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1.
BMC Infect Dis ; 23(1): 31, 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36658533

RESUMO

BACKGROUND: Congenital cytomegalovirus (CMV) infection (cCMV) can cause sensorineural hearing loss and neurodevelopmental disabilities in children. Oral valganciclovir (VGCV) therapy has been reported to improve long-term audiological and neurodevelopmental outcomes in patients with cCMV. The levels of CMV DNA in whole blood have been monitored in previous studies. However, quantitative methods using whole blood have not been standardized. Recently, the plasma viral load has been standardized and widely used in CMV-associated diseases. METHODS: CMV viral loads in whole blood and plasma were serially measured in 24 patients with a confirmatory diagnosis of cCMV during oral VGCV therapy using an in-house real-time PCR assay. Plasma samples were assayed using the Cobas 6800 system (Roche Diagnostics) in addition to an in-house assay. RESULTS: Plasma CMV viral loads were remarkably decreased at the end of therapy compared to before therapy. A significant correlation of CMV levels between whole blood and plasma was observed (Spearman's ρ = 0.566). The levels of CMV DNA before therapy were significantly correlated with the period of decreasing the viral loads to below the detection limit, not only in whole blood (Spearman's ρ = 0.901) but also in plasma (Spearman, ρ = 0.804). Finally, CMV viral loads between the in-house assay and commercially available standardized assay in 75 plasma samples with positive PCR results for CMV were compared; a significant correlation was observed between the results of both assays. CONCLUSIONS: There was a significant correlation between the two assays (Spearman, ρ = 0.882), suggesting that CMV plasma viral loads measured by the standardized assay are widely used to monitor the levels of CMV DNA in patients with cCMV during oral VGCV therapy.


Assuntos
Infecções por Citomegalovirus , Citomegalovirus , Criança , Humanos , Valganciclovir/uso terapêutico , Citomegalovirus/genética , Carga Viral/métodos , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/congênito , Reação em Cadeia da Polimerase em Tempo Real , DNA Viral/genética
2.
J Med Virol ; 95(1): e28391, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36484373

RESUMO

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.


Assuntos
Infecções por Citomegalovirus , Triagem Neonatal , Recém-Nascido , Gravidez , Feminino , Humanos , Análise Custo-Benefício , Valganciclovir , Valaciclovir , Japão/epidemiologia , Estudos Soroepidemiológicos , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/epidemiologia
3.
Int J Pediatr Otorhinolaryngol ; 164: 111420, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36563581

RESUMO

OBJECTIVES: Congenital cytomegalovirus (cCMV) is the leading nongenetic cause of sensorineural hearing loss (HL). However, there are no universally accepted approaches to diagnosis, follow-up and treatment. The aim of this study was to evaluate the main characteristics of cCMV-infected children, focusing on their management and long-term hearing outcomes. METHODS: This retrospective study included all children with cCMV infection who were referred to a third-level referral audiologic center for a 6-year hearing follow-up. The main information collected from the medical records included gestational age, birth weight, trimester of maternal seroconversion, hearing status at birth and after 6 years, hearing fluctuations, treatment with oral valganciclovir (within the first month of life and for 6 months), use of hearing devices, presence of speech-language delay, motor delay, cognitive delay and balance disorders, awareness of cCMV among parents, and parents' engagement in behaviors that could increase the risk of CMV infection during pregnancy. RESULTS: A total of 141 children with cCMV infection (72 males and 69 females; mean gestational age: 37+3 weeks; mean birth weight: 2893 g) were assessed. Overall, 48 children (34.0%) had a diagnosis of speech-language delay, 32 (22.7%) of sensorineural HL (59.4% bilaterally; 50% of profound degree), 18 (12.8%) of motor delay, 16 (11.3%) of balance disorders, and 6 (4.3%) of cognitive delay. Among children with HL, 8 (25.0%) were fitted with hearing aids (5 unilaterally and 3 bilaterally), and 5 (15.6%) had undergone cochlear implantation (1 unilaterally and 4 bilaterally), while a bimodal hearing solution was adopted for 2 (6.3%) patients. Compared to children with asymptomatic cCMV infection, symptomatic children had a higher prevalence of neurological and auditory sequelae (P < 0.01) and bilateral (P = 0.003) and severe-to-profound HL (P = 0.004). Overall, 23 children (16.3%) received oral valganciclovir, and only one of them experienced hearing deterioration. Only 14.9% of mothers and 5% of fathers were aware that cCMV could cause progressive or late-onset HL, and 87.9% of parents (248/282) had engaged in behaviors that increased the risk of CMV infection during pregnancy. CONCLUSION: This study confirmed the importance of performing a long audiological follow-up in children diagnosed with cCMV infection due to the possible late-onset, progressive and fluctuating nature of HL. Moreover, the study highlighted many current controversies in preventive (poor prenatal education), diagnostic (routine maternal serological screening) and therapeutic (valganciclovir administered to asymptomatic children) approaches to cCMV infection. More efforts should be made to improve prevention strategies and raise awareness of cCMV infection risks among the population.


