Concomitant congenital CMV infection and inherited liver diseases.

Inherited liver diseases may present in infancy as cholestatic jaundice progressing to severe hepatic dysfunction. Congenital cytomegalovirus (cCMV) infection may initially involve the liver, yet in otherwise healthy hosts rarely leads to long-term hepatic disease. We report a series of three patients, diagnosed with hereditary liver diseases: progressive familial intrahepatic cholestasis (PFIC) type IV, alpha 1 anti-trypsin deficiency (A1ATD) and Alagille syndrome (ALGS), who were also diagnosed with cCMV infection. All patients were treated with valgancilovir for symptomatic cCMV infection (6-12 months), followed by suppressive dosing in the 2 patients with PFIC and A1ATD. Following 15-24 months of follow-up - the patients with PFIC and A1ATD developed severe liver failure, and the third had ongoing cholestatic disease with stable synthetic function. We propose a significant contribution of cCMV infection to the course of the inherited primary disease, possibly leading to further compromise of the liver. We recommend screening patients with inherited liver disease for cCMV, and considering anti-viral treatment with valganciclovir to delay hepatic disease progression.

Optimization of Ganciclovir use in allogeneic hematopoietic cell transplant recipients - the role of therapeutic drug monitoring.

Introduction: Cytomegalovirus (CMV) is an opportunistic infectious complication that can occur after allogeneic hematopoietic cell transplantation (HCT). The mainstay of treatment and prevention of this infection is ganciclovir and its ester prodrug valganciclovir. There is conflicting evidence on the clinical utility of routine ganciclovir therapeutic drug monitoring (TDM) as a means to optimize treatment.Areas covered: This review aims to describe the current knowledge of the pharmacokinetic and pharmacodynamic characteristics of ganciclovir and valganciclovir, and to explore the evidence and challenges surrounding ganciclovir TDM within the allogeneic HCT cohort.Expert opinion: Ganciclovir TDM is important to optimize efficacy in selected patient groups where there are variable pharmacokinetic factors or inadequate response to treatment. However, defined pharmacokinetic exposures which correlate with treatment efficacy and toxicity remain elusive. Prospective clinical studies in specific patient groups are required to clarify this issue. Alternative TDM targets such as the intracellular ganciclovir triphosphate should be explored as they may prove to have better correlation with clinical outcomes and adverse effects. With recent advances in CMV immune monitoring, novel approaches integrating TDM with specific CMV immune phenotyping in a predictive model will be advantageous in optimizing ganciclovir dosing by combining TDM with a risk stratification approach.

Treating HIV-associated cytomegalovirus retinitis with oral valganciclovir and intra-ocular ganciclovir by primary HIV clinicians in southern Myanmar: a retrospective analysis of routinely collected data.

BACKGROUND: Cytomegalovirus retinitis (CMVR) is an opportunistic infection in HIV-infected people. Intraocular or intravenous ganciclovir was gold standard for treatment; however, oral valganciclovir replaced this in high-income countries. Low- and middle-income countries (LMIC) frequently use intraocular injection of ganciclovir (IOG) alone because of cost. METHODS: Retrospective review of all HIV-positive patients with CMVR from February 2013 to April 2017 at a Médecins Sans Frontièrs HIV clinic in Myanmar. Treatment was classified as local (IOG) or systemic (valganciclovir, or valganciclovir and IOG). The primary outcome was change in visual acuity (VA) post-treatment. Mortality was a secondary outcome. RESULTS: Fifty-three patients were included. Baseline VA was available for 103 (97%) patient eyes. Active CMVR was present in 72 (68%) eyes. Post-treatment, seven (13%) patients had improvement in VA, 30 (57%) had no change, and three (6%) deteriorated. Among patients receiving systemic therapy, four (12.5%) died, compared with five (24%) receiving local therapy (p = 0.19). CONCLUSIONS: Our results from the first introduction of valganciclovir for CMVR in LMIC show encouraging effectiveness and safety in patients with advanced HIV. We urge HIV programmes to include valganciclovir as an essential medicine, and to include CMVR screening and treatment in the package of advanced HIV care.

Impact of cytomegalovirus serologic status on heart transplantation.

