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.

The cost-effectiveness of maternal and neonatal screening for congenital cytomegalovirus infection in Japan.

Congenital cytomegalovirus infection is the most common congenital infection. Using a decision tree model, cost-effectiveness of maternal screening with subsequent prenatal valacyclovir treatment and newborn screening with neonatal valganciclovir treatment was evaluated. The incremental cost-effectiveness ratio (ICER) was calculated for (1) universal maternal antibody screening with prenatal valacyclovir treatment compared to targeted newborn screening, and (2) universal newborn screening with postnatal valganciclovir treatment compared to targeted newborn screening. We performed a one-way sensitivity analysis. Compared to targeted newborn screening, the ICERs for universal newborn screening and maternal screening were 2 966 296 Japanese Yen (JPY) (21 188 USD) and 1 026 984 JPY (7336 USD), respectively. In all scenarios in the one-way sensitivity analysis, the ICERs of the maternal screening and the universal newborn screening strategies were less than three gross domestic product per capita compared with the targeted newborn screening strategy. Both maternal and universal newborn screening strategies may be cost-effective than a targeted newborn screening program. The potential utility of the maternal screening with valacyclovir treatment strategy, while potentially cost effective in regions with lower baseline seroprevalence rates, requires further study as the modeling was based on limited evidence.

Risk Assessment of Neutropenia during Low-Dose Valganciclovir Prophylaxis for Heart Transplant Recipients.

The aim of this study was to investigate whether low-dose valganciclovir (VGCV) prophylaxis for cytomegalovirus (CMV) infection increased the risk of developing neutropenia in heart transplant recipients (HTRs). Forty-three HTRs receiving VGCV were divided into two groups: those who received VGCV prophylaxis (n = 22) and those who did not (n = 21). Neutropenia was defined as an absolute neutrophil count ˂1500/µL and was monitored for approximately one year post-transplantation. In the prophylaxis group, 77.3% (17/22) of HTRs experienced neutropenia, which was significantly higher than that in the no prophylaxis group (42.9% [9/21], p = 0.031). No significant differences in the duration of VGCV administration and cumulative dose up to the first neutropenia episode were observed between the groups. Meanwhile, the cumulative dose of mycophenolate mofetil was significantly higher in the prophylaxis group than in the no prophylaxis group (p = 0.018); the daily maintenance dose and regularly measured area under the concentration-time curve (AUC) of mycophenolic acid did not significantly differ between groups. In conclusion, the risk of developing neutropenia was higher in HTRs receiving low-dose VGCV prophylaxis than it was in those not receiving prophylaxis, probably not attributed to dosing period and cumulative dose of VGCV until the onset of neutropenia.

Assessment of mitochondrial toxicity in newborns and infants with congenital cytomegalovirus infection treated with valganciclovir.

BACKGROUND: Ganciclovir/valganciclovir is currently indicated during the first 6 months of life in symptomatic children with congenital cytomegalovirus (CMV) infection. However, this treatment may have the potential to induce mitochondrial toxicity due to off-target inhibition of DNA-polymerases. Similar anti-HIV drugs have been associated with mitochondrial toxicity but this has never been explored in CMV. OBJECTIVE: To determine the potential mitochondrial toxicity profile at the genetic, functional and biogenesis level in peripheral blood mononuclear cells from a cohort of newborns and infants with symptomatic congenital CMV infection (treated with valganciclovir, untreated and uninfected controls). DESIGN: Longitudinal, observational and controlled study. SETTING AND PATIENTS: Subjects were recruited at the tertiary referral Hospital Sant Joan de Déu and experiments were conducted at IDIBAPS-Hospital Clínic of Barcelona, Spain. CMV-infected newborns underwent comprehensive monthly clinical follow-up. METHODS: Mitochondrial parameters, audiometry and neurological assessment were measured at baseline, 3-6 and 12 months after inclusion in the study. The Kruskal-Wallis test for k-independent samples and Friedman tests for repeated measurements were applied. RESULTS: Complex IV, citrate synthase enzymatic activities and mtDNA remained preserved in congenital CMV-infected infants treated with valganciclovir compared with controls (p>0.05 in all cases). CONCLUSIONS: No evidence of mitochondrial toxicity was found in infants treated with valganciclovir for congenital CMV.

