ABSTRACT
BACKGROUND: The risk of cytomegalovirus (CMV) infection in solid organ transplant recipients has resulted in the frequent use of prophylaxis to prevent the clinical syndrome associated with CMV infection. This is an update of a review first published in 2005 and updated in 2008 and 2013. OBJECTIVES: To determine the benefits and harms of antiviral medications to prevent CMV disease and all-cause death in solid organ transplant recipients. SEARCH METHODS: We contacted the information specialist and searched the Cochrane Kidney and Transplant Register of Studies up to 5 February 2024 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing antiviral medications with placebo or no treatment, comparing different antiviral medications or different regimens of the same antiviral medications for CMV prophylaxis in recipients of any solid organ transplant. Studies examining pre-emptive therapy for CMV infection are studied in a separate review and were excluded from this review. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study eligibility, risk of bias and extracted data. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: This 2024 update found four new studies, bringing the total number of included studies to 41 (5054 participants). The risk of bias was high or unclear across most studies, with a low risk of bias for sequence generation (12), allocation concealment (12), blinding (11) and selective outcome reporting (9) in fewer studies. There is high-certainty evidence that prophylaxis with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment is more effective in preventing CMV disease (19 studies: RR 0.42, 95% CI 0.34 to 0.52), all-cause death (17 studies: RR 0.63, 95% CI 0.43 to 0.92), and CMV infection (17 studies: RR 0.61, 95% CI 0.48 to 0.77). There is moderate-certainty evidence that prophylaxis probably reduces death from CMV disease (7 studies: RR 0.26, 95% CI 0.08 to 0.78). Prophylaxis reduces the risk of herpes simplex and herpes zoster disease, bacterial and protozoal infections but probably makes little to no difference to fungal infection, acute rejection or graft loss. No apparent differences in adverse events with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment were found. There is high certainty evidence that ganciclovir, when compared with aciclovir, is more effective in preventing CMV disease (7 studies: RR 0.37, 95% CI 0.23 to 0.60). There may be little to no difference in any outcome between valganciclovir and IV ganciclovir compared with oral ganciclovir (low certainty evidence). The efficacy and adverse effects of valganciclovir or ganciclovir were probably no different to valaciclovir in three studies (moderate certainty evidence). There is moderate certainty evidence that extended duration prophylaxis probably reduces the risk of CMV disease compared with three months of therapy (2 studies: RR 0.20, 95% CI 0.12 to 0.35), with probably little to no difference in rates of adverse events. Low certainty evidence suggests that 450 mg/day valganciclovir compared with 900 mg/day valganciclovir results in little to no difference in all-cause death, CMV infection, acute rejection, and graft loss (no information on adverse events). Maribavir may increase CMV infection compared with ganciclovir (1 study: RR 1.34, 95% CI: 1.10 to 1.65; moderate certainty evidence); however, little to no difference between the two treatments were found for CMV disease, all-cause death, acute rejection, and adverse events at six months (low certainty evidence). AUTHORS' CONCLUSIONS: Prophylaxis with antiviral medications reduces CMV disease and CMV-associated death, compared with placebo or no treatment, in solid organ transplant recipients. These data support the continued routine use of antiviral prophylaxis in CMV-positive recipients and CMV-negative recipients of CMV-positive organ transplants.
Subject(s)
Antiviral Agents , Cytomegalovirus Infections , Ganciclovir , Organ Transplantation , Randomized Controlled Trials as Topic , Humans , Acyclovir/therapeutic use , Acyclovir/adverse effects , Antiviral Agents/therapeutic use , Antiviral Agents/adverse effects , Bias , Cause of Death , Cytomegalovirus Infections/prevention & control , Ganciclovir/therapeutic use , Ganciclovir/adverse effects , Ganciclovir/analogs & derivatives , Organ Transplantation/adverse effects , Postoperative Complications/prevention & control , Transplant Recipients , Valacyclovir/adverse effects , Valacyclovir/therapeutic use , Valganciclovir/adverse effects , Valganciclovir/therapeutic useABSTRACT
PURPOSE OF REVIEW: Universal and targeted screening of newborns for congenital cytomegalovirus (CMV) infection is increasing globally. Questions remain concerning the management of infants who have been identified with congenital CMV infection, especially those with "minimally symptomatic" or clinically inapparent infection. Our objective is to discuss current management of CMV-infected neonates with a focus on less affected infants with or without sensorineural hearing loss (SNHL). RECENT FINDINGS: Valganciclovir is being prescribed increasingly in neonates with congenital CMV infection for improvement in hearing outcomes through 2 years of age. Treatment initiated in the first month of age is recommended for clinically apparent disease. A recent study showed hearing improvement at 18-22âmonths of age when therapy was initiated at age 1-3 months in infants with clinically inapparent CMV infection and isolated SNHL. SUMMARY: Antiviral therapy with either ganciclovir or valganciclovir has shown moderate benefit in prevention of hearing deterioration among infants with clinically apparent CMV infection or isolated SNHL. Sustainability of benefit beyond 2 years of age remains unknown. At present, infants with clinically inapparent CMV infection (normal complete evaluation including hearing) should not receive antiviral therapy. All CMV-infected infants require close audiological and neurodevelopmental follow-up.