Assuntos
Apraxias , Infecções por Citomegalovirus , Perda Auditiva Neurossensorial , Recém-Nascido , Masculino , Feminino , Gravidez , Humanos , Criança , Lactente , Valganciclovir/uso terapêutico , Estudos Retrospectivos , Peso ao Nascer , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/tratamento farmacológico , Audição , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/epidemiologia , Perda Auditiva Neurossensorial/etiologia , Mães , Apraxias/complicações
4.
BMC Infect Dis ; 22(1): 872, 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36418967

RESUMO

BACKGROUND: Cytomegalovirus (CMV) infection is a leading cause of morbidity and mortality after transplantation. This study aimed to investigate CMV seroprevalence, infection, and disease in Chinese thoracic organ transplant recipients. METHODS: The clinical data of the patients who underwent lung and/or heart transplantation between January 2015 and October 2020 were retrospectively collected from four transplantation centers in China. RESULTS: A total of 308 patients were analyzed. The CMV serostatus was donor positive (D+) recipient negative (R-) in 19 (6.17%) patients, D+/R+ in 233 (75.65%), D-/R+ in 36 (11.69%), and D-/R- in 20 (6.50%). CMV DNAemia was detected in 52.3% of the patients and tissue-invasive CMV disease was diagnosed in 16.2% of the patients. Only 31.8% of the patients adhered to the postdischarge valganciclovir therapy. The D+/R- serostatus (odds ratio [OR]: 18.32; 95% confidence interval [CI]:1.80-188.68), no valganciclovir prophylaxis (OR: 2.64; 95% CI: 1.05-6.64), and higher doses of rabbit anti-human thymocyte globulin (> 2 mg/kg) (OR: 4.25; 95% CI: 1.92-9.42) were risk factors of CMV disease. CONCLUSION: CMV seroprevalence was high in Chinese thoracic organ transplant donors and recipients. The low adherence rate to the postdischarge CMV prophylaxis therapy in Chinese patients is still an unresolved issue.


Assuntos
Infecções por Citomegalovirus , Transplante de Órgãos , Humanos , Citomegalovirus , Estudos Retrospectivos , Estudos Soroepidemiológicos , Assistência ao Convalescente , Antivirais/uso terapêutico , Alta do Paciente , Valganciclovir/uso terapêutico , Infecções por Citomegalovirus/tratamento farmacológico , Transplante de Órgãos/efeitos adversos
5.
Antiviral Res ; 208: 105431, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36209985

RESUMO

Clusters of acute non HepA-E hepatitis cases in previously healthy children have been reported globally. At least, 1010 cases were identified in 35 countries, 5% of those cases required liver transplantation and 2% died. The exact cause is not yet known, but there is circumstantial evidence suggesting that human adenovirus F41 (HAdV-F41) might be playing a role. No antiviral drug has been approved for treating human adenovirus infections. Furthermore, HAdV-F41 is notoriously difficult to grow in cell culture, which hindered studying the efficacy of an antiviral compound against this virus. Here, we show that filociclovir (FCV), a nucleoside analog, is a potent inhibitor of HAdV-F41 in cell culture using 2 approaches, namely immunostaining of infected cells and virus yield reduction assay. The activity of FCV was compared to 3 other known antivirals: cidofovir (CDV), ganciclovir (GCV) and valganciclovir (VGCV). Among the 4 compounds examined in this study, FCV was the most potent, with an EC50 of 3.5 µM. These compounds can be ranked by potency as follows: FCV > CDV > GCV ≥ VGCV. In addition, FCV was 10-fold more potent than CDV in a virus yield reduction assay. This report provides timely and valuable methodologies to the research community for testing antivirals against HAdV-F41. Our findings also support the continued development of FCV for various therapeutic applications, including pediatric hepatitis, if a causal relationship is firmly established in the future.


