Novelties for the management of cytomegalovirus after kidney transplantation / Nouveautés dans la prise en charge du cytomégalovirus après transplantation rénale.

Cytomegalovirus (CMV) infection is the main opportunistic infection observed after kidney transplantation. Despite the use of prevention strategies, CMV disease still occurs, especially in high-risk patients (donor seropositive/recipient seronegative). Patients may develop complicated CMV, i.e. recurrent, refractory or resistant CMV infection. CMV prevention relies on either universal prophylaxis or preemptive therapy. In high-risk patients, universal prophylaxis is usually preferred. Currently, valganciclovir is used in this setting. However, valganciclovir can be responsible for severe leucopenia and neutropenia. A novel anti-viral drug, letermovir, has been recently compared to valganciclovir. It was as efficient as valganciclovir to prevent CMV disease and induced less hematological side-effects. It is still not available in France in this indication. Recent studies suggest that immune monitoring by ELISPOT or Quantiferon can be useful to determine the duration of prophylaxis. Other studies suggest that prophylaxis may be skipped in CMV-seropositive kidney-transplant patients given mTOR inhibitors. Refractory CMV is defined by the lack of decrease of CMV DNAemia of at least 1 log10 at 2 weeks after effective treatment. In case of refractory CMV infection, drug resistant mutations should be looked for. Currently, maribavir is the gold standard therapy for refractory/resistant CMV. At 8 weeks therapy and 8 weeks later, it has been shown to be significantly more effective than other anti-viral drugs, i.e. high dose of ganciclovir, foscarnet or cidofovir. However, a high rate of relapse was observed after ceasing therapy. Hence, other therapeutic strategies should be evaluated in order to improve the sustained virological rate.

L'infection à cytomégalovirus (CMV) est la principale infection opportuniste après transplantation rénale. Malgré les stratégies préventives, il persiste des maladies à CMV, notamment chez les patients à haut risque (donneur séropositif/receveur séronégatif). Certains patients présentent des formes complexes avec des récurrences et des infections réfractaires et/ou résistantes aux antiviraux. La prévention de l'infection à CMV repose soit sur une prophylaxie universelle, soit sur une stratégie préemptive. Chez les patients à haut risque, la stratégie prophylactique est le plus souvent utilisée. Elle repose sur l'utilisation du valganciclovir, qui peut être responsable de leucopénies et de neutropénies sévères. Un nouvel antiviral, le létermovir, qui n'est pas encore disponible sur le marché en France dans cette indication, a montré une efficacité similaire au valganciclovir avec peu d'effets secondaires hématologiques. Des études récentes suggèrent l'intérêt de l'immuno-surveillance par ELISPOT ou Quantiféron pour guider la durée de la prophylaxie. D'autres études suggèrent également la possibilité de se passer d'un traitement prophylactique anti-CMV chez des transplantés rénaux CMV-séropositifs recevant des inhibiteurs de la mTOR. Le CMV réfractaire est défini par une absence de baisse de la charge virale d'au moins 1 log10 après deux semaines de traitement efficace. En cas d'absence de baisse de la charge virale, une recherche de mutations de résistance aux antiviraux doit être effectuée. Actuellement, le maribavir constitue le traitement de référence pour les formes réfractaires et résistantes. La clairance virale à la fin du traitement, ou huit semaines plus tard, est significativement supérieure à celle observée avec les autres antiviraux tels que le ganciclovir donné à forte dose, le foscarnet, ou le cidofovir. Cependant, le taux de rechute à l'arrêt du traitement par maribavir reste important. D'autres stratégies thérapeutiques doivent être évaluées pour améliorer ce taux de réponse virologique soutenue.

Assessment of Dried Serum Spots (DSS) and Volumetric-Absorptive Microsampling (VAMS) Techniques in Therapeutic Drug Monitoring of (Val)Ganciclovir-Comparative Study in Analytical and Clinical Practice.