Changes in Valganciclovir Use Among Infants with Congenital Cytomegalovirus Diagnosis in the United States, 2009-2015 and 2016-2019.

From 2009-2015 to 2016-2019, the proportion of infants in the US with congenital cytomegalovirus treated with valganciclovir roughly doubled for infants enrolled with employer-sponsored insurance (from 16% to 29%) and Medicaid (from 16% to 36%). The proportion treated with valganciclovir increased for all congenital cytomegalovirus disease severity groups.

Health Care Resource Utilization and Economic Burden Associated With Congenital Cytomegalovirus Infection: A Longitudinal Analysis of Data From Clinical Practice at a Large Health Care Provider in Israel.

PURPOSE: Congenital cytomegalovirus infection (cCMVi) is the leading cause of nonhereditary sensorineural hearing loss and can cause other long-term neurodevelopmental disabilities; however, data on the economic burden of cCMVi during early childhood are scarce. The primary objective of the study was to describe longitudinal patterns of health care resource utilization (HCRU) and direct medical costs among infants with cCMVi compared to infants unexposed to cCMVi. METHODS: A retrospective cohort study was performed using data on infants born between 2013 and 2017, as captured in the database of Maccabi Healthcare Services, a 2.5 million-member health care organization in Israel. cCMVi cases were identified by physician diagnosis and/or dispensed valganciclovir within 90 days after birth. Infants born to mothers CMV-seronegative throughout pregnancy were selected for comparison (unexposed controls). Infants were retrospectively followed up through December 31, 2018, or 4 years of age (Y4). HCRU included physician visits, hospital admissions, audiology tests/procedures, imaging, and valganciclovir treatment. Direct medical costs, in US dollars per person per year (USD PPPY) were calculated from the health-system perspective. To compare costs of cCMVi cases and controls, direct medical costs were estimated using a generalized linear model with a log link function and γ distribution after adjustment for patient characteristics. FINDINGS: A total of 351 cCMVi cases and 11,733 control infants with continuous follow-up during their first year of life (Y1) were included in the study. In Y1, cases were more likely to have a hospital admission (8.5% cases vs 4.5% control; P < 0.001) and higher numbers of pediatrician visits (median, 18 vs 15), audiology visits and tests, and cranial ultrasounds (all, P < 0.05). Longitudinally, incremental costs associated with cases were highest in Y1 (1686.7 USD PPPY; cost ratio = 2.6; P < 0.001) and remained elevated through Y4. IMPLICATIONS: cCMVi was associated with substantial increases in HCRU and economic burden during early childhood, and particularly during the first year of life.

Low-Dose Valganciclovir Prophylaxis Is Safe and Cost-Saving in CMV-Seropositive Kidney Transplant Recipients.

Introduction: Observational studies suggest that low-dose valganciclovir prophylaxis (450 mg daily for normal renal function) is as effective as and perhaps safer than standard-dose valganciclovir (900 mg daily) in preventing CMV infection among kidney transplant recipients. However, this practice is not supported by current guidelines due to concerns for breakthrough infection from resistant CMV, mainly in high-risk CMV donor-seropositive/recipient-seronegative kidney transplant recipients. Standard-dose valganciclovir is costly and possibly associated with higher incidence of neutropenia and BKV DNAemia. Our institution adopted low-dose valganciclovir prophylaxis for intermediate-risk (seropositive) kidney transplant recipients in January 2018. Research Question: To analyze the efficacy (CMV DNAemia), safety (BK virus DNAemia, neutropenia, graft loss, and death), and cost savings associated with this change. Design: We retrospectively compared the above outcomes between CMV-seropositive kidney transplant recipients who received low-dose and standard-dose valganciclovir, transplanted within our institution, between 1/19/2014 and 7/15/2019, using propensity score-adjusted competing risk analyses. We also compared cost estimates between the two dosing regimens, for 3 months of prophylaxis, and for different percentage of patient-weeks with normal renal function, using the current average wholesale price of valganciclovir. Results: We studied 179 CMV-seropositive kidney transplant recipients, of whom 55 received low-dose and 124 standard-dose valganciclovir. The majority received nonlymphocyte depleting induction (basiliximab). Low-dose valganciclovir was at least as effective and safe as, and more cost-saving than standard-dose valganciclovir. Conclusion: This single-center study contributes to mounting evidence for future guidelines to be adjusted in favor of low-dose valganciclovir prophylaxis in CMV-seropositive kidney transplant recipients.

