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CPT: Pharmacometrics & Systems... May 2023Maribavir was approved by the US Food and Drug Administration for the treatment of patients aged ≥12 years and weighing ≥35 kg with posttransplant...
Population pharmacokinetic modeling and simulation of maribavir to support dose selection and regulatory approval in adolescents with posttransplant refractory cytomegalovirus.
Maribavir was approved by the US Food and Drug Administration for the treatment of patients aged ≥12 years and weighing ≥35 kg with posttransplant cytomegalovirus infection/disease refractory (with/without resistance) to valganciclovir, ganciclovir, cidofovir, or foscarnet, with an oral dose of 400 mg twice daily. With no pediatric clinical data available and difficulty in trial recruitment, population pharmacokinetic modeling and simulations were conducted to predict the pharmacokinetics and inform maribavir dosing in adolescents.
Topics: United States; Humans; Adolescent; Cytomegalovirus; Antiviral Agents; Ganciclovir; Cytomegalovirus Infections; Benzimidazoles; Ribonucleosides
PubMed: 36789522
DOI: 10.1002/psp4.12943 -
The Journal of Pediatric Pharmacology... 2023Congenitally acquired cytomegalovirus (CMV) infection is the most prevalent congenital infection worldwide and the most frequent cause of acquired sensorineural hearing...
Congenitally acquired cytomegalovirus (CMV) infection is the most prevalent congenital infection worldwide and the most frequent cause of acquired sensorineural hearing loss. The burden of the disease is even more important in premature and very low birth weight infants. However, few data exist on the treatment with intravenous ganciclovir and oral valganciclovir in this vulnerable population. We report the case of twins congenitally infected with CMV and born prematurely at 27 weeks' gestation. Treatment regimens were initially individualized for their prematurity and renal function, and then adjusted with therapeutic drug monitoring (TDM) to adapt to their continuously evolving physiologic maturation. As infants were aging, the plasmatic half-life of ganciclovir slowly decreased to term infant values around 10 weeks of chronological age, or 37 weeks of postmenstrual age. Results for blood polymerase chain reaction tests became negative and long-term follow-ups were satisfactory in both twins. The limited data for infants born before 32 weeks of gestation or at less than 1200 g and evolution of ganciclovir pharmacokinetic parameters justify the use of TDM in these settings.
PubMed: 36777981
DOI: 10.5863/1551-6776-28.1.93 -
Transplant International : Official... 2023
Topics: Humans; Valganciclovir; Cytokines; Secretome; Cytomegalovirus Infections; Antiviral Agents; Chemokines; Ganciclovir; Retrospective Studies
PubMed: 36776902
DOI: 10.3389/ti.2023.10979 -
Journal of Medical Case Reports Feb 2023Like other viral infections, severe acute respiratory syndrome coronavirus-2 infection could affect different human body systems, including host immune responses. Three...
Severe acute respiratory syndrome coronavirus-2 Alpha variant (B.1.1.7), original wild-type severe acute respiratory syndrome coronavirus 2, and cytomegalovirus co-infection in a young adult with acute lymphoblastic leukemia, case report, and review of the possible cytomegalovirus reactivation...
BACKGROUND
Like other viral infections, severe acute respiratory syndrome coronavirus-2 infection could affect different human body systems, including host immune responses. Three years after its pandemic, we learn more about this novel coronavirus. As we expected, different co-infections with various organisms, such as viruses, bacteria, and even fungi, have been reported. However, concurrent infection with two severe acute respiratory syndrome coronavirus-2 strains and cytomegalovirus is extremely unusual. We have only a rudimentary understanding of such co-infections and their long-term consequences for patients with cancer.