Subject(s)
Antiviral Agents , Cytomegalovirus Infections , Ganciclovir , Hearing Loss, Sensorineural , Valganciclovir , Humans , Cytomegalovirus Infections/congenital , Cytomegalovirus Infections/drug therapy , Cytomegalovirus Infections/diagnosis , Cytomegalovirus Infections/complications , Antiviral Agents/therapeutic use , Hearing Loss, Sensorineural/virology , Hearing Loss, Sensorineural/diagnosis , Hearing Loss, Sensorineural/etiology , Infant, Newborn , Valganciclovir/therapeutic use , Ganciclovir/therapeutic use , Ganciclovir/analogs & derivatives , Infant , Neonatal Screening/methodsABSTRACT
BACKGROUND: Valganciclovir (valG), a cytomegalovirus (CMV) prophylactic agent, has dose-limiting side effects. The tolerability and effectiveness of valacyclovir (valA) as CMV prophylaxis is unknown. METHODS: We conducted a randomized, open-label, single-center trial of valA versus valG for all posttransplant CMV prophylaxis in adult and pediatric kidney recipients. Participants were randomly assigned to receive valA or valG. Primary endpoints were the incidence of CMV viremia and side-effect related drug reduction with secondary assessment of incidence of EBV viremia. RESULTS: Of the 137 sequential kidney transplant recipients enrolled, 26 % were positive and negative for CMV antibody in donor and recipient respectively. The incidence of CMV viremia (4 of 71 [6 %]; 8 of 67 [12 %] P = 0.23), time to viremia (P = 0.16) and area under CMV viral load time curve (P = 0.19) were not significantly different. ValG participants were significantly more likely to require side-effect related dose reduction (15/71 [21 %] versus 1/66 [2 %] P = 0.0003). Leukopenia was the most common reason for valG dose reduction and granulocyte-colony stimulating factor was utilized for leukopenia recovery more frequently (25 % in valG vs 5 % in valA: P = 0.0007). Incidence of EBV viremia was not significantly different. CONCLUSIONS: ValA has significantly less dose-limiting side effects than valG. In our study population, a significant increase in CMV viremia was not observed, in adults and children after kidney transplant, compared to valG. TRIAL REGISTRATION NUMBER: NCT01329185.
Subject(s)
Antiviral Agents , Cytomegalovirus Infections , Ganciclovir , Kidney Transplantation , Transplant Recipients , Valacyclovir , Valganciclovir , Humans , Valacyclovir/therapeutic use , Cytomegalovirus Infections/prevention & control , Valganciclovir/therapeutic use , Valganciclovir/administration & dosage , Kidney Transplantation/adverse effects , Antiviral Agents/therapeutic use , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Male , Female , Adult , Child , Middle Aged , Adolescent , Ganciclovir/analogs & derivatives , Ganciclovir/therapeutic use , Ganciclovir/administration & dosage , Ganciclovir/adverse effects , Viremia/prevention & control , Viral Load , Young Adult , Valine/analogs & derivatives , Valine/therapeutic use , Valine/administration & dosage , Cytomegalovirus/immunology , Cytomegalovirus/drug effects , Child, Preschool , Acyclovir/therapeutic use , Acyclovir/analogs & derivatives , Acyclovir/administration & dosage , Acyclovir/adverse effects , Aged , Treatment Outcome , IncidenceABSTRACT
BACKGROUND AND OBJECTIVES: Ganciclovir (GCV) and valganciclovir (VGCV) show large interindividual pharmacokinetic variability, particularly in children. The objectives of this study were (1) to develop machine learning (ML) algorithms trained on simulated pharmacokinetics profiles obtained by Monte Carlo simulations to estimate the best ganciclovir or valganciclovir starting dose in children and (2) to compare its performances on real-world profiles to previously published equation derived from literature population pharmacokinetic (POPPK) models achieving about 20% of profiles within the target. MATERIALS AND METHODS: The pharmacokinetic parameters of four literature POPPK models in addition to the World Health Organization (WHO) growth curve for children were used in the mrgsolve R package to simulate 10,800 pharmacokinetic profiles. ML algorithms were developed and benchmarked to predict the probability to reach the steady-state, area-under-the-curve target (AUC0-24 within 40-60 mg × h/L) based on demographic characteristics only. The best ML algorithm was then used to calculate the starting dose maximizing the target attainment. Performances were evaluated for ML and literature formula in a test set and in an external set of 32 and 31 actual patients (GCV and VGCV, respectively). RESULTS: A combination of Xgboost, neural network, and random forest algorithms yielded the best performances and highest target attainment in the test set (36.8% for GCV and 35.3% for the VGCV). In actual patients, the best GCV ML starting dose yielded the highest target attainment rate (25.8%) and performed equally for VGCV with the Franck model formula (35.3% for both). CONCLUSION: The ML algorithms exhibit good performances in comparison with previously validated models and should be evaluated prospectively.
