Cytomegalovirus reactivation and disease amongst patients with allogeneic haematopoietic stem cell transplantation in Eastern India: Epidemiology, outcome and healthcare cost.

PURPOSE: Data from developing countries about incidence, prognosis and healthcare cost of cytomegalovirus (CMV) reactivation amongst patients with allogeneic hematopoietic stem cell transplantation (AHSCT) remain scarce. The purpose of the study was to describe the epidemiology, outcome and cost implications of CMV reactivation and CMV disease amongst patients with AHSCT in cancer hospital in Eastern India. MATERIALS AND METHODS: The study design was a retrospective audit of clinical records. RESULTS: Ninety-nine per cent of patients and 94% of the donors were found to be CMV seropositive. CMV reactivation rate was 43.8% amongst patients with AHSCT (n = 130 patients). CMV reactivation occurred 118 days after AHSCT (median; range: 28-943 days). Patients with any grade of graft-versus-host disease (GVHD) had higher CMV reactivation rate than patients without GVHD. Patients with CMV reactivation had more frequent GVHD than patients without CMV reactivation. Use of steroids was associated with CMV reactivation. We found no differences in overall survival of patients with or without CMV reactivation. The cost of in-house CMV-polymerase chain reaction at our centre was USD $57 (Rs. 3650), cost for intravenous ganciclovir was USD $26 (Rs. 1665) per infusion and oral valganciclovir USD $8 (Rs. 512)/900 mg tablet. The median duration of anti-CMV therapy was 14 days (interquartile range: 14-28 days) and the average cost per patient per month directed towards CMV management ranged between USD $800 and USD $1,300 (Rs. 51,238-Rs. 83,264). Three patients (2.3%) in this series had CMV disease, all of whom died. CONCLUSION: In an increasingly globalised world, where medical tourism is common, data from developing countries regarding cost and outcome of CMV infections in AHSCT patients are of relevance.

Successful Cost-Effective Prevention of Cytomegalovirus Disease in Kidney Transplant Recipients Using Low-Dose Valganciclovir.

OBJECTIVES: Low-dose valganciclovir prophylaxis is still under investigation in renal transplant procedures. Our aim was to assess the cost effectiveness of 450 mg versus 900 mg valganciclovir prophylaxis in kidney transplant recipients. MATERIALS AND METHODS: In this prospective trial, 201 kidney transplant patients were randomized (1:1) to receive 450 mg/d (group 1, n = 100) or 900 mg/d (group 2, n = 101) valganciclovir prophylaxis for the first 6 months after transplant. Patients were studied for incidence of cytomegalovirus disease, leucopenia episodes, rejection episodes, and graft outcomes along with associated costs over 1 year. Costs (in US dollars) of treatment of rejection were also analyzed. RESULTS: Demographic features of the studied groups were comparable. We found that the cost of cytomegalovirus care in group 1 patients was significantly lower (by 50% at 6 months; P < .001), with less leukopenia episodes (P = .04), lower doses of granulocyte colony-stimulating factor (by 30% at 6 months; P = .03), higher doses of mycophenolate mofetil (P = .04), and less rejection episodes (P = .01) compared with group 2. In group 2, there were more episodes of cytomegalovirus infection (P = .052) and BK virus nephropathy (P = .04). Graft and patient outcomes were satisfactory in both groups. CONCLUSIONS: Low-dose valganciclovir for cytomegalovirus prophylaxis after renal transplant is safer, effective and without breakthrough infection, and less costly than using the usual dose.

Combined environmental risk assessment for the antiviral pharmaceuticals ganciclovir and valganciclovir in Europe.

Potential environmental risks of the old antiviral pharmaceuticals ganciclovir (GCV) and valganciclovir (VGCV) were reassessed based on new environmental fate and chronic ecotoxicity tests and on actual use data for Europe. Valganciclovir is hydrolyzed to GCV by intestinal and hepatic esterases, and hence the new environmental tests only refer to GCV. A sorption study showed that GCV will not sorb significantly, excluding the soil as a relevant environmental compartment. Despite earlier data suggesting nondegradability, a new water/sediment fate test showed GCV to be primarily and ultimately degraded and to be nonpersistent. The chronic ecotoxicity tests with algae and daphnids resulted in no inhibition at the highest tested concentrations, whereas a fish partial life cycle test, selected in view of mammalian mutagenicity and reprotoxicity data, showed effects on growth of the young fish, but not on gametogenesis, fertilization, embryogenesis, or teratogenicity. Predicted environmental concentrations were derived based on actual per capita use data for European countries for 2004 to 2014, and the highest was selected for the risk assessment. A comparison of predicted environmental concentrations with predicted no-effect concentrations shows no significant risk for wastewater treatment, surface waters, groundwater, or sediment. In addition, potential risks to (semi)aquatic top predators or to human consumers of water and fish are exceedingly low. Environ Toxicol Chem 2017;36:2205-2216. © 2017 The Author. Environmental Toxicology and Chemistry Published by Wiley Periodicals, Inc. on behalf of SETAC.