CASE PRESENTATION
An 18-year-old young Iranian adult with acute lymphoblastic leukemia presented with abdominal pain, diarrhea, nausea, and vomiting following a recent history of severe acute respiratory syndrome coronavirus-2 infection. The patient never experienced respiratory symptoms, and the chest imaging study was normal on admission. His primary laboratory investigation revealed prerenal azotemia and severe abnormal liver function tests (blood urea nitrogen 32 mg/dL, creatinine 1.75 mg/dL, prothrombin time 66 s, partial thromboplastin time 44.5 s, international normalized ratio 5.14, total bilirubin 2.9 mg/dL, and direct bilirubin 2.59 mg/dL). Cytomegalovirus disease was diagnosed by polymerase chain reaction in his blood and stool samples. The patient's gastrointestinal signs and symptoms improved shortly after receiving intravenous ganciclovir treatment. His gastrointestinal symptoms continued intermittently for weeks despite maintenance valganciclovir prescription, necessitating frequent hospitalizations. The patient was complicated by the recurrence of gastrointestinal symptoms during the sixth hospitalization, even though he had no respiratory symptoms, and the nasopharyngeal test revealed severe acute respiratory syndrome coronavirus-2 Wuhan strain for the first time. Remdesivir and valganciclovir were administrated due to persistent enteritis and evidence of intestinal tissue invasion by severe acute respiratory syndrome coronavirus 2 and cytomegalovirus on multiple intestinal biopsies, which led to partial clinical responses. Cytomegalovirus and severe acute respiratory syndrome coronavirus-2 fecal shedding continued for more than 6 months despite repeated antiviral therapy, and the Wuhan and Alpha strains were also detected in his nasopharyngeal samples through repeated sampling (confirmed by four nasopharyngeal sampling and multiple stool specimens and several intestinal biopsies). Finally, during the Delta-variant (B.1.617.2) outbreak in Iran, the patient was admitted again with febrile neutropenia and decreased level of consciousness, necessitating respiratory support and mechanical ventilation. During the Delta-variant peak, the patient's nasopharyngeal sample once more tested positive for severe acute respiratory syndrome coronavirus 2. The patient died a few days later from cardiopulmonary arrest.
CONCLUSION
The coronavirus disease 2019 pandemic has encountered patients with cancer with critical diagnostic and treatment challenges. Patients who are immunocompromised may co-infect with multiple severe acute respiratory syndrome coronavirus-2 strains and cytomegalovirus, and even with timely diagnosis and treatment, the prognosis may be poor.
Topics: Male; Humans; Young Adult; Adolescent; SARS-CoV-2; COVID-19; Cytomegalovirus; Coinfection; Valganciclovir; Iran; Cytomegalovirus Infections; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 36765433
DOI: 10.1186/s13256-022-03750-8 -
Journal of Infection in Developing... Dec 2022The reactivation of CMV (Cytomegalovirus) in renal transplant recipients may be manifested across a clinical spectrum from asymptomatic viraemia to organ rejection. The...
INTRODUCTION
The reactivation of CMV (Cytomegalovirus) in renal transplant recipients may be manifested across a clinical spectrum from asymptomatic viraemia to organ rejection. The purpose of this study is to evaluate the patients who have experienced CMV infection after renal transplantation in the last twelve years, and to assess the efficacy of valacyclovir.
METHODOLOGY
Renal transplant recipients' demographic, clinical and laboratory data were evaluated retrospectively between 2006-2018. Valaciclovir was given at the standard prophylaxis dose of 2000 mg/daily. CMV Polymerase Chain reaction (PCR) was performed in 2-week intervals until 1 year after transplantation, and upon any symptoms attributable to CMV.
RESULTS
The entire study group had D+/R+ (donor-positive, recipient-positive) serological status of the CMV virus. 171 (59.2%) patients had only CMV infection, 60 (20.8%) had overall CMV antigen positivity until the end of the follow-up period and 7 (2.4%) patients had CMV disease. Rejection episodes were diagnosed in 31 (10.8%) patients; 20 (64.5%) of those were PCR positive for CMV; mortality rate was 12 (4.2%) but those who died had a non-CMV related disease.
CONCLUSIONS
Valaciclovir may be preferred in prophylaxis instead of valganciclovir as we used in our study since valganciclovir has prolonged treatment time, rapid development of drug resistance, drug toxicity and high cost.
Topics: Humans; Valacyclovir; Valganciclovir; Antiviral Agents; Ganciclovir; Kidney Transplantation; Retrospective Studies; Cytomegalovirus Infections; Immunoglobulin G
PubMed: 36753661
DOI: 10.3855/jidc.17218 -
Journal of the American Society of... May 2023Although cytomegalovirus (CMV) infection is an important factor in the pathogenesis of kidney allograft rejection, previous studies have not determined the optimal CMV... (Randomized Controlled Trial)
Randomized Controlled Trial
SIGNIFICANCE STATEMENT
Although cytomegalovirus (CMV) infection is an important factor in the pathogenesis of kidney allograft rejection, previous studies have not determined the optimal CMV prevention strategy to avoid indirect effects of the virus. In this randomized trial involving 140 kidney transplant recipients, incidence of acute rejection at 12 months was not lower with valganciclovir prophylaxis (for at least 3 months) compared with preemptive therapy initiated after detection of CMV DNA in whole blood. However, prophylaxis was associated with a lower risk of subclinical rejection at 3 months. Although both regimens were effective in preventing CMV disease, the incidence of CMV DNAemia (including episodes with higher viral loads) was significantly higher with preemptive therapy. Further research with long-term follow-up is warranted to better compare the two approaches.