BACKGROUND: Cytomegalovirus (CMV) infection has been associated with increased risk of mortality, cardiac allograft vasculopathy, and de novo malignancy following heart transplantation in prior institutional reports. This study examines the impact of the recipient and donor CMV status on heart recipients in the United States. METHODS: Adult heart transplant recipients were identified in the OPTN registry between 2005-2016. Recipients were stratified based on the recipient (R) and donor (D) CMV serologic status (+/-). The primary endpoint was survival 5-years after transplantation. The secondary endpoint was cardiac allograft vasculopathy 5-years after transplantation. Separate Cox proportional hazards regression models were developed to evaluate independent associations between CMV status and each of the study endpoints. RESULTS: A total of 21 878 recipients met the inclusion criteria. The breakdown of study arms by CMV serologic status was R-/D- = 3412, R+/D- = 4939; R-/D+ = 5230, and R+/D+ = 8,297. Five-year survival estimates were similar across groups (77-79%). CMV status was associated with increased mortality at 5-years (23%-41% increased risk) which was most evident in the first 3 months. The use of valganciclovir was associated with decreased risk of mortality (HR 0.56; 95% CI, 0.52-0.60). The cumulative incidence of cardiac allograft vasculopathy (R-/D- = 31%, R+/D- = 30%, R-/D+ = 31%, and R+/D+ = 30%) was similar across groups. CONCLUSIONS: CMV seropositivity at the time of transplantation is associated with increased long-term risk of mortality. Chemoprophylaxis with antivirals seems to mitigate this risk. There was no association with an increased risk of allograft vasculopathy.

Valganciclovir as Add-on to Standard Therapy in Glioblastoma Patients.

PURPOSE: Several groups have reported a prevalence of human cytomegalovirus (CMV) in glioblastoma close to 100%. Previously, we reported that treatment with the antiviral drug valganciclovir as an add-on to standard therapy significantly prolonged survival in 50 patients with glioblastoma. Here, we present an updated retrospective analysis that includes an additional 52 patients. EXPERIMENTAL DESIGN: From December 2006 to November 2019, 102 patients with newly diagnosed glioblastoma received valganciclovir as an add-on to standard therapy. No additional toxicity was observed. Contemporary controls were 231 patients with glioblastoma who received similar baseline therapy. RESULTS: Patients with newly diagnosed glioblastoma receiving valganciclovir had longer median overall survival (OS 24.1 vs. 13.3 months, P < 0.0001) and a 2-year survival rate (49.8% vs. 17.3%) than controls. Median time-to-tumor progression was also longer than in controls; 9.9 (0.7-67.5 months) versus 7.3 (1.2-49 months), P = 0.0003. Valganciclovir improved survival in patients with radical or partial resection and an unmethylated or methylated MGMT promoter gene. CONCLUSIONS: Valganciclovir prolonged median OS of patients with newly diagnosed glioblastoma (with methylated or unmethylated MGMT promoter gene) and was safe to use.

Cytomegalovirus renal infection: Rare manifestation of a common post-transplant viral infection-A case series.

Cytomegalovirus is the most common viral infection in organ transplant recipients that usually affects the brain, lungs, liver, and gastrointestinal tract. Renal involvement of Cytomegalovirus (CMV) is otherwise rare. We present six cases of biopsy-proven CMV renal infection. Five out of the six patients had detectable CMV viremia. Kidney biopsy revealed glomerulopathy in four cases and tubulointerstitial involvement in two cases. All patients exhibited decline in renal function at the onset of infection. Four out of six patients had improvement of renal function following treatment of CMV disease. To date, this is the largest case series of pure biopsy-proven CMV renal infection described in a single center.

Efficacy and Safety of Ultra-Low-Dose Valganciclovir Chemoprophylaxis for Cytomegalovirus Infection in High-Risk Kidney Transplantation Patients.