Pre-transplant assessment of pp65-specific CD4 T cell responses identifies CMV-seropositive patients treated with rATG at risk of late onset infection.

Assessment of CMV-specific T cell immunity might be a useful tool in predicting CMV infection after solid organ transplantation. We have investigated CD4 and CD8 T-cell responses to CMV pp65 and IE-1 antigens in a prospective study of 28 CMV-seropositive kidney transplant recipients who were administered lymphocyte-depleting antibodies (Thymoglobulin®) as induction treatment and with universal prophylaxis for CMV infection. The response was analyzed by intracellular flow cytometry analysis of IFN-γ production in pretransplant samples and at 1, 6, 12 and 24 months post-transplant. Overall, only pretransplant CD4 T-cell responses to pp65 were significantly lower (p = .004) in patients with CMV replication post-transplant. ROC curve analysis showed that pre-transplant frequencies of pp65-specific CD4 + T cells below 0.10% could predict CMV infection with 75% sensitivity and 83.33% specificity (AUC: 0.847; 95% CI: 0.693-1.001; p = .0054) and seem to be mandatory for efficient control of CMV viral replication by the host immune system. In conclusion, the functional assessment of CMV-specific CD4 T-cell immunity pretransplant in seropositive patients may allow the identification of Thymoglobulin®-treated kidney transplant recipients at risk of developing CMV infection post-transplantation.

Cytomegalovirus reactivation and disease amongst patients with allogeneic haematopoietic stem cell transplantation in Eastern India: Epidemiology, outcome and healthcare cost.

PURPOSE: Data from developing countries about incidence, prognosis and healthcare cost of cytomegalovirus (CMV) reactivation amongst patients with allogeneic hematopoietic stem cell transplantation (AHSCT) remain scarce. The purpose of the study was to describe the epidemiology, outcome and cost implications of CMV reactivation and CMV disease amongst patients with AHSCT in cancer hospital in Eastern India. MATERIALS AND METHODS: The study design was a retrospective audit of clinical records. RESULTS: Ninety-nine per cent of patients and 94% of the donors were found to be CMV seropositive. CMV reactivation rate was 43.8% amongst patients with AHSCT (n = 130 patients). CMV reactivation occurred 118 days after AHSCT (median; range: 28-943 days). Patients with any grade of graft-versus-host disease (GVHD) had higher CMV reactivation rate than patients without GVHD. Patients with CMV reactivation had more frequent GVHD than patients without CMV reactivation. Use of steroids was associated with CMV reactivation. We found no differences in overall survival of patients with or without CMV reactivation. The cost of in-house CMV-polymerase chain reaction at our centre was USD $57 (Rs. 3650), cost for intravenous ganciclovir was USD $26 (Rs. 1665) per infusion and oral valganciclovir USD $8 (Rs. 512)/900 mg tablet. The median duration of anti-CMV therapy was 14 days (interquartile range: 14-28 days) and the average cost per patient per month directed towards CMV management ranged between USD $800 and USD $1,300 (Rs. 51,238-Rs. 83,264). Three patients (2.3%) in this series had CMV disease, all of whom died. CONCLUSION: In an increasingly globalised world, where medical tourism is common, data from developing countries regarding cost and outcome of CMV infections in AHSCT patients are of relevance.

Valganciclovir Pharmacokinetics in Patients Receiving Oral Prophylaxis Following Kidney Transplantation and Model-Based Predictions of Optimal Dosing Regimens.

