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Cytomegalovirus reactivation is a substantial challenge after organ transplantation. In this phase 2 trial, maribavir, a benzimidazole riboside, is shown to have efficacy similar to that of valganciclovir for clearing of CMV viremia after hematopoietic-cell or solid-organ transplantation.

Background The EMPIRICAL trial aims to assess safety and efficacy of an empirical treatment against cytomegalovirus (CMV) and tuberculosis (TB) compared to standard of care (SoC), on adverse events and 15-day and 1-year mortality among infants living with HIV hospitalized with severe pneumonia in Africa. Methods and design The EMPIRICAL trial (NCT03915366) is an international multicenter phase II-III, open-label randomized factorial clinical trial conducted in six African countries. The trial has four randomization arms in a 1:1:1:1 fashion with patients allocated to (i) TB-Treatment plus SoC, (ii) valganciclovir plus SoC, (iii) both TB-Treatment and valganciclovir plus SoC, and (iv) SoC only. Discussion This paper describes the statistical analysis plan (SAP) for the trial which, per the study publication plan, needs to be published prior to the database lock and final analysis results. The SAP includes details of the analyses to be undertaken and unpopulated tables that will be reported to address primary and secondary endpoints. The database will be locked on 31st January 2025. Trial registration ClinicalTrials.gov: NCT03915366 (registered on April 16, 2019), Universal Trial Number: U111-1231–4736, Pan African Clinical Trial Registry: PACTR201994797961340.

IntroductionCytomegalovirus (CMV) anterior uveitis is a recognised cause of anterior uveitis in immunocompetent patients and is preventable cause of vision loss. Ocular sequelae include corneal endothelial damage which can cause corneal oedema and failure, as well as glaucoma. Recurrences of inflammation are common and therefore patients are often exposed to long-term therapy. Oral therapy is available in the form of valganciclovir, although with the caveat of systemic side effects such as bone marrow suppression and renal failure necessitating regular interval laboratory monitoring. Recent reports have demonstrated that topical 2% ganciclovir solution may offer promising treatment outcomes in patients with CMV anterior uveitis with superior safety, cost-effectiveness and convenience profiles. An investigation into the relative equipoise of these therapies is warranted for these reasons.Methods and analysisThe Systemic and Topical Control of Cytomegalovirus Anterior uveitis: Treatment Outcomes (STACCATO) trial is designed as a multicentre, block randomised by site, double-masked, placebo-controlled trial comparing the efficacy of oral valganciclovir, 2% topical ganciclovir and placebo in treating PCR-proven CMV anterior uveitis. Participant clinical evaluation will occur at three study time points by a masked study ophthalmologist over a 28-day period to assess resolution of ocular inflammation (secondary outcome). A control group will provide additional information about the possible impact that the infected host’s immune response may play in controlling local viral replication. The primary analysis is an analysis of covariance (three arms) correcting for baseline to compare quantitative CMV viral load in the anterior chamber (AC) aqueous fluid before and 7 days after treatment.Ethics and disseminationThe University of California San Francisco Committee on Human Research and the Khon Kaen University Institutional Review Board have given ethical approval. The results of this trial will be presented at local and international meetings and submitted for peer-reviewed journals for publication.Trial registration numberNCT03576898.

High HHV-8 viral load (VL) in Kaposi Sarcoma (KS) has been associated with Severe Immune Reconstitution Inflammatory Syndrome (Severe-IRIS-KS), which can occur after initiating cART, and leads to high mortality, particularly in patients with pulmonary involvement. We investigate if valganciclovir (as an anti-HHV-8 agent) initiated before cART reduces the mortality associated with Severe-IRIS-KS and the incidence of Severe-IRIS-KS. Open-label parallel-group randomized clinical trial in AIDS cART naïve patients with disseminated KS (DKS) as defined by at least two of the following: pulmonary, lymph-node, or gastrointestinal involvement, lymphedema, or ≥30 skin lesions. In the experimental group (EG), patients received valganciclovir 900 mg BID four weeks before cART and continued until week 48; in the control group (CG), cART was initiated on week 0. Non-severe-IRIS-KS was defined as: an increase in the number of lesions plus a decrease of ≥one log10 HIV-VL, or an increase of ≥50cells/mm3 or ≥2-fold in baseline CD4+cells. Severe-IRIS-KS was defined as abrupt clinical worsening of KS lesions and/or fever after ruling out another infection following cART initiation, and at least three of the following: thrombocytopenia, anemia, hyponatremia, or hypoalbuminemia. 40 patients were randomized and 37 completed the study. In the ITT analysis, at 48 weeks, total mortality was the same in both groups (3/20), severe-IRIS-KS attributable mortality was 0/20 in the EG, compared with 3/20 in the CG (p = 0.09), similar to the per-protocol analysis: 0/18 in the EG, and 3/19 in the control group (p = 0.09). The crude incidence rate of severe-IRIS-KS was four patients developed a total of 12 episodes of Severe-IRIS-KS in the CG and two patients developed one episode each in the EG. Mortality in patients with pulmonary KS was nil in the EG (0/5) compared with 3/4 in the CG (P = 0.048). No difference was found between groups in the number of non-S-IRIS-KS events. Among survivors at week 48, 82% achieved >80% remission. Although mortality attributable to KS was lower in the EG the difference was not statistically significant.