Ganciclovir (GCV) and its prodrug valganciclovir (VGCV) are antiviral medications primarily used to treat infections caused by cytomegalovirus (CMV), particularly in immunocompromised individuals such as solid organ transplant (SOT) recipients. Therapy with GCV is associated with significant side effects, including bone marrow suppression. Therefore, therapeutic drug monitoring (TDM) is mandatory for an appropriate balance between subtherapeutic and toxic drug levels. This study aimed to develop and validate three novel methods based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) for GCV determination in serum (reference methodology), dried serum spots (DSS), and VAMS-Mitra™ devices. The methods were optimized and validated in the 0.1-25 mg/L calibration range. The obtained results fulfilled the EMA acceptance criteria for bioanalytical method validation. Assessment of DSS and VAMS techniques extended GCV stability to serum for up to a minimum of 49 days (at room temperature, with desiccant). Developed methods were effectively evaluated using 80 clinical serum samples from pediatric renal transplant recipients. Obtained samples were used for DSS, and dried serum VAMS samples were manually generated in the laboratory. The results of GCV determination using serum-, DSS- and VAMS-LC-MS/MS methods were compared using regression analysis and bias evaluation. The conducted statistical analysis confirmed the interchangeability between developed assays. The DSS and VAMS samples are more accessible and stable during storage, transport and shipment than classic serum samples.

CMV neuroretinitis in an immunocompetent patient: a unique case report.

Aim: To report a case of cytomegalovirus (CMV) neuroretinitis observed in an immunocompetent patient. Materials and methods: The patient presented with a complaint of diminution of vision in both eyes (BE) and had a traumatic cataract in the right eye (RE). Fundus examination of the left eye (LE) revealed an active white, fluffy lesion with an overlying retinal hemorrhage patch with a macular star. The diagnosis of CMV neuroretinitis was established, and the patient commenced treatment with valganciclovir. Results: The patient exhibited no underlying risk factors. Subsequently, a positive response to oral valganciclovir treatment was observed. Discussion: Cytomegalovirus (CMV) neuroretinitis is typically associated with immunocompromised individuals, such as those with HIV/AIDS. The patient's presentation with a traumatic cataract in the right eye and a distinctive fundus appearance in the left eye posed a diagnostic challenge. The absence of common risk factors for CMV infection necessitated a thorough examination and consideration of rare infectious etiologies. The positive response to valganciclovir reinforces its efficacy in managing CMV-related ocular conditions. This case emphasized the necessity for ophthalmologists to maintain a high index of suspicion for CMV and other unusual pathogens when faced with neuroretinitis in patients who do not present with typical systemic immunosuppressive conditions. Early diagnosis and appropriate antiviral therapy prevent potential complications and preserve vision in such atypical presentations. Conclusion: This case underscores the importance of considering rare infectious agents in immunocompetent patients when encountering neuroretinitis, particularly in the absence of typical symptoms or signs of the disease. Abbreviations: CMV = Cytomegalovirus, BE = Both eyes, RE = Right eye, LE = Left eye, CBC = Complete Blood Count, ESR = Erythrocyte Sedimentation Rate, VDRL = Venereal Disease Research Laboratory, FTA-ABS = Fluorescent Treponemal Antibody Absorption, PPD = Purified Protein Derivative, ANA = Anti-Nuclear Antibodies, RF = Rheumatoid Factor, ACE = Anti Converting Enzyme, Ig G = Immunoglobulin G, HSV = Herpes simplex virus.

Cytomegalovirus reactivation is frequent in multiple myeloma patients treated with daratumumab-based regimens.

BACKGROUND: Viral reactivations are frequent in hematologial patients due to their cancer-related and drug-induced immunosuppressive status. Daratumumab, an anti-CD38 monoclonal antibody, is used for multiple myeloma (MM) treatment, and causes immunosuppression by targeting CD38-expressing normal lymphocytes. In this single-center two-arm real-life experience, we evaluated incidence of cytomegalovirus (CMV) reactivation in MM patients treated with daratumumab-based regimens as first- or second-line therapy. METHODS: A total of 101 consecutive MM patients were included in this study and were divided into two cohorts: daratumumab and nondaratumumab-based (control) regimens. Patients treated with >2 lines of therapies were excluded to reduce the confounding factor of multi-treated cases. Primary endpoint was the CMV reactivation rate. RESULTS: CMV reactivation rate was significantly higher in the daratumumab cohort compared to control group (33% vs. 4%; p < 0.001), also with higher CMV-DNA levels (>1000 UI/mL in 12% of cases; p < 0.05). However, only one subject developed a CMV disease with severe pneumonia, while 12% of patients were successfully treated with preemptive therapy with valganciclovir. No subjects in the control cohort required anti-CMV agents (p = 0.02). CONCLUSION: Our single-center retrospective experience showed that daratumumab might significantly increase the risk of CMV reactivation in MM, while currently underestimated and related to morbility and mortality in MM patients under treatments. However, further validation on larger and prospective clinical trials are required.