BACKGROUND AND OBJECTIVES: Valganciclovir is used as oral prophylaxis for cytomegalovirus (CMV) infection in kidney transplant recipients. However, limited pharmacokinetic data exist to guide dosing in this patient group. This study aimed to describe the population pharmacokinetics of valganciclovir in a large sample of kidney transplant recipients and predict optimal dosing based on Monte Carlo simulations. METHODS: Therapeutic drug monitoring (TDM) data from adult kidney transplant recipients who received valganciclovir prophylaxis during a 10-year study period were collected retrospectively. A non-parametric pharmacokinetic analysis and Monte Carlo simulations to determine the probabilities of reaching an area under the drug concentration-time curve (AUC) target of 40-50 mg·h/L with various dosing regimens at different levels of renal function were conducted using the Pmetrics™ package for R. RESULTS: This study included 792 ganciclovir concentration measurements derived from 97 patients. A one-compartment oral absorption model best described the data. The final covariate model was as follows: CL(ganciclovir) = TVCL × (CLCR/51)0.75, where CL is the clearance, TVCL is the typical value of ganciclovir clearance, creatinine clearance (CLCR) according to the Cockcroft-Gaultt equation and 51 is the mean CLCR determined in the study. In the simulations, the probability of reaching the targeted AUC was insufficient when using the recommended dosing regimens for prophylaxis, especially in patients with impaired renal function at CLCR < 50 mL/min. CONCLUSIONS: Higher doses of valganciclovir corrected to renal function are suggested for use as oral prophylaxis for CMV infection in kidney transplant recipients. Further study is required to establish TDM targets to ensure adequate drug concentrations while avoiding potentially toxic drug exposures.

Valganciclovir Use Among Commercially and Medicaid-insured Infants With Congenital CMV Infection in the United States, 2009-2015.

PURPOSE: The aim of this study was to assess the clinical characteristics and trends in valganciclovir use among infants diagnosed with congenital cytomegalovirus (CMV) disease in the United States. METHODS: We analyzed data from medical claims dated 2009-2015 from the Truven Health MarketScan® Commercial Claims and Encounters and Medicaid databases. We identified infants with a live birth code in the first claim who were continuously enrolled for at least 45 days. Among infants diagnosed with congenital CMV disease, identified by an ICD-9-CM or ICD-10-CM code for congenital CMV infection or CMV disease within 45 days of birth, we assessed data from claims containing codes for any CMV-associated clinical condition within the same period, and data from claims for hearing loss and/or valganciclovir within the first 180 days of life. FINDINGS: In the commercial and Medicaid databases, we identified 257 (2.5/10,000) and 445 (3.3/10,000) infants, respectively, diagnosed with congenital CMV disease, among whom 135 (53%) and 282 (63%) had ≥1 CMV-associated condition, 30 (12%) and 32 (7%) had hearing loss, and 41 (16%) and 78 (18%) had a claim for valganciclovir. Among infants with congenital CMV disease who had a claim for valganciclovir, 37 (90%) among commercially insured infants and 68 (87%) among Medicaid-insured infants had ≥1 CMV-associated condition and/or hearing loss. From 2009 to 2015, the percentages with a claim for valganciclovir increased from 0% to 29% among commercially insured infants and from 4% to 37% among Medicaid-insured infants (P < 0.0001). IMPLICATIONS: During 2009-2015, there was a strong upward trend in valganciclovir claims among insured infants who were diagnosed with congenital CMV disease, the majority of whom had CMV-associated conditions and/or hearing loss.

Successful Cost-Effective Prevention of Cytomegalovirus Disease in Kidney Transplant Recipients Using Low-Dose Valganciclovir.