INTRODUCTION: Valganciclovir (VGCV) prophylaxis of 900 mg twice daily for 6 months is recommended to prevent cytomegalovirus (CMV) infection, which is a major cause of decreased graft and patient survival in kidney transplant recipients. However, recent studies have shown the efficacy of 900 mg once daily for 3 to 6 months. Maintaining VGCV compliance is difficult because of high drug costs and side effects, such as thrombocytopenia and leukopenia. Therefore, we studied the efficacy of ultra-low dose, short-duration VGCV (450 mg every other day for 3 months) in preventing CMV infection in ABO-incompatible (ABOiKT) and deceased donor kidney transplant (DDKT) recipients. METHODS: We retrospectively reviewed the medical records of all kidney transplant patients > 18 years old treated at Bong Seng Memorial Hospital from June 2009 to July 2016 who received ultra-low-dose VGCV prophylaxis (450 mg every other day for 3 months). The review included 74 CMV seropositive donor/seropositive recipient (D+/R+) ABOiKT and 78 CMV D+/R+DDKT recipients. The primary outcome was occurrence of CMV infection. Secondary outcomes were graft and patient survival and hematologic side effects. RESULTS: Mean prophylaxis and follow-up were 3 and 98 months, respectively. CMV disease occurrence was significantly higher in DDKT than in ABOiKT (12 cases, 8.1%, vs 1 case, .7%, P < .01). There were no significant differences in patient survival rate, graft survival rate, or hematologic side effects between the groups. CONCLUSION: Ultra-low-dose VGCV prophylaxis to prevent CMV infection is effective in ABOiKT, but other treatment protocols are needed for DDKT patients.

Clinical outcomes of valganciclovir prophylaxis in high-risk (D+/R-) renal transplant recipients experiencing delayed graft function.

BACKGROUND: Cytomegalovirus (CMV) outcomes with valganciclovir prophylaxis in renal transplant recipients experiencing delayed graft function (DGF) are unclear. METHODS: This single center, retrospective, cohort study of CMV high-risk (D+/R- with alemtuzumab induction) deceased donor renal transplant recipients receiving valganciclovir prophylaxis assessed CMV outcomes in patients experiencing DGF (n = 72) versus those with immediate graft function (IGF; n = 66). RESULTS: Cytomegalovirus viremia by 12 months occurred at similar rates in the IGF and DGF groups (30.3% vs 26.4%, respectively, P = 0.71) with 89.7% (35/39) of all cases classified as CMV disease. The median time to CMV viremia post transplant was day 141 and 138 in the IGF and DGF groups, respectively (P = 0.30). The incidence of biopsy-proven acute rejection (BPAR) was higher in the DGF group (18.1% vs 4.6%, P = 0.02) with BPAR preceding CMV in only 1 patient. There was no significant difference in graft loss (1.5% vs 4.2%, P = 0.62) or patient survival (98.5% vs 95.8%, P = 0.62) at 1 year between the IGF and DGF groups, respectively. CONCLUSION: Valganciclovir prophylaxis in patients experiencing DGF yielded similar CMV outcomes up to 1-year post transplant when compared to use in patients with IGF.

Extended Efficacy of Low-Dose Valganciclovir for Prevention of Cytomegalovirus Disease in Intermediate-Risk Kidney Transplant Recipients: Two-Year Follow-Up.

OBJECTIVES: In a previous study, we evaluated 1-year outcomes of using low-dose valganciclovir prophylaxis for cytomegalovirus infection in intermediate-risk kidney transplant recipients. Whether this effect persists in the long term is unknown. We aimed to evaluate the 2-year follow up of such adopted prophylaxis. MATERIALS AND METHODS: We randomized 2 matched groups of kidney transplant recipients (1:1) to receive valganciclovir as 450 mg daily (group 1) or 900 mg daily (group 2) for the first 6 months after kidney transplant. The final analysis included 196 patients as intermediate-risk patients (98 in each treatment group) after exclusion of 5 high-risk patients. Serologically, all patients were at moderate risk for cytomegalovirus infection. Long-term outcomes including cytomegalovirus disease, acute rejection, new-onset diabetes after transplant, graft loss, and patient survival were assessed. RESULTS: Through year 2 of follow-up, cytomegalovirus infection was reported in only 1 patient in group 1 (at month 13) and 1 patient in group 2 (at month 19) (not significant). Biopsy-proven acute rejection episodes were not statistically different between the groups (2 episodes in group 1 and 6 in group 2; P = .431). New-onset diabetes posttransplant was reported in 8.1% in group 1 and 13.2% in group 2 (P = .535). Graft failure was equal in both groups (1 in each group) at 2 years of follow up (not significant). Patient survival was comparable in both groups (100% in group 1 versus 97.9% in group 2; P = .661). The total number of cytomegalovirus infections at 2 years was numerically less in group 1 (P = .128). CONCLUSIONS: Low-dose valganciclovir prophylaxis for 6 months was associated with sustained reduction of cytomegalovirus infection up to 2 years after kidney transplant without significant impact on the acute rejection, new-onset diabetes posttransplant, or patient and graft outcomes.