Treatment outcomes in cytomegalovirus anterior uveitis.

This retrospective cohort study investigated patients with cytomegalovirus anterior uveitis (CMV AU) and compared treatment outcomes between regional and systemic antiviral therapies. Treatment modalities included topical (2% ganciclovir [GCV] eye drops or 0.2% GCV eye gel) and systemic (intravenous GCV or oral valganciclovir) groups. The comparison parameters included response rates, time to response, recurrence rates, time to recurrence, and complications. Forty-four patients (54.5% male) with a mean age of 56 ± 9.87 years were enrolled, with 31 eyes in the topical group and 13 eyes in the systemic group. The median response time was significantly slower in the topical group (63 days [IQR 28-112]) compared to the systemic group (28 days [IQR 24-59]) (p = 0.04). Treatment response rates were 87.1% (27/31) in the topical group and 100% (13/13) in the systemic group (p = 0.30), while recurrence rates were 37% (10/27) and 69.2% (9/13) (p = 0.056), with a median time to recurrence of 483 days [IQR 145-1388] and 392 days [IQR 203.5-1907.5] (p = 0.20), respectively. In conclusion, both topical and systemic GCV treatments demonstrated favorable outcomes for CMV AU. Systemic GCV showed rapid control of intraocular inflammation.

"Minimally symptomatic" congenital cytomegalovirus infection: latest data and emerging concepts.

PURPOSE OF REVIEW: Universal and targeted screening of newborns for congenital cytomegalovirus (CMV) infection is increasing globally. Questions remain concerning the management of infants who have been identified with congenital CMV infection, especially those with "minimally symptomatic" or clinically inapparent infection. Our objective is to discuss current management of CMV-infected neonates with a focus on less affected infants with or without sensorineural hearing loss (SNHL). RECENT FINDINGS: Valganciclovir is being prescribed increasingly in neonates with congenital CMV infection for improvement in hearing outcomes through 2 years of age. Treatment initiated in the first month of age is recommended for clinically apparent disease. A recent study showed hearing improvement at 18-22 months of age when therapy was initiated at age 1-3 months in infants with clinically inapparent CMV infection and isolated SNHL. SUMMARY: Antiviral therapy with either ganciclovir or valganciclovir has shown moderate benefit in prevention of hearing deterioration among infants with clinically apparent CMV infection or isolated SNHL. Sustainability of benefit beyond 2 years of age remains unknown. At present, infants with clinically inapparent CMV infection (normal complete evaluation including hearing) should not receive antiviral therapy. All CMV-infected infants require close audiological and neurodevelopmental follow-up.

Predictors of Cytomegalovirus Recurrence Following Cessation of Posttransplant Prophylaxis.

INTRODUCTION: Cytomegalovirus (CMV) infection is associated with a poor prognosis after lung transplantation, and donor and recipient CMV serostatus is a risk factor for reactivation. CMV prophylaxis is commonly administered in the first year following transplantation to reduce CMV infection; however, the risk factors for long-term reactivation remain unclear. We investigated the timing and risk factors of CMV infection after prophylactic administration. METHODS: This study was a retrospective review of the institutional lung transplantation database from June 2014 to June 2022. Data on patient characteristics, pretransplantation laboratory values, postoperative outcomes, and CMV infection were collected. Donor CMV-IgG-positive and recipient CMV-IgG-negative groups were defined as the CMV mismatch group. RESULTS: During the study period, 257 patients underwent lung transplantation and received a prophylactic dose of valganciclovir hydrochloride for up to 1 y. CMV infection was detected in 69 patients (26.8%): 40 of 203 (19.7%) in the non-CMV mismatch group and 29 of 54 (53.7%) in the CMV mismatch group (P < 0.001). CMV infection after prophylaxis occurred at a median of 425 and 455 d in the CMV mismatch and non-CMV mismatch groups, respectively (P = 0.07). Multivariate logistic regression analysis revealed that preoperative albumin level (odds ratio [OR] = 0.39, P = 0.04), CMV mismatch (OR = 15.7, P < 0.001), and donor age (OR = 1.05, P = 0.009) were significantly associated with CMV infection. CONCLUSIONS: CMV mismatch may have increased the risk of CMV infection after lung transplantation, which decreased after prophylaxis. In addition to CMV mismatch, low preoperative albumin level and donor age were independent predictors of CMV infection.