OBJECTIVES: Low-dose valganciclovir prophylaxis is still under investigation in renal transplant procedures. Our aim was to assess the cost effectiveness of 450 mg versus 900 mg valganciclovir prophylaxis in kidney transplant recipients. MATERIALS AND METHODS: In this prospective trial, 201 kidney transplant patients were randomized (1:1) to receive 450 mg/d (group 1, n = 100) or 900 mg/d (group 2, n = 101) valganciclovir prophylaxis for the first 6 months after transplant. Patients were studied for incidence of cytomegalovirus disease, leucopenia episodes, rejection episodes, and graft outcomes along with associated costs over 1 year. Costs (in US dollars) of treatment of rejection were also analyzed. RESULTS: Demographic features of the studied groups were comparable. We found that the cost of cytomegalovirus care in group 1 patients was significantly lower (by 50% at 6 months; P < .001), with less leukopenia episodes (P = .04), lower doses of granulocyte colony-stimulating factor (by 30% at 6 months; P = .03), higher doses of mycophenolate mofetil (P = .04), and less rejection episodes (P = .01) compared with group 2. In group 2, there were more episodes of cytomegalovirus infection (P = .052) and BK virus nephropathy (P = .04). Graft and patient outcomes were satisfactory in both groups. CONCLUSIONS: Low-dose valganciclovir for cytomegalovirus prophylaxis after renal transplant is safer, effective and without breakthrough infection, and less costly than using the usual dose.

Combined environmental risk assessment for the antiviral pharmaceuticals ganciclovir and valganciclovir in Europe.

Potential environmental risks of the old antiviral pharmaceuticals ganciclovir (GCV) and valganciclovir (VGCV) were reassessed based on new environmental fate and chronic ecotoxicity tests and on actual use data for Europe. Valganciclovir is hydrolyzed to GCV by intestinal and hepatic esterases, and hence the new environmental tests only refer to GCV. A sorption study showed that GCV will not sorb significantly, excluding the soil as a relevant environmental compartment. Despite earlier data suggesting nondegradability, a new water/sediment fate test showed GCV to be primarily and ultimately degraded and to be nonpersistent. The chronic ecotoxicity tests with algae and daphnids resulted in no inhibition at the highest tested concentrations, whereas a fish partial life cycle test, selected in view of mammalian mutagenicity and reprotoxicity data, showed effects on growth of the young fish, but not on gametogenesis, fertilization, embryogenesis, or teratogenicity. Predicted environmental concentrations were derived based on actual per capita use data for European countries for 2004 to 2014, and the highest was selected for the risk assessment. A comparison of predicted environmental concentrations with predicted no-effect concentrations shows no significant risk for wastewater treatment, surface waters, groundwater, or sediment. In addition, potential risks to (semi)aquatic top predators or to human consumers of water and fish are exceedingly low. Environ Toxicol Chem 2017;36:2205-2216. © 2017 The Author. Environmental Toxicology and Chemistry Published by Wiley Periodicals, Inc. on behalf of SETAC.

Impact of Pharmacist Involvement in Early Identification and Enrollment in Patient Assistance Programs on CMV Outcomes in Transplantation.

BACKGROUND: No data exist evaluating the utilization of patient assistance programs (PAPs) on cytomegalovirus (CMV)-related outcomes. OBJECTIVE: To determine whether early identification and enrollment in PAPs can prevent CMV-related events. METHODS: Retrospective analysis of patients at risk of CMV reactivation who received kidney and/or pancreas transplants. Two groups were evaluated with patients receiving oral valganciclovir for CMV prophylaxis through enrollment in PAPs or oral acyclovir with preemptive CMV monitoring. Primary outcomes include the incidence of CMV infection. Secondary outcomes include a cost benefit analysis, incidence of rejection, patient/graft survival, and time to CMV infection. RESULTS: There were 97 patients identified; valganciclovir through PAPs (n = 39) and preemptive CMV quantitative nucleic acid testing monitoring (n = 58). The incidence of CMV viremia was lower in the PAP group (12.8% vs 36.2%, respectively; P = .021). There were no significant differences in CMV syndrome/disease, acute rejection, graft loss, or death between the groups. The time to CMV infection was shorter in the preemptive group. Cost benefit analysis found that hiring a full time pharmacy employee for enrolling patients in PAPs was cost beneficial for the institution/health care system. CONCLUSION: Early identification and enrollment of patients in PAPs reduces the incidence of CMV viremia. Pharmacists play a crucial role in this process.

Valganciclovir versus valacyclovir prophylaxis for prevention of cytomegalovirus: an economic perspective.