Subject(s)
Antiviral Agents , Ganciclovir , Machine Learning , Monte Carlo Method , Valganciclovir , Humans , Ganciclovir/pharmacokinetics , Ganciclovir/administration & dosage , Ganciclovir/analogs & derivatives , Valganciclovir/pharmacokinetics , Valganciclovir/administration & dosage , Child , Antiviral Agents/pharmacokinetics , Antiviral Agents/administration & dosage , Child, Preschool , Male , Female , Adolescent , Infant , Models, Biological , Algorithms , Area Under Curve , Computer SimulationABSTRACT
INTRODUCTION: Insurance coverage for oral valganciclovir (VGCV) began in Japan in April 2023 on the basis of results, including our clinical trials for symptomatic congenital cytomegalovirus (CMV) disease. The VGCV treatment is available throughout Japan, so clinicians must consider the likelihood of hearing improvement and the possibility of neutropenia before dosing. MATERIALS AND METHODS: We performed a substudy of an investigator-initiated, single-arm, prospective, multicenter, clinical trial in which 24 infants with symptomatic congenital CMV disease were orally administered 16 mg/kg VGCV twice daily for 6 months as an intervention. We examined the infants' baseline characteristics associated with improved hearing impairment or a severely reduced neutrophil count. RESULTS: Of the 24 patients, 4 had normal hearing on assessment of their ear with the best hearing. Hearing impairment improved in 14 patients and did not respond to VGCV treatment in 6 patients at the 6-month hearing assessment. CMV DNA levels in plasma at baseline were higher in patients in whom hearing did not respond to treatment. A neutrophil count <500/mm3 occurred in 5 (21%) patients for the first 6 weeks and in 8 (33%) patients for the first 6 months. A neutrophil count at screening and the lowest neutrophil count over the 6 months showed the highest correlation (r = 0.477, p = 0.019). CONCLUSIONS: Infants with a low plasma viral load at screening tend to have an improvement in hearing impairment. Clinicians should be aware of neutropenia during VGCV treatment particularly in patients with a low neutrophil count during screening.
Subject(s)
Antiviral Agents , Cytomegalovirus Infections , Cytomegalovirus , Neutropenia , Valganciclovir , Humans , Valganciclovir/therapeutic use , Valganciclovir/administration & dosage , Cytomegalovirus Infections/drug therapy , Cytomegalovirus Infections/virology , Antiviral Agents/therapeutic use , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Female , Infant , Male , Prospective Studies , Administration, Oral , Cytomegalovirus/isolation & purification , Cytomegalovirus/drug effects , Cytomegalovirus/genetics , Infant, Newborn , Japan , Treatment Outcome , Hearing Loss/virology , DNA, Viral/blood , Ganciclovir/analogs & derivatives , Ganciclovir/administration & dosage , Ganciclovir/therapeutic use , Ganciclovir/adverse effects , Neutrophils/drug effectsABSTRACT
OBJECTIVE: To assess the efficacy of valganciclovir in infants with hearing loss and clinically inapparent congenital cytomegalovirus infection (cCMV), as there is no consensus on treatment of this group. STUDY DESIGN: A nationwide, nonrandomized controlled trial, comparing 6 weeks of oral valganciclovir to no treatment in infants with cCMV, recruited after newborn hearing screening resulted in referral to an audiologist. The choice whether to treat was left to parents of subjects. Eligible subjects were full term infants aged <13 weeks with sensorineural hearing loss and diagnosed with cCMV through dried blood spot testing. The primary outcome, measured by linear and ordinal logistic regression, was change in best-ear hearing from baseline to follow-up at 18-22 months of age. RESULTS: Thirty-seven participants were included in the final analysis, of whom 25 were in the treatment group and 12 in the control group. The majority of subjects in both groups had neuroimaging abnormalities, which were mostly mild. Hearing deterioration was more likely in the control group compared with the treatment group (common OR 0.10, 95% CI 0.02-0.45, P = .003). Mean best-ear hearing deteriorated by 13.7 dB in the control group, compared with improvement of 3.3 dB in the treatment group (difference 17 dB, 95% CI 2.6 - 31.4, P = .02). CONCLUSIONS: We investigated treatment in children with hearing loss and clinically inapparent cCMV. Although our study was nonrandomized, it is the first prospective and controlled trial in this population. Valganciclovir-treated children with hearing loss and inapparent cCMV had less hearing deterioration at 18 through 22 months of age than control subjects. EUDRACT REGISTRY NUMBER: 2013-003068-30.