Evaluating the efficacy and safety of letermovir compared to valganciclovir for the prevention of human cytomegalovirus disease in adult lung transplant recipients.

BACKGROUND: Lung transplant recipients are at high risk for severe cytomegalovirus (CMV) disease. Off-label use of letermovir (LET) may avert myelotoxicity associated with valganciclovir (VGCV), but data in lung transplantation are limited. This study aims to evaluate the outcomes of LET prophylaxis among lung transplant recipients. METHODS: This retrospective, matched cohort study included lung transplant recipients who received LET for primary CMV prophylaxis following VGCV intolerance. Patients were matched 1:1 to historical VGCV controls based on age, serostatus group, and time from transplant. The primary outcome was CMV breakthrough within 1 year post-LET initiation; secondary outcomes included hematologic changes. RESULTS: A total of 124 lung transplant recipients were included per group (32% CMV mismatch, D+R-), with LET initiated a median of 9.6 months post-transplantation. One CMV breakthrough event (0.8%) was observed in the LET group versus four (3.2%) in the VGCV group (p = .370). The median (interquartile range) white blood cell (WBC) count was 3.1 (2.1-5.6) at LET initiation which increased to 5.1 (3.9-7.2) at the end of follow-up (p <.001). For VGCV controls, WBC was 4.8 (3.4-7.2) at baseline and 5.4 (3.6-7.2) at the end of follow-up; this difference was not statistically significant (p = .395). Additionally, 98.4% of LET patients experienced ≥1 leukopenia episode in the year prior to LET compared to 71.8% the year after initiation (p <.001). Similar results were observed for neutropenia (48.4% and 17.7%, p <.001). CONCLUSION: LET prophylaxis was associated with a low rate of CMV reactivation and leukopenia recovery. LET may represent a reasonable prophylaxis option for lung transplant recipients unable to tolerate VGCV.

Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients.

BACKGROUND: The risk of cytomegalovirus (CMV) infection in solid organ transplant recipients has resulted in the frequent use of prophylaxis to prevent the clinical syndrome associated with CMV infection. This is an update of a review first published in 2005 and updated in 2008 and 2013. OBJECTIVES: To determine the benefits and harms of antiviral medications to prevent CMV disease and all-cause death in solid organ transplant recipients. SEARCH METHODS: We contacted the information specialist and searched the Cochrane Kidney and Transplant Register of Studies up to 5 February 2024 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing antiviral medications with placebo or no treatment, comparing different antiviral medications or different regimens of the same antiviral medications for CMV prophylaxis in recipients of any solid organ transplant. Studies examining pre-emptive therapy for CMV infection are studied in a separate review and were excluded from this review. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study eligibility, risk of bias and extracted data. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: This 2024 update found four new studies, bringing the total number of included studies to 41 (5054 participants). The risk of bias was high or unclear across most studies, with a low risk of bias for sequence generation (12), allocation concealment (12), blinding (11) and selective outcome reporting (9) in fewer studies. There is high-certainty evidence that prophylaxis with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment is more effective in preventing CMV disease (19 studies: RR 0.42, 95% CI 0.34 to 0.52), all-cause death (17 studies: RR 0.63, 95% CI 0.43 to 0.92), and CMV infection (17 studies: RR 0.61, 95% CI 0.48 to 0.77). There is moderate-certainty evidence that prophylaxis probably reduces death from CMV disease (7 studies: RR 0.26, 95% CI 0.08 to 0.78). Prophylaxis reduces the risk of herpes simplex and herpes zoster disease, bacterial and protozoal infections but probably makes little to no difference to fungal infection, acute rejection or graft loss. No apparent differences in adverse events with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment were found. There is high certainty evidence that ganciclovir, when compared with aciclovir, is more effective in preventing CMV disease (7 studies: RR 0.37, 95% CI 0.23 to 0.60). There may be little to no difference in any outcome between valganciclovir and IV ganciclovir compared with oral ganciclovir (low certainty evidence). The efficacy and adverse effects of valganciclovir or ganciclovir were probably no different to valaciclovir in three studies (moderate certainty evidence). There is moderate certainty evidence that extended duration prophylaxis probably reduces the risk of CMV disease compared with three months of therapy (2 studies: RR 0.20, 95% CI 0.12 to 0.35), with probably little to no difference in rates of adverse events. Low certainty evidence suggests that 450 mg/day valganciclovir compared with 900 mg/day valganciclovir results in little to no difference in all-cause death, CMV infection, acute rejection, and graft loss (no information on adverse events). Maribavir may increase CMV infection compared with ganciclovir (1 study: RR 1.34, 95% CI: 1.10 to 1.65; moderate certainty evidence); however, little to no difference between the two treatments were found for CMV disease, all-cause death, acute rejection, and adverse events at six months (low certainty evidence). AUTHORS' CONCLUSIONS: Prophylaxis with antiviral medications reduces CMV disease and CMV-associated death, compared with placebo or no treatment, in solid organ transplant recipients. These data support the continued routine use of antiviral prophylaxis in CMV-positive recipients and CMV-negative recipients of CMV-positive organ transplants.