Assuntos
Adenovírus Humanos , Humanos , Criança , Antivirais/farmacologia , Antivirais/uso terapêutico , Valganciclovir , Ganciclovir/uso terapêutico , Cidofovir/farmacologia
6.
Am J Transplant ; 22(12): 3012-3020, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35971847

RESUMO

Prophylaxis with valganciclovir (VGCV) is used routinely to prevent cytomegalovirus (CMV) infections in at-risk pediatric solid organ transplant (SOT) recipients. However, the rate and factors associated with toxicities in this population are not well-described. We conducted a retrospective cohort study of children undergoing SOT at our hospital from January 2012-June 2018. We evaluated the frequency of hematologic and renal toxicities from day 15 through 1-year post-SOT in relation to antiviral exposures, focused on VGCV prophylaxis. Marginal rate models were used to determine the risk of kidney injury and neutropenia in relation to VGCV prophylaxis. Among 281 SOTs, VGCV prophylaxis was administered on 20.1% of all follow-up days. The incidence rates of kidney injury, leukopenia, and neutropenia were significantly higher during VGCV prophylaxis compared to when no antiviral agents were given. Using multivariable marginal rate models, receipt of VGCV prophylaxis was associated with development of kidney injury (rate ratio [RR] 1.79, 95% confidence interval [CI]: 1.22-2.65) and neutropenia (RR 4.82, 95% CI: 3.08-7.55). VGCV dosing did not impact the development of kidney injury or neutropenia. Toxicities are common with VGCV prophylaxis in pediatric SOT recipients.


Assuntos
Infecções por Citomegalovirus , Transplante de Rim , Neutropenia , Humanos , Criança , Antivirais/efeitos adversos , Ganciclovir/uso terapêutico , Estudos Retrospectivos , Valganciclovir/uso terapêutico , Transplantados , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/prevenção & controle , Neutropenia/induzido quimicamente , Neutropenia/tratamento farmacológico
7.
Transplant Proc ; 54(6): 1615-1617, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35914968

RESUMO

In simultaneous pancreas-kidney transplantation (SPK) recipients, cytomegalovirus (CMV) infection is a major complication that has been associated with the use of tacrolimus (TAC)-based immunosuppression. As one of the immunosuppressive drug options, the use of mammalian target of rapamycin inhibitors (mTORi) results in reduced rates of CMV infection in the field of solid organ transplantation. However, little is known about mTORi usage in pancreas transplantation. We report a case of recurrent CMV infection that was controlled by the introduction of mTORi (everolimus) in addition to a TAC-based immunosuppression regimen in SPK. A 52-year-old man underwent SPK. Graft duodenal perforation occurred on the 13th day of surgery, and graft duodenal resection was performed after long-term abscess drainage treatment. After graft duodenal resection, he was diagnosed with CMV viremia, and valganciclovir was started. However, because of recurrent febrile neutropenia caused by cytopenia as a side effect of valganciclovir, there was a repeated need for granulocyte-colony stimulating factor treatment. Immunosuppressive drug taper adjustment was attempted to control recurrent CMV viremia, and everolimus was introduced with the aim of reducing the dose of TAC and mycophenolate mofetil. This resulted in a continuously negative CMV antigenemia test and a stable general condition. Understanding the characteristics of various immunosuppressive agents and appropriately controlling and managing infectious diseases is crucial for the good postoperative management of patients with SPK.


Assuntos
Infecções por Citomegalovirus , Transplante de Rim , Transplante de Pâncreas , Fatores Estimuladores de Colônias/farmacologia , Fatores Estimuladores de Colônias/uso terapêutico , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/tratamento farmacológico , Everolimo/efeitos adversos , Rejeição de Enxerto/tratamento farmacológico , Sobrevivência de Enxerto , Humanos , Imunossupressores/efeitos adversos , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/uso terapêutico , Pâncreas , Transplante de Pâncreas/efeitos adversos , Transplante de Pâncreas/métodos , Serina-Treonina Quinases TOR , Tacrolimo/uso terapêutico , Valganciclovir/uso terapêutico , Viremia/tratamento farmacológico
8.
Antimicrob Agents Chemother ; 66(9): e0240521, 2022 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-35916518

RESUMO

Maribavir was approved by the U.S. Food and Drug Administration in November 2021 for the treatment of adult and pediatric patients with post-transplant cytomegalovirus (CMV) infection/disease that is refractory to treatment (with or without genotypic resistance) with ganciclovir, valganciclovir, cidofovir, or foscarnet. Maribavir is an oral benzimidazole riboside with potent and selective multimodal anti-CMV activity. It utilizes a novel mechanism of action which confers activity against CMV strains that are resistant to traditional anti-CMV agents, and also offers a more favorable safety profile relative to the dose-limiting side effects of previously available therapies. Maribavir was initially studied as an agent for CMV prophylaxis in solid organ and hematopoietic stem cell recipients, but initial phase III trials failed to meet clinical efficacy endpoints. It has been more recently studied as a therapeutic agent at higher doses for refractory-resistant (R-R) CMV infections with favorable outcomes. After an overview of maribavir's chemistry and clinical pharmacology, this review will summarize clinical efficacy, safety, tolerability, and resistance data associated with maribavir therapy.