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.

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.

Valganciclovir (VGCV) is the first-line drug for preemptive therapy of cytomegalovirus (CMV) infections. However, even when administered at the dose specified in the package insert, there is significant interindividual variability in the plasma concentrations of ganciclovir (GCV). In addition, correlations have been reported between the area under the concentration-time curve and therapeutic efficacy or adverse events. Therefore, therapeutic drug monitoring (TDM) can be used to improve the efficacy and safety of preemptive VGCV therapy. This study aims to evaluate whether the dosage adjustment of VGCV based on TDM in patients undergoing preemptive therapy for CMV infections is associated with the successful completion rate of treatment without severe hematological adverse effects. This phase II, single-center, single-arm trial aims to enroll 40 patients admitted at the Department of Rheumatology and Clinical Immunology, Kobe University Hospital, who will receive oral VGCV as preemptive therapy for CMV infections. Participants will begin treatment with VGCV at the dose recommended in the package insert, with subsequent dose adjustments based on weekly TDM results. The primary end point will be the proportion of patients who achieve CMV antigenemia negativity within 3 weeks without severe hematological adverse events. The secondary end points will include weekly changes in CMV antigen levels, total VGCV dose, and duration of preemptive therapy. For safety evaluation, the occurrence, type, and severity of VGCV-related adverse events will be analyzed. Additionally, this study will explore the correlations between the efficacy and safety of preemptive therapy and the pharmacokinetic parameters of GCV, CMV-polymerase chain reaction values, and nudix hydrolase 15 (NUDT15) genetic polymorphisms. The correlation between GCV plasma concentrations obtained from regular venous blood and blood concentrations will be examined using dried blood spots. This study began with patient recruitment in September 2024, with 5 participants enrolled as of June 16, 2025. The target enrollment is 40 participants, and the anticipated study completion is set for July 2027. This is the first study to investigate the impact of TDM intervention in patients receiving VGCV as preemptive therapy. The findings are postulated to provide valuable evidence regarding the utility of TDM in patients receiving VGCV as preemptive therapy. Japan Registry of Clinical Trials jRCTs051240080; https://jrct.mhlw.go.jp/latest-detail/jRCTs051240080. DERR1-10.2196/72549.

ObjectivesValganciclovir (VGCV) treatment is recommended for the prevention of cytomegalovirus (CMV) infection in renal allograft recipients. The aim of the present study is to investigate the pharmacokinetic characteristics of ganciclovir (GCV) after administration of VGCV in Chinese adult renal allograft recipients and estimate the exposure to GCV using limited sampling strategy (LSS).MethodsForty Chinese renal allograft recipients were given 450 mg or 900 mg VGCV daily. Blood samples were drawn before treatment and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 h after 5 days of VGCV therapy, and the plasma concentrations of VGCV and GCV were determined using a liquid chromatography-mass spectrometry assay. The major pharmacokinetic parameters for GCV and VGCV were determined using a noncompartmental assay. Multiple stepwise linear regression analysis was conducted to establish a model equation for the estimation of the GCV AUC0–24 h in Chinese patients using LSS.ResultsIn the 450 and 900 mg groups, the Cmax for VGCV was 0.2 ± 0.10 and 0.4 ± 0.16 mg/L, respectively; the Cmax for GCV was 4.2 ± 1.1 and 8.6 ± 1.6 mg/L, respectively; and the AUC0–24 h for GCV was 28.4 ± 8.4 and 60.7 ± 17.5 mg·h/L, respectively. For the establishment of LSS models, 40 patients were divided into the training group (n = 24) and validation group (n = 16). The model equations used for the calculation of AUC0–24 h for GCV were established in the training group by using multiple linear regression assay. Equations including AUC = 8.1 + 29.7 × C0 + 5.7 × C4 (r2 = 0.91) and AUC = − 0.4 + 11.0 × C0 + 2.1 × C2 + 13.7 × C8 (r2 = 0.98) were acceptable. The %MPE and %MAPE values obtained from the validation group for the two model equations were 5.89 ± 14.5% and 12.1 ± 9.53%, and − 1.30 ± 4.40% and 3.28 ± 3.11%, respectively.ConclusionsThe LSS models that included C0 and C4 or C0, C2, and C8 in the estimation of AUC0–24 h for GCV had favorable performance and can be used for therapeutic drug monitoring in the prevention of CMV infection using VGCV in Chinese renal allograft recipients.