BACKGROUND
The optimal regimen for preventing cytomegalovirus (CMV) infection in kidney transplant recipients, primarily in reducing indirect CMV effects, has not been defined.
METHODS
This open-label, single-center, randomized clinical trial of valganciclovir prophylaxis versus preemptive therapy included kidney transplant recipients recruited between June 2013 and May 2018. After excluding CMV-seronegative recipients with transplants from seronegative donors, we randomized 140 participants 1:1 to receive valganciclovir prophylaxis (900 mg, daily for 3 or 6 months for CMV-seronegative recipients who received a kidney from a CMV-seropositive donor) or preemptive therapy (valganciclovir, 900 mg, twice daily) that was initiated after detection of CMV DNA in whole blood (≥1000 IU/ml) and stopped after two consecutive negative tests (preemptive therapy patients received weekly CMV PCR tests for 4 months). The primary outcome was the incidence of biopsy-confirmed acute rejection at 12 months. Key secondary outcomes included subclinical rejection, CMV disease and DNAemia, and neutropenia.
RESULTS
The incidence of acute rejection was lower with valganciclovir prophylaxis than with preemptive therapy (13%, 9/70 versus 23%, 16/70), but the difference was not statistically significant. Subclinical rejection at 3 months was lower in the prophylaxis group (13% versus 29%, P = 0.027). Both regimens prevented CMV disease (in 4% of patients in both groups). Compared with prophylaxis, preemptive therapy resulted in significantly higher rates of CMV DNAemia (44% versus 75%, P < 0.001) and a higher proportion of patients experiencing episodes with higher viral load (≥2000 IU/ml), but significantly lower valganciclovir exposure and neutropenia.
CONCLUSION
Among kidney transplant recipients, the use of valganciclovir prophylaxis did not result in a significantly lower incidence of acute rejection compared with the use of preemptive therapy.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER
Optimizing Valganciclovir Efficacy in Renal Transplantation (OVERT Study), ACTRN12613000554763 .
Topics: Humans; Valganciclovir; Antiviral Agents; Kidney Transplantation; Cytomegalovirus Infections; Cytomegalovirus; Neutropenia; Transplant Recipients
PubMed: 36749127
DOI: 10.1681/ASN.0000000000000090 -
Indian Journal of Sexually Transmitted... 2022Cytomegalovirus (CMV) can cause life-threatening disease in immunocompromised patients, such as those with human immunodeficiency virus. It is a rare but important cause...
Cytomegalovirus (CMV) can cause life-threatening disease in immunocompromised patients, such as those with human immunodeficiency virus. It is a rare but important cause of ulceration in the female genital tract. Although cutaneous manifestations are rare, there are growing reports of CMV infections in genital and perigenital ulcers in immunocompromised individuals. CMV disease of the female genital tract may result in significant morbidity, with fever, pain, bleeding, and superinfection, and it may be associated with the development of pelvic inflammatory disease and cervical intraepithelial neoplasia. There are several options for diagnosis and for safe treatment.
PubMed: 36743082
DOI: 10.4103/ijstd.ijstd_127_20 -
Therapeutic Drug Monitoring Aug 2023Cytomegalovirus causes morbidity and mortality, especially in immunocompromised patients, and is treated with (val)ganciclovir. Therapeutic drug monitoring of...
BACKGROUND
Cytomegalovirus causes morbidity and mortality, especially in immunocompromised patients, and is treated with (val)ganciclovir. Therapeutic drug monitoring of ganciclovir is often performed; however, clinically established target trough levels corresponding to efficacy are lacking. In 2021, our clinic increased the target trough level for ganciclovir from 1 to 2 mg/L to 2-4 mg/L. This study aims to compare both target trough levels in efficacy, toxicity, and occurrence of resistance.
METHODS
A retrospective cohort study was performed in adult solid organ recipients treated for cytomegalovirus infection with (val)ganciclovir. Clinical efficacy was defined as the absence of treatment failure, defined as > 1 log 10 increase in viral load within 2 weeks of treatment initiation, therapy switch to foscarnet, and/or request for resistance analysis.
RESULTS
A total of 46 patients were involved in the study, with 200 ganciclovir trough levels obtained. The composite endpoint was recorded in 23 (69.7%) and 10 (76.9%) patients in the 1-2 mg/L and the 2-4 mg/L group, respectively ( P = 0.18). No association was found between ganciclovir trough levels and the composite endpoint ( P = 1.0). However, a correlation was found between ganciclovir trough levels and the occurrence of lymphopenia ( P = 0.02).