Assuntos
Anti-Infecciosos , Infecções por Citomegalovirus , Adulto , Anti-Infecciosos/farmacologia , Antivirais/farmacologia , Antivirais/uso terapêutico , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Criança , Cidofovir , Infecções por Citomegalovirus/prevenção & controle , Diclororribofuranosilbenzimidazol/análogos & derivados , Farmacorresistência Viral , Foscarnet , Ganciclovir/uso terapêutico , Humanos , Valganciclovir/uso terapêutico
9.
J Heart Lung Transplant ; 41(9): 1258-1267, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35868965

RESUMO

BACKGROUND: The Quantiferon-Cytomegalovirus (QF-CMV) assay was introduced to predict CMV infection and inform prophylaxis duration in our lung transplant recipients (LTR) from 2012. The aims of this retrospective cohort study were to review our QF-CMV experience, understand factors associated with positive results and further explore its predictive utility. METHODS: LTR with QF-CMV testing performed at 5 months post-transplant were included. Patients receiving QF-directed prophylaxis (5 or 11 months) were compared to those receiving our prior standard of care (5 months). Outcomes were CMV infection >1,000 IU/mL in blood and/or bronchoalveolar lavage fluid. Factors associated with positive QF-CMV results were identified. Patients were compared based on serostatus, QF-CMV results and prophylaxis duration. RESULTS: Our cohort included 263 LTR (59 D+/R-, 204 R+). QF-directed prophylaxis was used in 195 of 263 (74%) and was associated with reduced CMV infection (84/195, 43% vs 41/68, 60%, p < .001). Patients receiving extended prophylaxis experienced less CMV if negative and/or indeterminate (43% vs 70%, p < .01) or positive (10% vs 51%, p < .01). Only 5 of 59 (8%) D+/R- patients were QF-CMV positive compared to 155 of 204 (76%) R+ patients (adjusted OR 0.03, 0.01-0.07, p < .001). After controlling for prophylaxis duration, only D+/R- serostatus remained independently associated with CMV infection (adjusted HR 4.90, 95% CI 2.68-9.00, p < .0001). CONCLUSIONS: QF-CMV results were strongly correlated with serostatus, with D+/R- patients unlikely to test positive while receiving prophylaxis. Extended prophylaxis was associated with delayed onset, reduced frequency and severity of CMV infection across all subgroups. After accounting for serostatus, the incremental predictive value of QF-CMV in this cohort was limited.


Assuntos
Infecções por Citomegalovirus , Transplantados , Antivirais/uso terapêutico , Citomegalovirus , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/prevenção & controle , Seguimentos , Humanos , Pulmão , Estudos Retrospectivos , Valganciclovir/uso terapêutico
10.
Indian J Ophthalmol ; 70(7): 2472-2475, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35791137

RESUMO

Purpose: To study clinical efficacy of valganciclovir in cytomegalovirus retinitis (CMVR) in human immunodeficiency virus (HIV)-positive-positive patients in a tertiary care clinic in a developing nation. Methods: In a retrospective study, systemic and ocular records of HIV patients suffering from CMVR and treated with valganciclovir, were analyzed. Primary outcome measures were involvement of the other eye, incidence of retinal detachment, systemic involvement, and mortality encountered. Secondary outcome measures included change in BCVA. Results: Out of nine patients who were included, two patients developed CMVR in the other eye and only one patient (11.11%) developed retinal detachment during the course of the study. No patient developed any systemic manifestations or had mortality during the course of the study. The change in BCVA was not statistically significant. Conclusion: Use of oral valganciclovir showed good outcome and was found to be a better alternative compared to the use of intravitreal ganciclovir in the literature. Introduction of valganciclovir at an affordable price in developing nations can decrease disease burden.