Efficacy of Ultralow-Dose Valganciclovir Chemoprophylaxis for Cytomegalovirus Infection in ABO-Incompatible Kidney Transplantation Recipients.

BACKGROUND: Cytomegalovirus (CMV) infection can increase morbidity and mortality in kidney transplant (KT) patients. Chemoprophylaxis with valganciclovir (VGCV) is recommended for ABO-incompatible (ABOi) KT patients as it significantly reduces CMV disease and infection. The recommended dose of VGCV for prevention of CMV in a KT recipient is 900 mg once daily, and the treatment duration is 6 months. However, because it is expensive, sufficient amounts might not be administered. METHODS: We investigated whether ultralow-dose VGCV (450 mg every other day) and short dosing period (3 months) was sufficient to prevent CMV infection after ABOi KT. We retrospectively evaluated 74 adult CMV-seropositive donor/CMV-seropositive recipient (D+/R+) ABOi KT recipients from June 2009 to July 2016 who received ultralow-dose VGCV prophylaxis for 3 months. The primary outcome was occurrence of CMV infection. Secondary outcomes were leukopenia and thrombocytopenia. RESULT: All patients received intravenous rituximab 200 mg once and plasmapheresis for reduction of anti-A/B antibodies and interleukin-2 antibodies before undergoing ABOi KT. Mean prophylaxis and follow-up durations were 3 and 52 months, respectively. One patient died of bacterial pneumonia. Four patients lost graft function and were undergoing hemodialysis; 3 cases were caused by antibody-mediated rejection, and 1 was due to mechanical complication after surgery. Fortunately, CMV infection did not occur in any patient. CONCLUSION: Ultralow-dose VGCV is an effective prophylaxis for D+/R+ ABOi KT recipients. Especially, ultralow-dose VGCV CMV infection prevention protocol in Asian populations reduced the side effects and cost.

Effect of Low-Dose Vs Standard-Dose Valganciclovir in the Prevention of Cytomegalovirus Disease in Kidney Transplantation Recipients: A Systemic Review and Meta-Analysis.

BACKGROUND: Valganciclovir is widely used to prevent post-transplant cytomegalovirus (CMV) infection in kidney transplant patients. However, the currently used dose remains controversial because the continuous use of this drug decreases kidney function and can induce leukopenia. OBJECTIVE: The purpose of this study was to measure the appropriate dose of valganciclovir required to prevent CMV infection. METHODS: A systematic review and meta-analysis were performed by using a random effects model. The Cochrane Central Register, MEDLINE, EMBASE, and PubMed databases were searched up to April 15, 2017. We conducted analysis on low-dose (450 mg) and standard-dose (900 mg) valganciclovir groups. RESULTS: After completion of the research, the analysis revealed that the glomerular filtration rate, graft loss, tacrolimus level, antibody-mediated rejection, and fungal and Candida infection rates did not differ between the 2 groups. However, the incidence of CMV tended to decrease in the low-dose group (0.584 [95% confidence interval [CI], 0.352-0.967]; P = .036). The biopsy-proven rejection rate decreased by 0.427 times in the low-dose group compared with the standard-dose group (95% CI, 0.274-0.667; P = .002). Furthermore, the incidence of leukopenia decreased by 0.371 times in the low-dose group compared with the standard-dose group (95% CI, 0.264-0.523; P = .001). CONCLUSIONS: The 450-mg dose of valganciclovir effectively prevented post-transplantation CMV infection and decreased drug-induced side effects such as leukopenia. In the future, the lower dose of valganciclovir should be considered to prevent CMV infection and enhance cost-effectiveness.

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.