CONCLUSIONS
Our study could not establish a difference in clinical efficacy or toxicity between target trough levels of 1-2 mg/L or 2-4 mg/L because of the lack of clinical differences between the compared groups. However, a correlation was found between ganciclovir trough levels and lymphopenia, which warrants further investigation.
Topics: Adult; Humans; Ganciclovir; Cytomegalovirus; Antiviral Agents; Retrospective Studies; Drug Monitoring; Cytomegalovirus Infections; Organ Transplantation; Lymphopenia
PubMed: 36730727
DOI: 10.1097/FTD.0000000000001054 -
Frontiers in Pediatrics 2022Primary infection or reactivation of Epstein-Barr Virus (EBV) is a significant cause of morbidity and mortality in pediatric kidney transplantation. Valganciclovir (VGC)...
INTRODUCTION
Primary infection or reactivation of Epstein-Barr Virus (EBV) is a significant cause of morbidity and mortality in pediatric kidney transplantation. Valganciclovir (VGC) treatment is recommended for prophylaxis of cytomegalovirus infection, but its role for the prevention of EBV infection remains controversial.
PATIENTS AND METHODS
All pediatric kidney transplant recipients aged <18 years old were considered for inclusion in this retrospective study. EBV negative recipients with an EBV positive donor (a group at risk of primary infection) or EBV positive recipients (a group at risk of reactivation) were included. Severe infection was defined by post-transplant lymphoproliferative disorder (PTLD), symptomatic EBV infection or by asymptomatic EBV infection with a viral load >4.5 log/ml. Outcomes were compared between patients receiving VGC prophylaxis (group P+) and those not receiving VGC prophylaxis (group P-).
RESULTS
A total of 79 patients were included, 57 (72%) in the P+ group and 22 (28%) in the P- group; 25 (31%) were at risk of primary infection and 54 (69%) at risk of reactivation. During the first year post-transplant, the occurrence of severe EBV infection was not different between the P+ group ( = 13, 22.8%) and the P- group ( = 5, 22.7%) ( = 0.99). Among patients at risk of primary infection, the rate of severe EBV infection was not different between the two groups (42.1% in P+ vs. 33.3% in P-). A higher frequency of neutropenia was found in the P+ group (66.6%) than in the P- group (33.4%) ( < 0.01).
CONCLUSION
Our observational study suggests no effect of VGC for the prevention of EBV infection in pediatric kidney transplant recipients, irrespective of their EBV status. Adverse effects revealed an increased risk of neutropenia.
PubMed: 36704127
DOI: 10.3389/fped.2022.1085101 -
Viruses Jan 2023Little is known regarding anterior uveitis (AU), the most common ocular disease associated with cytomegalovirus (CMV) infection in immunocompetent populations. CMV AU is... (Review)
Review
Little is known regarding anterior uveitis (AU), the most common ocular disease associated with cytomegalovirus (CMV) infection in immunocompetent populations. CMV AU is highly prevalent in Asia, with a higher incidence in men. Clinically, it manifests mainly as anterior chamber inflammation and elevated intraocular pressure (IOP). Acute CMV AU may resemble Posner-Schlossman syndrome with its recurrent hypertensive iritis, while chronic CMV AU may resemble Fuchs uveitis because of its elevated IOP. Without prompt treatment, it may progress to glaucoma; therefore, early diagnosis is critical to prognosis. Knowledge regarding clinical features and aqueous humor analyses can facilitate accurate diagnoses; so, we compared and summarized these aspects. Early antiviral treatment reduces the risk of a glaucoma surgery requirement, and therapeutic effects vary based on drug delivery. Both oral valganciclovir and topical ganciclovir can produce positive clinical outcomes, and higher concentration and frequency are beneficial in chronic CMV retinitis. An extended antiviral course could prevent relapses, but should be limited to 6 months to prevent drug resistance and side effects. In this review, we have systematically summarized the pathogenesis, clinical features, diagnostic and therapeutic aspects, and immunological mechanisms of CMV AU with the goal of providing a theoretical foundation for early clinical diagnosis and treatment.
Topics: Male; Humans; Cytomegalovirus; Eye Infections, Viral; Ganciclovir; Antiviral Agents; Cytomegalovirus Infections; Uveitis, Anterior; Glaucoma; Retrospective Studies; DNA, Viral
PubMed: 36680225
DOI: 10.3390/v15010185