Pitfalls in Valganciclovir Prophylaxis Dose Adjustment Based on Renal Function in Kidney Transplant Recipients.

Valganciclovir (VGC) is administered as prophylaxis to kidney transplant recipients (KTR) CMV donor (D)+/recipient (R)- and CMV R+ after thymoglobulin-induction (R+/TG). Although VGC dose adjustments based on renal function are recommended, there is paucity of real-life data on VGC dosing and associations with clinical outcomes. This is a retrospective Swiss Transplant Cohort Study-embedded observational study, including all adult D+/R- and R+/TG KTR between 2010 and 2020, who received prophylaxis with VGC. The primary objective was to describe the proportion of inappropriately (under- or over-) dosed VGC week-entries. Secondary objectives included breakthrough clinically significant CMV infection (csCMVi) and potential associations between breakthrough-csCMVi and cytopenias with VGC dosing. Among 178 KTR, 131 (73.6%) patients had ≥2 week-entries for the longitudinal data of interest and were included in the outcome analysis, with 1,032 VGC dose week-entries. Overall, 460/1,032 (44.6%) were appropriately dosed, while 234/1,032 (22.7%) and 338/1,032 (32.8%) were under- and over-dosed, respectively. Nineteen (14.5%) patients had a breakthrough-csCMVi, without any associations identified with VCG dosing (p = 0.44). Unlike other cytopenias, a significant association between VGC overdosing and lymphopenia (OR 5.27, 95% CI 1.71-16.22, p = 0.004) was shown. VGC prophylaxis in KTR is frequently inappropriately dosed, albeit without meaningful clinical associations, neither in terms of efficacy nor safety.

Tailoring cytomegalovirus prophylaxis based on T cell immunity panel assessment in kidney transplant patients at high risk of cytomegalovirus.

BACKGROUND: Valganciclovir prophylaxis against cytomegalovirus (CMV) is recommended for solid organ transplant recipients, but is associated with drawbacks, including expense and leukopenia. Our center adopted a strategy of serial assessment with a CMV-specific T cell immunity panel (CMV-TCIP) and cessation of valganciclovir prophylaxis upon demonstration of adequate CD4+ responses in kidney transplant patients at high risk of CMV disease. METHODS: We retrospectively reviewed adult recipients of a kidney or pancreas transplant between August 2019 and July 2021 undergoing serial CMV-TCIP monitoring. Included patients were considered high risk for CMV, defined by donor positive (D+)/recipient negative (R-) CMV IgG serostatus, or recipient positive (R+) patients who received induction with a lymphocyte-depleting agent. Prophylaxis was discontinued after a patient's first CMV-specific CD4+ T cell value of ≥0.20%. Risk of clinically significant CMV infection (csCMVi) in those who underwent early discontinuation of CMV prophylaxis and predictors of CMV T cell immunity were analyzed. RESULTS: Of 54 included patients, 22 stopped prophylaxis early due to CMV-specific CD4+ T cell immunity at a median of 4.7 (IQR: 3.8-5.4) months after transplant. No instances of csCMVi were observed in the 22 patients who had prophylaxis discontinued early, of whom 19/22 were CMV R+ and 3/22 were CMV D+/R-. Donor/recipient CMV serostatus was predictive of immunity (p <.001). CONCLUSION: Early discontinuation of valganciclovir prophylaxis in patients with CMV CD4+ T cellular immunity appears safe and potentially beneficial in this preliminary series, especially in R+ patients. Further study is warranted, given that truncated prophylaxis may yield patient-level benefits.