Assuntos
Retinite por Citomegalovirus , Infecções por HIV , Soropositividade para HIV , Descolamento Retiniano , Antivirais/uso terapêutico , Retinite por Citomegalovirus/diagnóstico , Retinite por Citomegalovirus/tratamento farmacológico , Retinite por Citomegalovirus/epidemiologia , HIV , Infecções por HIV/complicações , Soropositividade para HIV/complicações , Humanos , Índia/epidemiologia , Descolamento Retiniano/complicações , Estudos Retrospectivos , Centros de Atenção Terciária , Valganciclovir/uso terapêutico
11.
Transplant Proc ; 54(6): 1679-1681, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35842318

RESUMO

Cytomegalovirus (CMV) is considered one of the most notable pathogens that affect patients after solid organ transplantation (SOT), especially small bowel transplant patients with a risk of high mortality rate. Its management relies historically on the use of CMV DNA polymerase inhibitors (namely, ganciclovir and valganciclovir). Second-line options include foscarnet and cidofovir, which are highly nephrotoxic and thus less preferred and only used in ganciclovir intolerance or resistance cases. Letermovir is a novel antiviral agent approved for CMV prophylaxis in hematopoietic stem cell transplant, but not for SOT (neither for prophylaxis nor for treatment). We report the first case on the successful use of letermovir in treating CMV disease in a small bowel transplant patient who failed to achieve viral clearance due to ganciclovir resistance and severe intolerance to foscarnet.


Assuntos
Infecções por Citomegalovirus , Citomegalovirus , Acetatos , Antivirais/uso terapêutico , Cidofovir , Citomegalovirus/genética , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/prevenção & controle , Farmacorresistência Viral , Foscarnet/uso terapêutico , Ganciclovir/uso terapêutico , Humanos , Inibidores da Síntese de Ácido Nucleico/farmacologia , Inibidores da Síntese de Ácido Nucleico/uso terapêutico , Quinazolinas , Transplantados , Valganciclovir/uso terapêutico
12.
Transplant Proc ; 54(6): 1589-1593, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35840432

RESUMO

There are particularly few reports on kidney transplantation after hematopoietic stem cell transplantation (HSCT) for malignant lymphoma, and none of the cases reported a favorable outcome in patients who received kidney transplantation from a different donor to HSCT. In this report, we describe the first case of kidney transplantation from a different donor to HSCT with a successful outcome. Furthermore, we reviewed the previously reported cases. A 59-year-old female patient received an HSCT from her younger brother after chemotherapy for malignant lymphoma. After HSCT, she did not have graft-versus-host disease (GVHD) requiring maintenance treatment. The patient developed chronic kidney disease requiring kidney replacement therapy, probably due to drug toxicity or cardio-renal syndrome. At age 65, she underwent an ABO-compatible, HLA-A, -B, -DR 5/6 mismatched kidney transplantation from her husband. Immunosuppressive therapy with tacrolimus, mycophenolate mofetil, methylprednisolone, and basiliximab was administered. The patient had urinary tract infections at 7 days, 9 weeks, and 4 months after kidney transplantation, and cytomegalovirus antigenemia at 9 weeks after kidney transplantation, which improved with antibiotic and valganciclovir, respectively. When each infection occurred, we weakened immunosuppressive therapy. Four years after kidney transplantation, the patient is in good clinical condition with a serum creatinine of 1.2 mg/dL, without critical infection or malignancy. In this case, we believe that it was important to optimize the immunosuppressive therapy. In addition, from a review of previous cases, it seemed important that there was no GVHD requiring maintenance therapy in order to prevent excessive immunosuppression.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Linfoma , Idoso , Antibacterianos/uso terapêutico , Basiliximab , Creatinina , Feminino , Doença Enxerto-Hospedeiro/etiologia , Antígenos HLA-A , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunossupressores/efeitos adversos , Rim , Linfoma/etiologia , Masculino , Metilprednisolona , Pessoa de Meia-Idade , Ácido Micofenólico/uso terapêutico , Tacrolimo , Valganciclovir
13.
BMC Infect Dis ; 22(1): 568, 2022 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-35733089