INTRODUCTION: Valganciclovir (vGCV) and valacyclovir (vACV) are used in cytomegalovirus (CMV) prophylaxis in renal transplant recipients. The aim of this study was to compare the economic impact of both regimens during 1-year follow-up. METHODS: A total of 117 renal transplant recipients at risk for CMV were randomized to 3-month prophylaxis either with vGCV (900 mg/day, n = 60) or vACV (8 g/day, n = 57) and their data used in a pharmacoeconomic analysis. The pharmacoeconomic evaluation involved all direct CMV-related expenses in the first year after transplantation. Sensitivity analysis was employed to examine the effects of various prices of antiviral drugs and diagnostic procedures on overall CMV-related costs. Simulation of the more expensive US healthcare perspective was performed, and a scenario involving costs of acute rejection (AR) was examined. RESULTS: Overall CMV-related costs were significantly lower in the vACV arm; median United States dollars (USD) 3473 (3108-3745) vs. USD 5810 (4409-6757; P < 0.001) per patient, respectively. Our data showed that the critical determinant of the major disparity between the prophylactic regimens was the prophylaxis price. Median cost of prophylaxis in the vACV group was USD 1729 (1527-2173) compared to USD 3968 (2683-4857) in the vGCV group (P < 0.001). In sensitivity analysis of the overall CMV-related costs, the least and the most expensive pharmacotherapy and diagnostic scenarios were used; nevertheless, the vACV arm remained markedly less expensive. Simulation considering the higher physician/nurse and hospitalization fees of the US healthcare system and the scenario including expenditure associated with AR episodes also favored vACV. CONCLUSION: VACV prophylaxis for CMV is associated with a significant 44% lower cost than vGCV at the first year after renal transplantation.

Assessment of the efficacy and safety of pre-emptive anti-cytomegalovirus (CMV) therapy in HIV-infected patients with CMV viraemia.

A number of studies have demonstrated that cytomegalovirus (CMV) viraemia is a strong predictor for CMV end-organ disease (EOD) and death in HIV-infected patients. We assess the efficacy and safety of pre-emptive anti-CMV therapy (PACT) for preventing these events. We performed a retrospective study of all HIV-infected patients seen in our institution who had detectable CMV viraemia in 2007. Seventy-one patients with advanced HIV disease (median CD4 cell count = 61 cells/mm(3)) were studied. Sixteen patients received PACT (mainly valganciclovir). Patients who received PACT had lower CD4 cell counts and higher blood CMV DNA levels. The cumulative incidence of CMV EOD and death at one year was 44% and 21% in patients with and without PACT, respectively (p = 0.013). Both PACT and high blood CMV DNA levels were significantly associated with CMV EOD and death in unadjusted analysis. In adjusted analyses, only blood CMV DNA levels remained significantly associated with the risk of CMV EOD and death, whereas PACT was associated with a non-significant trend towards reduced CMV EOD or death (hazard ratio: 0.25, p = 0.13). Five patients with PACT experienced severe drug-related adverse events. In conclusion, the use of PACT in HIV-infected patients with CMV viraemia could improve outcome but is associated with significant toxicity.

New algorithm for valganciclovir dosing in pediatric solid organ transplant recipients.

CMV infections are common after SOT. v-GCV is increasingly used in children. The aim of this study was to evaluate presently used dosing algorithms. Data from 104 pediatric SOT recipients (kidney, liver, and heart) aged 0.3-16.9 yr and receiving v-GCV once a day were used for model development and validation with the Pmetrics package for R. Monte Carlo simulations were performed to compare the probability of a GCV AUC 40-60 mg*h/L with the different algorithms across a range of ages, weights, and GFRs. GCV pharmacokinetics was well described by the non-parametric model. Clearance was dependent on GFR and Cockcroft-Gault estimates improved the model fit over Schwartz. Simulations showed that our new algorithm, where v-GCV dose is: Weight [kg]*(0.07*GFR [mL/min]+k), where k = 5 for GFR ≤ 30 mL/min, k = 10 for GFR > 30 mL/min and weight > 30 kg and k = 15 for GFR > 30 mL/min and weight ≤ 30 kg, outperformed the other algorithms. Thirty-three percent of all patients achieve an exposure above and 21% within the therapeutic window. We propose a simple algorithm for initial v-GCV dosing that standardizes plasma drug exposure better than current algorithms. Subsequent TDM is strongly suggested to achieve individual drug levels within the therapeutic window.