Valacyclovir or valganciclovir for cytomegalovirus prophylaxis: A randomized controlled trial in adult and pediatric kidney transplant recipients.

BACKGROUND: Valganciclovir (valG), a cytomegalovirus (CMV) prophylactic agent, has dose-limiting side effects. The tolerability and effectiveness of valacyclovir (valA) as CMV prophylaxis is unknown. METHODS: We conducted a randomized, open-label, single-center trial of valA versus valG for all posttransplant CMV prophylaxis in adult and pediatric kidney recipients. Participants were randomly assigned to receive valA or valG. Primary endpoints were the incidence of CMV viremia and side-effect related drug reduction with secondary assessment of incidence of EBV viremia. RESULTS: Of the 137 sequential kidney transplant recipients enrolled, 26 % were positive and negative for CMV antibody in donor and recipient respectively. The incidence of CMV viremia (4 of 71 [6 %]; 8 of 67 [12 %] P = 0.23), time to viremia (P = 0.16) and area under CMV viral load time curve (P = 0.19) were not significantly different. ValG participants were significantly more likely to require side-effect related dose reduction (15/71 [21 %] versus 1/66 [2 %] P = 0.0003). Leukopenia was the most common reason for valG dose reduction and granulocyte-colony stimulating factor was utilized for leukopenia recovery more frequently (25 % in valG vs 5 % in valA: P = 0.0007). Incidence of EBV viremia was not significantly different. CONCLUSIONS: ValA has significantly less dose-limiting side effects than valG. In our study population, a significant increase in CMV viremia was not observed, in adults and children after kidney transplant, compared to valG. TRIAL REGISTRATION NUMBER: NCT01329185.

Congenital and Postnatal Cytomegalovirus: Case Series and State of the Science for Neonatal Providers.

Cytomegalovirus (CMV), a beta-herpes virus, is the most common viral infection in infants. Transmission may occur congenitally (cCMV) or postnatally (pCMV). Early detection and intervention are crucial in reducing morbidities, notable developmental delays, and sensorineural hearing loss. However, more than 90% of infants are asymptomatic at birth. Treatment involves intravenous ganciclovir or the oral prodrug, valganciclovir, drugs usually reserved for use with symptomatic infants because of the toxicity profile. Research currently supports standardized antenatal CMV screening and treatment of affected pregnant patients with hyperimmune globulin as well as vaccination against CMV in unaffected pregnant patients, although widespread adoption is lacking. Standardized postnatal CMV screening is a proven, cost-effective way to detect and diagnose CMV and optimize outcomes across the lifespan. This article presents a case series of cCMV and pCMV and a review of the state of science of CMV as well as promising scientific advances that are on the horizon.

Assessment of patients' characteristics associated with the efficacy and safety of oral valganciclovir treatment for infants with symptomatic congenital cytomegalovirus disease.

INTRODUCTION: Insurance coverage for oral valganciclovir (VGCV) began in Japan in April 2023 on the basis of results, including our clinical trials for symptomatic congenital cytomegalovirus (CMV) disease. The VGCV treatment is available throughout Japan, so clinicians must consider the likelihood of hearing improvement and the possibility of neutropenia before dosing. MATERIALS AND METHODS: We performed a substudy of an investigator-initiated, single-arm, prospective, multicenter, clinical trial in which 24 infants with symptomatic congenital CMV disease were orally administered 16 mg/kg VGCV twice daily for 6 months as an intervention. We examined the infants' baseline characteristics associated with improved hearing impairment or a severely reduced neutrophil count. RESULTS: Of the 24 patients, 4 had normal hearing on assessment of their ear with the best hearing. Hearing impairment improved in 14 patients and did not respond to VGCV treatment in 6 patients at the 6-month hearing assessment. CMV DNA levels in plasma at baseline were higher in patients in whom hearing did not respond to treatment. A neutrophil count <500/mm3 occurred in 5 (21%) patients for the first 6 weeks and in 8 (33%) patients for the first 6 months. A neutrophil count at screening and the lowest neutrophil count over the 6 months showed the highest correlation (r = 0.477, p = 0.019). CONCLUSIONS: Infants with a low plasma viral load at screening tend to have an improvement in hearing impairment. Clinicians should be aware of neutropenia during VGCV treatment particularly in patients with a low neutrophil count during screening.

Cytomegalovirus-Associated Non-Necrotizing Retinopathy, Occlusive Retinal Vasculitis, and Neovascularization.