Subject(s)
Antiviral Agents , Cytomegalovirus Infections , Hearing Loss, Sensorineural , Valganciclovir , Humans , Valganciclovir/therapeutic use , Cytomegalovirus Infections/drug therapy , Cytomegalovirus Infections/congenital , Cytomegalovirus Infections/complications , Antiviral Agents/therapeutic use , Male , Female , Infant , Infant, Newborn , Hearing Loss, Sensorineural/drug therapy , Treatment Outcome , Ganciclovir/analogs & derivatives , Ganciclovir/therapeutic use , Neonatal Screening , Prospective Studies , Follow-Up Studies , Administration, OralABSTRACT
OBJECTIVE: The objective of this study was to determine if valganciclovir initiated after 1 month of age improves congenital cytomegalovirus-associated sensorineural hearing loss. STUDY DESIGN: We conducted a randomized, double-blind, placebo-controlled phase 2 trial of 6 weeks of oral valganciclovir at US (n = 12) and UK (n = 9) sites. Patients of ages 1 month through 3 years with baseline sensorineural hearing loss were enrolled. The primary outcome was change in total ear hearing between baseline and study month 6. Secondary outcome measures included change in best ear hearing and reduction in cytomegalovirus viral load in blood, saliva, and urine. RESULTS: Of 54 participants enrolled, 35 were documented to have congenital cytomegalovirus infection and were randomized (active group: 17; placebo group: 18). Mean age at enrollment was 17.8 ± 15.8 months (valganciclovir) vs 19.5 ± 13.1 months (placebo). Twenty (76.9%) of the 26 ears from subjects in the active treatment group did not have worsening of hearing, compared with 27 (96.4%) of 28 ears from subjects in the placebo group (P = .09). All other comparisons of total ear or best ear hearing outcomes were also not statistically significant. Saliva and urine viral loads decreased significantly in the valganciclovir group but did not correlate with change in hearing outcome. CONCLUSIONS: In this randomized controlled trial, initiation of antiviral therapy beyond the first month of age did not improve hearing outcomes in children with congenital cytomegalovirus-associated sensorineural hearing loss. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01649869.
Subject(s)
Antiviral Agents , Cytomegalovirus Infections , Ganciclovir , Hearing Loss, Sensorineural , Valganciclovir , Humans , Cytomegalovirus Infections/drug therapy , Cytomegalovirus Infections/congenital , Cytomegalovirus Infections/complications , Valganciclovir/therapeutic use , Valganciclovir/administration & dosage , Hearing Loss, Sensorineural/drug therapy , Hearing Loss, Sensorineural/virology , Hearing Loss, Sensorineural/etiology , Antiviral Agents/therapeutic use , Antiviral Agents/administration & dosage , Male , Female , Double-Blind Method , Infant , Administration, Oral , Ganciclovir/analogs & derivatives , Ganciclovir/therapeutic use , Ganciclovir/administration & dosage , Child, Preschool , Treatment Outcome , Viral Load , Infant, NewbornABSTRACT
Introduction: Heart transplantation remains as the treatment of choice when the heart failure is refractory to the medical or surgical therapy. Therefore, cytomegalovirus disease is an important post-heart-transplant infectious complication. Aims: To describe the prevalence and clinical characteristics of the cytomegalovirus disease after heart transplant surgery. Materials and Methods: A retrospective, descriptive study was conducted. It enrolled 35 heart-transplant patients attended in the Cardiovascular National Institute (INCOR), between 2010 and 2015. The information was obtained through the review of medical records. The demographic and relevant clinical variables were analyzed for the cytomegalovirus disease cases. Results: The population mean age was 39.49 ± 15.07 years and most of them were male patients (63%). The prevalence of the cytomegalovirus disease was 5.7% (two patients), both were seronegative for cytomegalovirus before transplantation. One of the patients had the disease before finishing the valganciclovir prophylaxis and the other after the end of it. Conclusion: The prevalence of the cytomegalovirus disease is slightly lower than in other studies. Moreover, the cytomegalovirus disease can remit with a prompt diagnosis and the proper medical treatment.
Introducción: El trasplante cardiaco es el tratamiento de elección ante la falla cardiaca refractaria a la terapia médica o quirúrgica. En base a ello, la enfermedad por citomegalovirus (CMV) es una importante complicación infecciosa post-trasplante de corazón. Objetivos: Describir la prevalencia y las características clínicas de los pacientes que desarrollaron enfermedad por CMV posttrasplante de corazón. Materiales y Métodos: Se realizó un estudio retrospectivo y descriptivo, donde se incluyó a los 35 pacientes que recibieron trasplante de corazón en el Instituto Nacional Cardiovascular entre el período 2010-2015. La información se obtuvo mediante la revisión de historias clínicas. Se analizaron las variables demográficas y clínicas relevantes de los casos con enfermedad por CMV. Resultados: La edad media de la población fue de 39,49 ± 15,07 años, siendo la mayoría de sexo masculino (63%). La prevalencia de la enfermedad por CMV fue de 5,7%, -dos pacientes-, ambos con serología negativa para CMV previa al trasplante. Uno de ellos presentó la enfermedad antes de terminar la profilaxis con valganciclovir y el otro luego del cese de la misma. Conclusión: La prevalencia de la enfermedad por CMV es ligeramente menor que en otros estudios. Asimismo, ésta puede remitir con un pronto diagnóstico y el adecuado tratamiento médico.
