,21]. Studies to determine the effectiveness of valganciclovir in infected but asymptomatic or isolated deaf newborns are ongoing (NCT03301415, NCT03107871, NCT01649869) [22,23,24], and a study evaluating the pharmacokinetics of letermovir in the treatment program is scheduled for 2022 [1,6].…”