[The evaluation of cost-effectiveness and cost-utility of valganciclovir for the prophylaxis of cytomegalovirus disease to 200 days after kidney transplantation]. / Ocena kosztowej efektywnosci i kosztowej uzytecznosci stosowania walgancyklowiru w profilaktyce wystapienia choroby cytomegalowirusowej do 200. dnia od przeszczepu nerki.

UNLABELLED: Standard procedure for cytomegalovirus disease (CMV) prophylaxis in kidney transplant patients was the administration of valganciclovir for up to 110 days after organ transplant. This prophylaxis has been extended up to 200 days in Poland since 2011. The decision was based on the results of clinical trials which showed significant clinical benefit in case of prolonged administration of the drug. The aim of the analysis was to provide the economic evaluation of extending the CMV prophylaxis with co-financed from public funds Valcyte (valganciclovirum; 60 tab. a 450 mg; Roche Polska Sp. z o.o.) from 110 to 200 days, in the high risk patients group after kidney transplant (seronegative recipient and infected donor, D+/R-). The analysis was performed from the Polish healthcare payer's perspective. MATERIAL AND METHODS: All methods used in the following study were consistent with the Requirements of the Polish HTA Agency (AHTAPOL). The cost-effectiveness and the cost-utility analysis were performed on the basis of a randomised study which was identified as a result of the systematic search of the medical databases, comparing 200 days valgancyclovir administration with 100 days drug use as a prophylaxis of CMV disease in the patients group mentioned above. The Markov model was developed, simulating the disease evolution over time considering a high risk patient after kidney transplant treated with valgancicloviras the CMV disease prophylaxis. The disease period was divided into health states that are the most probable for this condition and the transitions probabilities between them were identified and assigned. Based on the clinical trial results, registry database of health conditions usability and experts' opinion, all health states (i.e. death, kidney transplant, CMV disease) were attributed with utilities and costs. The direct costs, important from the Polish healthcare payer's perspective, were included in the analysis. Extension of the proposed model in the series of one month time cycles made it possible to assess long-term (assumed time horizon was median patient's life expectancy--23,5 years) costs and clinical effects of the compared technologies. RESULTS: The Incremental Cost-Effectiveness Ratio (ICER) was 39 669 008 PLN and The Incremental Cost-Utility Ratio (ICUR) was 48 008 PLN in the specified time horizon. The result is well below the accepted threshold of profitability in Poland (assuming tripled GDP per capita cost-utility threshold, i.e. 99 543 PLN), which means that the therapy is cost-effective. CONCLUSIONS: The results of the analysis confirmed that the 200 days use of valganciclovirin the prevention of CMV disease compared to standard 110 days therapy is economically justified from the Polish healthcare payer's perspective.

Valganciclovir: prevención y tratamiento de infecciones por CMV en pacientes trasplantados / Valganciclovir: prevention and treatment of CMV infections in transplant patients