Subject(s)
Humans , Male , Female , Adult , Heart Transplantation/adverse effects , Cytomegalovirus Infections/prevention & control , Ganciclovir/analogs & derivatives , Ganciclovir/therapeutic use , Retrospective Studies , Cytomegalovirus Infections/etiology , Valganciclovir , Immunosuppressive Agents/therapeutic useABSTRACT
INTRODUÇÃO: Citomegalovírus (CMV) pertence à família dos Herpesvírus, e possui a característica de se manter no hospedeiro por tempo prolongado, como uma infecção latente, após a resolução da fase aguda, com maior risco para indivíduos imunossuprimidos. A soroprevalência do CMV oscila conforme a área geográfica, idade e se mostra mais alta em países desenvolvidos, com uma taxa de 50% na população adulta dos EUA. A doença por CMV não apresenta um quadro clínico específico, podendo se manifestar por meio de febre, leucopenia, mononucleose, trombocitopenia, hepatite, encefalite ou infecção do trato gastrointestinal. Os meios de transmissão do vírus ocorrem por contato sexual, ou por exposição ao sangue e tecidos, como no caso dos transplantes de órgãos sólidos de doadores positivos. Grande parte dos casos não estão associados a nenhum sintoma em hospedeiros imunocompetentes. E nos casos de pacientes com infecção por CMV sintomática, como a síndrome de mononucleose, a doença se apresenta auto-limitada, com recuperação completa ao longo de um período de dias a semanas. Nesses casos a terapia antiviral nem está comumente indicada. A infecção por CMV é uma importante causa de morbidade e mortalidade em receptores de transplantes de órgãos sólidos, nos primeiros seis meses pós-transplante, devido à imunossupressão. E tem sido bem descrita como a complicação de maior ocorrência em transplantes, com um risco cinco vezes aumentado para mortalidade global e onze vezes para óbito associado à infecção por CMV. Portanto, prevenção e tratamento da infecção e doença por CMV é de extrema importância para assegurar o sucesso de um transplante. A prevalência da doença em pacientes transplantados oscila entre 30% e 50%, dependendo do tipo de órgão sólido. Pode ocorrer em aproximadamente 60% dos transplantados categorizados como de alto risco, onde o receptor é negativo e o doador soropositivo. Mas também no grupo de receptores com sorologia positiva pré-transplante, onde o risco de infecção por reativação da doença é de 10% a 30%. Além de estar associada a aumentado risco de rejeição do enxerto em transplantes. TECNOLOGIAS Valganciclovir (VG) é um medicamento antiviral, pró-fármaco do ganciclovir. Atua por inibição da síntese do DNA viral. Aprovado em 2001 pela Food and Drug Administration (FDA), e com registro na Agência Nacional de Vigilância Sanitária (ANVISA) sob a forma de comprimidos revestidos de 450 mg. Indicado para o tratamento de retinite em pacientes portadores do HIV/Aids e para a prevenção da doença por CMV em pacientes transplantados de rim, coração e pâncreas. A recomendação para a profilaxia da doença pelo CMV, em pacientes pós transplante de rim, coração e pâncreas é de 900 mg por dia, via oral. E para o tratamento da infecção ou terapia preemptiva é de 900 mg 2 x ao dia por 21 dias. Ganciclovir (GC) é um análogo do nucleosídeo 2'-desoxiguanosina, com uma estrutura semelhante à do aciclovir. Sua atividade inibidora dos Herpesvírus tem especial ação contra o CMV. Eliminação renal elevada necessitando de ajuste da dose em pacientes com insuficiência renal. Possui baixa biodisponibilidade por via oral (6% a 9%) e tem sido comercializado sob a forma endovenosa, na concentração de 1 mg/ml com registro autorizado pela ANVISA. Indicado para o tratamento e prevenção de infecções por CMV em imunodeprimidos (transplantes). A dose recomendada é de 5 mg/Kg 2 x ao dia, por 14 ou 21 dias. PERGUNTA CLÍNICA: O medicamento Valganciclovir na apresentação oral para o tratamento de pacientes pós-transplante cardíaco com diagnóstico de viremia por citomegalovírus é mais custo-efetivo comparado ao tratamento padrão com Ganciclovir na apresentação endovenosa? ANÁLISE DA EVIDÊNCIA: Evidências descritas pelo demandante: -Eficácia no tratamento de viremia por CMV e na doença órgão específico por via oral, com boa biodisponibilidade e tolerância; -O tratamento por via oral possibilita a liberação do paciente para o domicílio e possui menor risco de complicações em comparação ao uso endovenoso (acesso vascular, internação); -Pequeno número de pacientes com indicação.MÉTODO: O demandante solicitou a avaliação de custos do medicamento Valganciclovir por via oral, como opção ao uso endovenoso do Galvanciclovir. E como justificativa descreveu a possibilidade de evitar a internação e os riscos inerentes ao uso de medicação endovenosa para os pacientes em pós-operatório de transplante cardíaco, que apresentam sorologias positivas para CMV durante o acompanhamento ambulatorial e necessitam de tratamento para a viremia. DISCUSSÃO: O Valganciclovir é um medicamento largamente indicado, como opção dentre as estratégias de terapia preemptiva para a doença por CMV, sendo mais