RESUMO

BACKGROUND: Congenital human cytomegalovirus (cCMV) infection can cause sensorineural hearing loss and neurodevelopmental disabilities in children. Ganciclovir and valganciclovir (GCV/VGCV) improve long-term audiologic and neurodevelopmental outcomes for patients with cCMV infection; however, antiviral drug resistance has been documented in some cases. Long-read sequencing can be used for the detection of drug resistance mutations. The objective of this study was to develop full-length analysis of UL97 and UL54, target genes with mutations that confer GCV/VGCV resistance using long-read sequencing, and investigate drug resistance mutation in patients with cCMV infection. METHODS: Drug resistance mutation analysis was retrospectively performed in 11 patients with cCMV infection treated with GCV/VGCV. UL97 and UL54 genes were amplified using blood DNA. The amplicons were sequenced using a long-read sequencer and aligned with the reference gene. Single nucleotide variants were detected and replaced with the reference sequence. The replaced sequence was submitted to a mutation resistance analyzer, which is an open platform for drug resistance mutations. RESULTS: Two drug resistance mutations (UL54 V823A and UL97 A594V) were found in one patient. Both mutations emerged after 6 months of therapy, where viral load increased. Mutation rates subsided after cessation of GCV/VGCV treatment. CONCLUSIONS: Antiviral drug resistance can emerge in patients with cCMV receiving long-term therapy. Full-length analysis of UL97 and UL54 via long-read sequencing enabled the rapid and comprehensive detection of drug resistance mutations.


Assuntos
Antivirais , Infecções por Citomegalovirus , Farmacorresistência Viral , Antivirais/uso terapêutico , Criança , Infecções por Citomegalovirus/congênito , Infecções por Citomegalovirus/tratamento farmacológico , Farmacorresistência Viral/genética , Ganciclovir/uso terapêutico , Humanos , Mutação , Estudos Retrospectivos , Valganciclovir/uso terapêutico
14.
Microbiol Spectr ; 10(3): e0268421, 2022 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-35658598

RESUMO

Cytomegalovirus infection during antiviral prophylaxis occurs in transplant recipients despite individualized regimens based on renal function. Fifty kidney transplant recipients were assessed between 2016 and 2019 for valganciclovir dosing, ganciclovir exposure, cytomegalovirus infection, and genotypic resistance markers during the first year posttransplant. Ganciclovir plasma concentrations were measured using mass spectrometry. Population pharmacokinetics was used to determine individual ganciclovir exposure and to evaluate the ability of manufacturer dosing guidelines to meet therapeutic target daily area under the curve (AUC24) of 40 to 50 µg·h/mL. Full-length UL54 and UL97 were assessed using high-throughput sequencing in cytomegalovirus DNA-positive patient specimens. Valganciclovir doses administered to recipients with creatinine clearance of <40 mL/min were higher than specified by guidelines, and they were lower for recipients with creatinine clearance of ≥40 mL/min. The mean ganciclovir AUC24 was 33 ± 13 µg·h/mL, and 82% of subjects did not attain the therapeutic target. Pharmacokinetic simulations showed that the guidelines similarly could not attain the therapeutic target in 79% of individuals. Cytomegalovirus breakthrough occurred in 6% (3/50) of recipients, while 12% (6/50) developed late-onset infection. The mean AUC24s of recipients with (n = 3) and without (n = 47) infection were not significantly different (P = 0.528). However, one recipient with an AUC24 of 20 µg·h/mL acquired two UL97 ganciclovir resistance mutations. Current prophylaxis guidelines resulted in subtherapeutic ganciclovir exposure in several study recipients, including the emergence of resistance genotypes. IMPORTANCE This study examined the pharmacokinetics and viral genomic data from a prospective cohort of kidney transplant recipients undergoing valganciclovir prophylaxis for cytomegalovirus (CMV) prevention. We showed for the first time using high-throughput sequencing the detection of ganciclovir resistance mutations in breakthrough CMV infection during subtherapeutic plasma ganciclovir as indicated by the pharmacokinetic parameter daily area under the curve (AUC24). In addition, we found that current valganciclovir dosing guidelines for CMV prophylaxis are predicted to attain therapeutic targets in only 21% of recipients, which is consistent with previous pharmacokinetic studies. The novel findings of resistance mutations during subtherapeutic ganciclovir exposure presented here can inform future studies investigating the dynamics of drug selection pressure and the emergence of resistance mutations in vivo.


Assuntos
Infecções por Citomegalovirus , Transplante de Rim , Antivirais/uso terapêutico , Creatinina/uso terapêutico , Citomegalovirus/genética , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/prevenção & controle , Ganciclovir/uso terapêutico , Humanos , Transplante de Rim/efeitos adversos , Transplante de Rim/métodos , Estudos Prospectivos , Transplantados , Valganciclovir/uso terapêutico
15.
Transplant Proc ; 54(4): 1158-1166, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35760629