PURPOSE: To report a rare case of cytomegalovirus (CMV)-associated non-necrotizing viral retinopathy, occlusive retinal vasculitis, papillitis, and retinal neovascularization in a young 41-year-old woman. METHODS: Case report. RESULTS: The patient presented with features of papillitis, peripapillary cotton-wool spots, pre-retinal hemorrhages, and occlusive vasculitis. Her visual acuity was 20/100 in the left eye. She developed a worsening of the disease upon initiation of systemic corticosteroids. Her serum immunoglobulins (Ig) (both IgG and IgM) were highly positive for CMV. Anterior chamber paracentesis was positive for CMV DNA using real-time polymerase chain reaction. After stopping systemic corticosteroids, she was initiated on oral valganciclovir, with rapid resolution of the vasculitis and cotton-wool spots. After three months, the patient developed retinal neovascularization and underwent pan-retinal photocoagulation. However, her uveitis was inactive, and her visual acuity improved to 20/25. CONCLUSIONS: Non-necrotizing viral retinopathy has been associated with either varicella zoster virus (VZV) or herpes simplex virus (HSV). Our case highlights that CMV can also lead to non-necrotizing retinopathy and must be suspected in patients who may be negative for VZV and HSV. Appropriate anti-viral treatment can prevent severe vision loss in these patients.

Optimization of Ganciclovir and Valganciclovir Starting Dose in Children by Machine Learning.

BACKGROUND AND OBJECTIVES: Ganciclovir (GCV) and valganciclovir (VGCV) show large interindividual pharmacokinetic variability, particularly in children. The objectives of this study were (1) to develop machine learning (ML) algorithms trained on simulated pharmacokinetics profiles obtained by Monte Carlo simulations to estimate the best ganciclovir or valganciclovir starting dose in children and (2) to compare its performances on real-world profiles to previously published equation derived from literature population pharmacokinetic (POPPK) models achieving about 20% of profiles within the target. MATERIALS AND METHODS: The pharmacokinetic parameters of four literature POPPK models in addition to the World Health Organization (WHO) growth curve for children were used in the mrgsolve R package to simulate 10,800 pharmacokinetic profiles. ML algorithms were developed and benchmarked to predict the probability to reach the steady-state, area-under-the-curve target (AUC0-24 within 40-60 mg × h/L) based on demographic characteristics only. The best ML algorithm was then used to calculate the starting dose maximizing the target attainment. Performances were evaluated for ML and literature formula in a test set and in an external set of 32 and 31 actual patients (GCV and VGCV, respectively). RESULTS: A combination of Xgboost, neural network, and random forest algorithms yielded the best performances and highest target attainment in the test set (36.8% for GCV and 35.3% for the VGCV). In actual patients, the best GCV ML starting dose yielded the highest target attainment rate (25.8%) and performed equally for VGCV with the Franck model formula (35.3% for both). CONCLUSION: The ML algorithms exhibit good performances in comparison with previously validated models and should be evaluated prospectively.

Comparison of valganciclovir versus foscarnet for the treatment of cytomegalovirus viremia in adult acute leukemia patients after allogeneic hematopoietic cell transplantation.

Cytomegalovirus (CMV) reactivation increases treatment-related mortality (TRM) after allogeneic hematopoietic cell transplantation (allo-HCT). We analyzed 141 adult acute leukemia (AL) patients suffered allo-HCT between 2017 and 2021, who developed CMV viremia post-HCT and treated with valganciclovir or foscarnet, to evaluate effectiveness and safety of both drugs. Viremia clearance rates (14 and 21 d post treatment) and toxicities were similar in two groups. However, valganciclovir was associated with a lower cumulative incidence of CMV recurrence within 180 days (16.7% vs. 35.7%, p=0.029) post CMV clearance. Finally, 2-year TRM was lower in valganciclovir group (9.7% ± 0.2% vs. 26.2% ± 0.3%, p = 0.026), result a superior 2-year overall survival (OS; 88.1% ± 5.2% vs. 64.4% ± 5.5%, p = 0.005) and leukemia-free survival (LFS; 82.0% ± 5.9% vs. 58.9% ± 5.6%, p = 0.009). Valganciclovir might decrease CMV viremia recurrence and led to better long-term outcome than foscarnet in adult AL patients developed CMV viremia post-HCT. Considering the inherent biases of retrospective study, well-designed trials are warranted to validate our conclusion.