INTRODUCCIÓN: Existen varios estudios clínicos, detallados con anterioridad, que demostraron que valganciclovir v.o. es igual de efectivo que ganciclovir en la prevención de enfermedad por CMV en pacientes trasplantados de alto riesgo. También demostró tener un perfil de seguridade similar con una clara conveniencia en pacientes que pueden recibir tratamiento ambulatorio. La diferencia de costos podría ser compensada por la disminución en los gastos por internación y complicaciones asociadas. Por lo tanto, consideramos que valganciclovir v.o. es una alternativa adecuada y costo-efectiva para la prevención de enfermedad por CMV en pacientes trasplantados de alto riesgo. EVALUACIÓN DE LA SEGURIDAD: Valganciclovir es un profármaco, droga precursora del Ganciclovir, y por consiguiente cabe esperar que los efectos adversos observados con Valganciclovir sean similares, cualitativamente y cuantitativamente, a los asociados al Ganciclovir. De hecho todos los eventos adversos observados en los estudios frente a la administración de Valganciclovir ya se habían detectado con el Ganciclovir. DISCUSIÓN: Este estudio muestra una mayor eficacia del tratamiento anticipado en comparación a la profilaxis antiviral, en cuanto a la variable de supervivencia del injerto en pacientes con trasplante renal. Sin embargo, estos resultados no son del todo confiables ya que el estudio presenta varias limitaciones metodológicas. En primer lugar, este estudio no fue diseñado con el objetivo de analizar la supervivencia del injerto. Por otro lado, la muestra estudiada es pequeña y la proporción de pacientes con alto riesgo (D+/R-) de desarrollo de enfermedad por CMV que incorpora en el análisis es menor del 20% del total estudiado (12%, n=4) en el caso de la profilaxis y un 17% (n=6) en el grupo preventivo). Finalmente, existen varios estudios previos cuyos resultados son contradictorios con los de este estudio. CONCLUSIONES: Eficacia: Existe evidencia de que valganciclovir vía oral tiene una eficacia similar a ganciclovir endovenoso en la profilaxis de enfermedad por CMV en pacientes con transplante de órganos sólidos de alto riesgo. Seguridad: Ganciclovir y valganciclovir presentan un perfil de seguridad similar. Sin embargo, valganciclovir se ha asociado a una mayor incidencia de eventos adversos hematológicos (principalmente leucopenia y neutropenia). Por esta razón no se recomenda su uso en pacientes que presenten recuentos de neutrófilos menor a 500 cel. /ml, recuento de plaquetas es <25,000/ micro litro ó pacientes con una concentración de Hb <8 g/dl. Conveniencia: Valganciclovir tiene la ventaja de ser administrado por vía oral y en una sola toma diaria, mientras que ganciclovir se administra sólo por vía endovenosa. El uso de valganciclovir permite el tratamiento ambulatorio de pacientes trasplantados. Si bien no se encuentran mayores beneficios clínicos en comparación con el uso de ganciclovir por vía oral, sólo existe valganciclovir disponible por esta vía en nuestro país. Costo: el análisis comparativo de costos entre valganciclovir vo y ganciclovir ev, en la profilaxis de enfermedad por CMV, muestra una diferencia de $ 12840 a favor de ganciclovir. Proponemos la inclusión del valganciclovir al formulario terapéutico del Hospital.

Cost analysis in favor of a combined approach for cytomegalovirus after kidney transplantation: a single-center experience.

BACKGROUND: In kidney transplant recipients, cytomegalovirus (CMV) can cause significant morbidity, mortality, and costs, which can be prevented by universal antiviral prophylaxis or preemptive therapy. METHODS: With the aim to improve our understanding of the advantages and disadvantages of these interventions, we documented resource use for 101 consecutive kidney transplant recipients in our center receiving preemptive therapy and estimated resource use for 2 alternative scenarios. RESULTS: At 100 days after transplantation, the mean total costs of our preemptive strategy including monitoring and treatment with intravenous ganciclovir was €2545 per patient. At €4853 per patient, these costs were highest for the CMV-positive donor/CMV-negative recipient (D+/R-) patient subgroup (n = 28), who frequently require recurrent treatment. A treatment scenario with valganciclovir prophylaxis for D+/R- and R+ patients, in which we ignored late-onset disease after discontinuation of prophylaxis, resulted in an estimated cost of €1892 per patient. A combined approach using valganciclovir prophylaxis in the D+/R- group and a preemptive strategy in the R+ groups would result in the lowest mean and median costs per patient (€1701). CONCLUSION: Our study suggests that a combined approach, using valganciclovir prophylaxis in D+/R- patients and preemptive treatment in R+ patients, may result in the lowest cost. This approach seems reasonable as it restricts expensive prophylactic drug therapy to those who would benefit the most, whereas it limits the risk for drug toxicity and late-onset disease in those at lower risk for CMV.