Background Pneumonia is the primary cause of death among HIV-infected children in Africa, with mortality rates as high as 35–40% in infants hospitalized with severe pneumonia. Bacterial pathogens and Pneumocystis jirovecii are well known causes of pneumonia-related death, but other important causes such as cytomegalovirus (CMV) and tuberculosis (TB) remain under-recognized and undertreated. The immune response elicited by CMV may be associated with the risk of developing TB and TB disease progression, and CMV may accelerate disease caused both by HIV and TB. Minimally invasive autopsies confirm that CMV and TB are unrecognized causes of death in children with HIV. CMV and TB may also co-infect the same child. The aim of this study is to compare the impact on 15-day and 1-year mortality of empirical treatment against TB and CMV plus standard of care (SoC) versus SoC in HIV-infected infants with severe pneumonia. Methods This is a Phase II-III, open-label randomized factorial (2 × 2) clinical trial, conducted in six African countries. The trial has four arms. Infants from 28 to 365 days of age HIV-infected and hospitalized with severe pneumonia will be randomized (1:1:1:1) to (i) SoC, (ii) valganciclovir, (iii) TB-T, and (iv) TB-T plus valganciclovir. The primary endpoint of the study is all-cause mortality, focusing on the short-term (up to 15 days) and long-term (up to 1 year) mortality. Secondary endpoints include repeat hospitalization, duration of oxygen therapy during initial admission, severe and notable adverse events, adverse reactions, CMV and TB prevalence at enrolment, TB incidence, CMV viral load reduction, and evaluation of diagnostic tests such as GeneXpert Ultra on fecal and nasopharyngeal aspirate samples and urine TB-LAM. Discussion Given the challenges in diagnosing CMV and TB in children and results from previous autopsy studies that show high rates of poly-infection in HIV-infected infants with respiratory disease, this study aims to evaluate a new approach including empirical treatment of CMV and TB for this patient population. The potential downsides of empirical treatment of these conditions include toxicity and medication interactions, which will be evaluated with pharmacokinetics sub-studies. Trial registration ClinicalTrials.gov , NCT03915366, Universal Trial Number U111-1231-4736, Pan African Clinical Trial Registry PACTR201994797961340.

A novel, environmentally sustainable spectrofluorimetric method was developed and validated for sensitive determination of ganciclovir in rabbit plasma following valganciclovir administration. The method is based on fluorescence quenching of Erythrosin B probe through static complex formation with ganciclovir, as confirmed by comprehensive spectroscopic characterization using UV-visible absorption and fluorescence spectroscopy. Furthermore, temperature-dependent Stern-Volmer analysis revealed static quenching mechanism with Stern-Volmer constants decreasing from 3.77 × 10 5 to 2.79 × 10 5 M − 1 upon temperature increase from 298 to 313 K. Moreover, thermodynamic studies demonstrated spontaneous, exothermic interactions with negative Gibbs free energy and enthalpy changes, while positive entropy indicated favorable complex formation. Additionally, Job’s method confirmed 1:1 stoichiometry, while semiempirical PM3 quantum mechanical calculations identified halogen bonding and electrostatic interactions as primary binding mechanisms. Experimental conditions were systematically optimized to achieve maximum quenching efficiency at pH 5.0 with 10 µg/mL Erythrosin B concentration and 5-minute reaction time. The method demonstrated excellent analytical performance with good linearity (r 2  = 0.9991) over 0.05–3.0 µg/mL range and adequate sensitivity for therapeutic monitoring applications. Furthermore, comprehensive validation according to ICH M10 guidelines confirmed method reliability with accuracy ranging from 96.04% to 104.76% and precision below 4.61% RSD across all quality control levels. Subsequently, successful pharmacokinetic application in New Zealand white rabbits provided key parameters including C max of 4.25 µg/mL, half-life of 2.94 h, and AUC ₀₋∞ of 21.6 µg·h/mL, consistent with published clinical data. Finally, environmental sustainability assessment using four complementary evaluation tools confirmed favorable green analytical chemistry and analytical practicality traits with scores of 0.71, 76%, 70.0, and 65% for AGREE, MoGAPI, BAGI, and CACI, respectively. In conclusion, the developed spectrofluorimetric method offers significant advantages including cost-effectiveness, minimal waste generation, and elimination of derivatization steps, positioning it as an attractive alternative to conventional methods.