RESUMO

Cytomegalovirus (CMV) poses a significant threat to solid organ transplant recipients (SOTR). The incidence of CMV disease in SOTR varies according to immunosuppressive therapy, antiviral prophylaxis, donor and recipient serologic compatibility, and the transplanted organ: 9% to 23%, 22% to 29% and 8% to 32% after heart, liver and kidney transplant, respectively. CMV retinitis (CMVR) is a rare manifestation of CMV with a high risk of blindness. Infection may vary in severity, from initially clinically silent cases to full-blown advanced changes involving the eye. The most characteristic effects are changes in the retina, which usually begin at the retina's periphery and are asymptomatic, then these changes spread toward the center as the disease progresses and impairs vision. We describe CMV vitritis and retinitis in a 74-year-old patient after heart transplantation conducted in 1992. The first symptom of the disease was low vision in the left eye. Initially no blood viremia was observed; then the CMV viral load in the blood and vitreous body of the right eye was 2454 and 26 million IU/mL.Despite the initiation of treatment (intravitreal and then intravenous ganciclovir), the inflammatory process progressed rapidly and vision in the left eye was lost, although functional visual acuity in the right eye was maintained. Systemic antiviral therapy with intravenous ganciclovir lasted 6 weeks until the eradication of CMV viremia. The patient was on prophylactic therapy with oral valganciclovir for 12 months. A clinically silent course of CMVR delays diagnosis and therapy. Therefore, it is recommended that all SOTR undergo periodic ophthalmologic control to avoid delayed diagnosis.


Assuntos
Retinite por Citomegalovirus , Transplante de Coração , Idoso , Antivirais/uso terapêutico , Citomegalovirus , Retinite por Citomegalovirus/diagnóstico , Retinite por Citomegalovirus/tratamento farmacológico , Ganciclovir/uso terapêutico , Transplante de Coração/efeitos adversos , Humanos , Valganciclovir/uso terapêutico , Viremia/tratamento farmacológico
16.
Trials ; 23(1): 531, 2022 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-35761406

RESUMO

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.


Assuntos
Infecções por Citomegalovirus , Infecções por HIV , Pneumonia , Tuberculose , Criança , Ensaios Clínicos Fase II como Assunto , Citomegalovirus , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por HIV/complicações , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Humanos , Lactente , Estudos Multicêntricos como Assunto , Pneumonia/complicações , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Tuberculose/diagnóstico , Tuberculose/tratamento farmacológico , Valganciclovir/uso terapêutico
17.
Med. clín (Ed. impr.) ; 158(11): 543-546, junio 2022. tab
Artigo em Espanhol | IBECS | ID: ibc-204672

RESUMO

Antecedentes y objetivo:Se han comparado la eficacia y seguridad de la profilaxis primaria estándar o prolongada de la infección por citomegalovirus (CMV) en el trasplante de órgano sólido.Materiales y métodos:Estudio retrospectivo de los receptores CMV seronegativos de donante seropositivo (D+/R−) que recibieron profilaxis frente a CMV tras un trasplante de órgano sólido (2007-2017). Se comparó la frecuencia de infección por CMV en los 2 primeros años postrasplante en los receptores que recibieron profilaxis durante más o menos de 100 días. Se evaluó asimismo la mielotoxicidad durante la profilaxis.Resultados:Se analizaron 66 pacientes. De ellos el 43,9% (n=29) presentaron infección por CMV. El 68,2% (n=45) recibieron profilaxis prolongada, sin asociarse su uso con una menor tasa de infección (42,2 vs. 47,6%, p=0,44) ni de enfermedad posprofilaxis (15,6 vs. 19%, p=0,72). La profilaxis prolongada se asoció con una mayor frecuencia de mielotoxicidad (68,9 vs. 42,9%, p<0,05).Conclusiones:La prolongación de la profilaxis primaria más de 100 días no aumenta su efectividad pero sí la toxicidad hematológica. (AU)


Background and objective:We compared the efficacy and safety of standard vs. extended primary cytomegalovirus (CMV) prophylaxis in solid organ transplantation.Materials and methods:Retrospective cohort study of CMV seronegative recipients who received CMV prophylaxis after solid organ transplantation from seropositive donor (D+/R−) (2007–2017). CMV infection in the first two years after transplantation in recipients with prophylaxis longer or shorter than 100 days were compared.Results:CMV infection occurred in 29 of 66 patients (43.9%) with prophylaxis. Forty-five patients (68.2%) received extended prophylaxis. CMV infection and disease rates were not different between patients with extended and standard prophylaxis. However, extended prophylaxis was associated with a higher rate of myelotoxicity (68.9% vs. 42.9%, p<0.05).Conclusions:Extending primary CMV prophylaxis over 100 days did not prevent late-onset infection but it was associated with hematological toxicity. (AU)