utilizado em pacientes submetidos ao transplante de órgãos sólidos, apesar de seu alto custo. Uma das principais razões para sua popularidade está associada à sua apresentação por via oral, que demonstrou maior eficácia e biodisponibilidade do que os demais antivirais disponíveis. Diversos estudos demonstram eficácia semelhante do Valganciclovir comparado aos demais antivirais. Entretanto, poucos estudos compararam diretamente VG ao GC, e alguns ainda classificaram profilaxia como terapia preemptiva. No entanto, recentemente uma revisão sistemática com metanálise comparou o uso do VG oral ao GC em sua apresentação endovenosa, confirmando similar eficácia entre os dois medicamentos, o que permite garantir um tratamento mais confortável para o paciente imunossuprimido. As diferentes estratégias de prevenção do CMV e algumas questões relativas à eficácia e economia permanecem em discussão. Importante salientar que, uma das indicações de uso para o valganciclovir é o paciente ambulatorial, que se submeteu a um transplante de órgão sólido e, dessa forma pode evitar uma internação hospitalar relativamente longa, com os riscos já conhecidos para um paciente imunossuprimido, mantido em um acesso venoso. Sem considerar os benefícios intangíveis, como o stress pelo afastamento familiar, o risco de qualquer intercorrência durante sua internação e a oportunidade de utilizar o leito hospitalar para outro paciente. O custo incremental entre os dois tratamentos foi elevado, no entanto o impacto orçamentário anual não foi grande, face a uma baixa prevalência de casos positivos (2 casos/ano), pode ser considerado favorável ao se ponderar que o benefício ao paciente pós transplante cardíaco será a prevenção de doença por CMV e suas possíveis complicações em pacientes transplantados sucesso do paciente transplantado representa um benefício institucional e já implica em uma grande utilização de recursos prévia. RECOMENDAÇÃO: Recomendação fraca a favor da Incorporação do Valganciclovir com controle de dispensação conforme protocolo.
Subject(s)
Humans , Ganciclovir/analogs & derivatives , Ganciclovir/therapeutic use , Technology Assessment, Biomedical , Viremia/drug therapy , Health Evaluation/economics , Cost-Benefit Analysis , Cytomegalovirus Infections/drug therapyABSTRACT
Introducción: Valganciclovir es un medicamento de uso oral, que se metaboliza rápidamente a ganciclovir y es una opción para la profilaxis y el tratamiento de la infección por citomegalovirus en pacientes receptores e trasplante de órgano sólido. Esta evaluación tecnológica se desarrolló en el marco de la actualización integral del Plan Obligatorio de Salud para el año 2015. Objetivo: Evaluar la efectividad y seguridad del uso de valganciclovir para la prevención y el tratamiento de infección por citomegalovirus comparada con gancinclovir, valaciclovir y aciclovir en pacientes receptores de trasplante de órgano sólido. Metodología: La evaluación fue realizada de acuerdo con un protocolo definido a priori por el grupo desarrollador. Se realizó una búsqueda sistemática en MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects y LILACS, con restricción al idioma inglés y español y limitada a revisiones sistemáticas publicadas en los últimos cinco años y ensayos clínicos sin restricción de tiempo. Las búsquedas electrónicas fueron hechas entre octubre y diciembre de 2014 y se complementaron mediante búsqueda manual en bola de nieve y una consulta con expertos temáticos. La tamización de referencias se realizó por un revisor. La selección de estudios fue realizada mediante la revisión en texto completo de las referencias preseleccionadas, verificando los criterios de elegibilidad. La calidad de los estudios fue valorada con la herramienta de riesgo de sesgo de la Colaboración Cochrane. Las características de los estudios fueron extraídas a partir de las publicaciones originales. Se realizó una síntesis narrativa de las estimaciones del efecto para las comparaciones y desenlaces de interés a partir de los estudios de mejor calidad. Se estimaron medidas combinadas del efecto a través de un metanálisis con el método de Mantel-Haenszel y un modelo de efectos aleatorios, empleando el programa RevMan 5.2. Resultados: En relación a efectividad: Valganciclovir es tan efectivo como ganciclovir intravenoso y valaciclovir oral en la profilaxis de enfermedad por citomegalovirus en pacientes receptores de trasplante de órgano sólido, pues no se encontraron diferencias con significancia estadística en los desenlaces enfermedad por citomegalovirus a los seis y doce meses (RR=0.76 (0.47, 1.24) y RR 0.93 (0.60, 1.44) respectivamente), rechazo del órgano trasplantado a los seis y doce meses (RR 0.85 (0.64, 1.14) y RR 0.78 (0.49, 1.23)) y supervivencia del paciente al año (RR=1.01 (0.97, 1.06). Valganciclovir es tan efectivo como ganciclovir oral en el tratamiento de enfermedad por CMV de pacientes receptores de trasplante de órgano sólido, pues no se encontraron diferencias con significancia estadística en los desenlaces cura clínica a los 21 días (77.4% para valganciclovir oral y 80.3% ganciclovir intravenoso, p=no significativa), cura clínica a los 49 días (85.4% para valganciclovir oral y 84.1% ganciclovir intravenoso, p=no significativa) y supervivencia del paciente a los 49 días. En relación a seguridad: Valganciclovir es tan seguro como ganciclovir y valaciclovir en la producción de eventos adversos, sin embargo, tiene una menor proporción de eventos adversos que lleven a la suspensión del medicamento antiviral (RR=0.1, (0.02, 0.51)), en el escenario de la profilaxis universal de la infección por CMV en pacientes receptores de trasplante de órgano sólido. Conclusiones: Valganciclovir es similar en seguridad y eficacia que ganciclovir intravenoso y valaciclovir oral en el escenario de la profilaxis de la infección por CMV en el paciente receptor de trasplante de órgano sólido y además valganciclovir es semejante a ganciclovir intravenoso en el tratamiento de esta infección en esta misma población.(AU)
Subject(s)
Humans , Acyclovir/administration & dosage , Acyclovir/analogs & derivatives , Ganciclovir/administration & dosage , Ganciclovir/analogs & derivatives , Organ Transplantation , Transplant Recipients , Reproducibility of Results , Treatment Outcome , Colombia , Biomedical TechnologyABSTRACT
TECNOLOGIA: Valganciclovir. INDICAÇÃO: Prevenção da doença por citomegalovírus em receptores de transplante de órgão sólido rim, coração, pâncreas. CARACTERIZAÇÃO DA TECNOLOGIA: Valganciclovir é um medicamento antiviral, L-valil éster (pró-fármaco) do ganciclovir. Atua inibindo a síntese do DNA viral, por meio da inibição competitiva da incorporação da desoxiguanosina trifosfato pela DNA polimerase viral e pela incorporação do trifosfato de ganciclovir ao DNA viral. PERGUNTA: O uso do valganciclovir é mais eficaz e seguro que as alternativas terapêuticas existentes para prevenção da doença pelo citomegalovírus em receptores de transplante de órgão sólido? TECNOLOGIA: Valganciclovir. INDICAÇÃO: Prevenção da doença por citomegalovírus em receptores de transplante de órgão sólido rim, coração, pâncreas. CARACTERIZAÇÃO DA TECNOLOGIA: Valganciclovir é um medicamento antiviral, L-valil éster (pró-fármaco) do ganciclovir. Atua inibindo a síntese do DNA viral, por meio da inibição competitiva da incorporação da desoxiguanosina trifosfato pela DNA polimerase viral e pela incorporação do trifosfato de ganciclovir ao DNA viral. PERGUNTA: O uso do valganciclovir é mais eficaz e seguro que as alternativas terapêuticas existentes para prevenção da doença pelo citomegalovírus em receptores de transplante de órgão sólido? BUSCA E QUALIDADE DAS EVIDÊNCIAS CIENTÍFICAS: Foram pesquisadas as bases de dados The Cochrane Library (via Bireme), Medline (via Pubmed), LILACS e Centre for Reviews and Dissemination (CRD). Incluíram-se revisões sistemáticas (RS) e metanálises de ensaios clínicos que comparassem valganciclovir com outros medicamentos antivirais. Os estudos foram avaliados segundo o sistema GRADE. Foi realizada, também, busca por avaliações de tecnologias em saúde (ATS) em sites de agências internacionais e da Rede Brasileira de Avaliação de Tecnologias em Saúde (REBRATS). RESUMO DOS RESULTADOS DOS ESTUDOS SELECIONADOS: Foram selecionadas sete revisões sistemáticas, cuja qualidade variou de muito baixa a baixa. A maioria delas não mostrou eficácia significativamente superior do valganciclovir na prevenção da doença pelo citomegalovírus em pacientes receptores de transplante de órgãos sólidos, quando comparado às alternativas terapêuticas existentes. Além disso, o seu uso, sobretudo na dose de 900mg/dia, mostrou-se estatisticamente associado ao risco de desenvolvimento de leucopenia e/ou neutropenia. Não foi recuperada nenhuma ATS nos sites da REBRATS e das principais agências internacionais. RECOMENDAÇÕES: Considerando a qualidade da evidência, os resultados apresentados e o maior custo frente às alternativas terapêuticas existentes, recomenda-se fracamente contra o uso do valganciclovir na prevenção da doença pelo citomegalovírus em pacientes receptores de transplante de órgãos sólidos. Contudo, mais estudos transplante-específicos são necessários para avaliação da sua eficácia, conforme o tipo de órgão sólido transplantado.(AU)
TECHNOLOGY: Valganciclovir. INDICATION: Prevention of cytomegalovirus disease in solid organ transplant recipients. CHARACTERIZATION OF THE TECHNOLOGY: Valganciclovir is an antiviral drug, L-valyl ester (prodrug) of ganciclovir. It acts by inhibiting the viral DNA synthesis by a competitive inhibition of deoxyguanosine triphosphate incorporation to the viral DNA. QUESTION: Is valganciclovir more effective and safer than other available therapies for cytomegalovirus prevention in solid organ transplant patients? ? SEARCH AND ANALYSIS OF SCIENTIFIC EVIDENCE: We searched the Medline (via Pubmed), The Cochrane Library (via Bireme), Lilacs and the Centre for Reviews Dissemination (CRD). Systematic Reviews (SR) of clinical trials comparing valganciclovir to other antiviral drugs