Assuntos
Humanos , Antivirais/uso terapêutico , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/prevenção & controle , Citomegalovirus , Ganciclovir/uso terapêutico , Transplantes , Estudos Retrospectivos , Valganciclovir/uso terapêutico
18.
Transpl Infect Dis ; 24(4): e13843, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35596686

RESUMO

Graft-versus-hostdisease (GVHD) following liver transplantation (LT) is rare but can lead tosignificant mortality. The leading cause of death following GVHD diagnosis isinfectious complications. However, there is a lack of clear descriptions concerning infection and antimicrobial management patterns. Our study aims toprovide the focused details of all infectious complications of acute GVHDfollowing LT. We retrospectively reviewed all adult LT recipients with acute GVHD at Mayo Clinic's Transplant Centers from January 1, 2010, to December 31, 2021. Detailed characteristics of infection in each case were described. Among 4,585 LTs performed during this period, 12 (0.3%) patients developed acuteGVHD. The median time from transplantation to GVHD diagnosis was 49.0 days [IQR 31.5-99.0]. Ten (83.3%) patients developed severe infections leading tomortality. The most common cause of infection was nosocomial bacteremia fromenteric bacteria such as vancomycin-resistant enterococci and gram-negative bacilli. Other infections included breakthrough invasive fungal infections,cytomegalovirus (CMV) reactivation, and Clostridioides difficile colitis. Antimicrobial prophylaxis strategies in most cases were based on the degree of neutropenia-these include levofloxacin for bacterial prophylaxis, nebulized pentamidine for Pneumocystis jiroveci pneumonia prophylaxis, posaconazole for invasive fungal prophylaxis, and valganciclovir based on CMVstatus. All GVHD patients with severe infections succumbed to thesecomplications. Ourstudy reiterates that despite prophylaxis, infectious complications in GVHDfollowing LT are common and lead to exceptionally high mortality. Individualizedantimicrobial treatment, prophylaxis and monitoring strategies remain a criticalcomponent of GVHD management. Further study to optimize these practices isrequired.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Transplante de Fígado , Pneumonia por Pneumocystis , Doença Aguda , Adulto , Antibacterianos/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Transplante de Fígado/efeitos adversos , Pneumonia por Pneumocystis/tratamento farmacológico , Estudos Retrospectivos , Valganciclovir/uso terapêutico
19.
Antivir Ther ; 27(2): 13596535211060968, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35499094

RESUMO

In the mid 1980's, I flew from Birmingham, Alabama to San Francisco, rented a car, and drove to Palo Alto so that I could meet with John Martin at Syntex. John, along with Julian Verheyden, synthesized ganciclovir, which had significant in vitro activity against cytomegalovirus (CMV) in vitro. This drug provided my colleagues and me an opportunity to evaluate it as a therapeutic agent for congenital CMV infection, knowing full well that it was mutagenic, teratogenic, and carcinogenic. John in his wisdom convinced the management of Syntex to provide ganciclovir for this disease, allowing me to study this drug in symptomatic congenitally infected children through the NIAID Collaborative Antiviral Study Group (CASG). Certainly, no other person or company would advocate for the use of such a medication in children, regardless of disease severity, because of its toxicity profile. Since these early days, ganciclovir, and subsequently its prodrug valganciclovir, have become the standard of care for the treatment of congenital cytomegalovirus infection. The following commentary defines the need and progress in the development of therapy.


Assuntos
Infecções por Citomegalovirus , Antivirais/farmacologia , Antivirais/uso terapêutico , Criança , Citomegalovirus , Infecções por Citomegalovirus/tratamento farmacológico , Ganciclovir/uso terapêutico , Humanos , Valganciclovir/uso terapêutico
20.
J Pediatric Infect Dis Soc ; 11(8): 379-382, 2022 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-35532552

RESUMO

Among 342 US infants with congenital cytomegalovirus treated with antivirals, 114 (33%) received ganciclovir (with or without valganciclovir) and 228 (67%) received valganciclovir only, for a median of 8 and 171 days, starting at a median of 15 and 45 days of life, respectively, with neutropenia diagnosed in 25% and 17%.


Assuntos
Infecções por Citomegalovirus , Ganciclovir , Antivirais/uso terapêutico , Citomegalovirus , Infecções por Citomegalovirus/congênito , Infecções por Citomegalovirus/tratamento farmacológico , Registros Eletrônicos de Saúde , Ganciclovir/uso terapêutico , Humanos , Lactente , Estados Unidos , Valganciclovir/uso terapêutico
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