were included. Health Technologies Assessment (HTA) reports of international agencies were also searched. The quality of evidence and strength of recommendation were assessed using the GRADE system. SUMMARY OF RESULTS OF SELECTED STUDIES: Seven SR were included and most of them presented low quality. None showed significantly superior efficacy of valganciclovir in cytomegalovirus prevention in solid organ transplants patients, when compared to therapeutic alternatives. In addition, its use, especially in 900mg/day dose, was statistically associated with the risk of leucopenia or neutropenia. We did not include any HTA. RECOMMENDATIONS: The strength of recommendation is weak against valganciclovir for cytomegalovirus prevention in solid organ transplants patients, considering the quality of the evidence and the higher cost of treatment compared to therapeutic alternatives. However, more transplant-specific studies are needed to evaluate its effectiveness in each type of solid organ transplant.(AU)
TECNOLOGÍA: Valganciclovir. INDICACIÓN: La prevención de la enfermedad por citomegalovirus en los receptores de trasplante de órgano sólido. CARACTERIZACIÓN DE LA TECNOLOGÍA: El valganciclovir es un fármaco antiviral, éster L-valina (profármaco) del ganciclovir. Actúa mediante la inhibición de la síntesis de ADN viral por medio de la inhibición competitiva de la incorporación de trifosfato de desoxiguanosina por la ADN polimerasa viral y la incorporación de trifosfato de ganciclovir para el ADN viral. PREGUNTA: ¿El uso de valganciclovir es más eficaz y más seguro que las alternativas terapéuticas existentes para la prevención de la enfermedad por citomegalovirus en los receptores de trasplante de órgano sólido? BÚSQUEDA Y ANÁLISIS DE LA EVIDENCIA CIENTÍFICA: Las bases de datos de la Cochrane Library (vía Bireme), MEDLINE (vía PubMed), LILACS y Centro de Revisiones y Difusión (CRD) fueron investigados. Se incluyeron revisiones sistemáticas (SR) y meta-análisis de los ensayos clínicos que compararon valganciclovir con otros antivirales. Los estudios fueron evaluados de acuerdo con el sistema GRADE.También se seleccionaron Evaluaciones de Tecnologías Sanitarias (ETS) en los sitios de agencias internacionales. RESUMEN DE LOS RESULTADOS DE LOS ESTUDIOS SELECCIONADOS: Siete revisiones sistemáticas fueron seleccionadas, cuya calidad varió de muy bajo a bajo. La mayoría no mostró ninguna eficacia significativamente superior de valganciclovir en la prevención de la enfermedad por citomegalovirus en pacientes que reciben trasplantes de órganos sólidos, en comparación con las alternativas terapéuticas existentes. Además, su uso, especialmente en dosis de 900mg/dia, mostró estar estadísticamente asociado con el riesgo de leucopenia y / o neutropenia. No se incluyó ninguna ETS. RECOMENDACIONES: Debido a baja calidad de las pruebas, a los resultados presentados y el mayor costo hacia las alternativas terapéuticas existentes, el uso del valganciclovir, en la prevención de la enfermedad por citomegalovirus en pacientes que reciben trasplantes de órganos sólidos, es débilmente recomendado contra. Sin embargo, se necesitan adicionales estudios de trasplante específico para evaluar su eficacia, conforme el tipo de trasplante de órganos sólidos.(AU)
Subject(s)
Humans , Antiviral Agents/administration & dosage , Cytomegalovirus Infections/prevention & control , Ganciclovir/administration & dosage , Ganciclovir/analogs & derivatives , Transplant Recipients , Cost-Benefit Analysis , Technology Assessment, Biomedical , Treatment OutcomeABSTRACT
La infección por Citomegalovirus representa un desafío considerable tras el trasplante hepático, limitando la supervivencia del injerto a través de efectos directos, pero también a través de una modulación del sistema inmune, favoreciendo otras infecciones y el rechazo al injerto. La identificación de la condición serológica del donante y el receptor permite establecer el riesgo posterior de contraer la infección, además de la administración juiciosa de la profilaxis antiviral, lo cual limita ostensiblemente el riesgo de desarrollar una infección por Citomegalovirus tras el trasplante hepático. Hoy en día se cuenta con terapias antivirales efectivas pero que, lamentablemente también tienen efectos adversos importantes, lo cual hace aún más relevante la administración de profilaxis en los casos que lo ameritan y estar alerta al desarrollo de la infección en el post trasplante.
Cytomegalovirus infection is an important challenge to liver transplant clinicians, because it can be life threatening and because of its indirect effects on the immune system and the graft. Identification of the serologic condition of the donor and the receptor and risk factors to develop this condition allow us to establish a rational prophylaxis and to rapidly detect the infection. Currently there are effective antiviral treatments; which unfortunately also have important adverse effects. This emphasizes the importance of antiviral prophylaxis after liver transplantation.