Impact of Pharmacist Involvement in Early Identification and Enrollment in Patient Assistance Programs on CMV Outcomes in Transplantation.

BACKGROUND: No data exist evaluating the utilization of patient assistance programs (PAPs) on cytomegalovirus (CMV)-related outcomes. OBJECTIVE: To determine whether early identification and enrollment in PAPs can prevent CMV-related events. METHODS: Retrospective analysis of patients at risk of CMV reactivation who received kidney and/or pancreas transplants. Two groups were evaluated with patients receiving oral valganciclovir for CMV prophylaxis through enrollment in PAPs or oral acyclovir with preemptive CMV monitoring. Primary outcomes include the incidence of CMV infection. Secondary outcomes include a cost benefit analysis, incidence of rejection, patient/graft survival, and time to CMV infection. RESULTS: There were 97 patients identified; valganciclovir through PAPs (n = 39) and preemptive CMV quantitative nucleic acid testing monitoring (n = 58). The incidence of CMV viremia was lower in the PAP group (12.8% vs 36.2%, respectively; P = .021). There were no significant differences in CMV syndrome/disease, acute rejection, graft loss, or death between the groups. The time to CMV infection was shorter in the preemptive group. Cost benefit analysis found that hiring a full time pharmacy employee for enrolling patients in PAPs was cost beneficial for the institution/health care system. CONCLUSION: Early identification and enrollment of patients in PAPs reduces the incidence of CMV viremia. Pharmacists play a crucial role in this process.

Análise de custo do uso oral de Valganciclovir para tratamento de viremia por citomegalovírus / Cost analysis of oral use of Valganciclovir for treatment of cytomegalovirus viremia

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.

Valganciclovir versus valacyclovir prophylaxis for prevention of cytomegalovirus: an economic perspective.

INTRODUCTION: Valganciclovir (vGCV) and valacyclovir (vACV) are used in cytomegalovirus (CMV) prophylaxis in renal transplant recipients. The aim of this study was to compare the economic impact of both regimens during 1-year follow-up. METHODS: A total of 117 renal transplant recipients at risk for CMV were randomized to 3-month prophylaxis either with vGCV (900 mg/day, n = 60) or vACV (8 g/day, n = 57) and their data used in a pharmacoeconomic analysis. The pharmacoeconomic evaluation involved all direct CMV-related expenses in the first year after transplantation. Sensitivity analysis was employed to examine the effects of various prices of antiviral drugs and diagnostic procedures on overall CMV-related costs. Simulation of the more expensive US healthcare perspective was performed, and a scenario involving costs of acute rejection (AR) was examined. RESULTS: Overall CMV-related costs were significantly lower in the vACV arm; median United States dollars (USD) 3473 (3108-3745) vs. USD 5810 (4409-6757; P < 0.001) per patient, respectively. Our data showed that the critical determinant of the major disparity between the prophylactic regimens was the prophylaxis price. Median cost of prophylaxis in the vACV group was USD 1729 (1527-2173) compared to USD 3968 (2683-4857) in the vGCV group (P < 0.001). In sensitivity analysis of the overall CMV-related costs, the least and the most expensive pharmacotherapy and diagnostic scenarios were used; nevertheless, the vACV arm remained markedly less expensive. Simulation considering the higher physician/nurse and hospitalization fees of the US healthcare system and the scenario including expenditure associated with AR episodes also favored vACV. CONCLUSION: VACV prophylaxis for CMV is associated with a significant 44% lower cost than vGCV at the first year after renal transplantation.

Assessment of the efficacy and safety of pre-emptive anti-cytomegalovirus (CMV) therapy in HIV-infected patients with CMV viraemia.

A number of studies have demonstrated that cytomegalovirus (CMV) viraemia is a strong predictor for CMV end-organ disease (EOD) and death in HIV-infected patients. We assess the efficacy and safety of pre-emptive anti-CMV therapy (PACT) for preventing these events. We performed a retrospective study of all HIV-infected patients seen in our institution who had detectable CMV viraemia in 2007. Seventy-one patients with advanced HIV disease (median CD4 cell count = 61 cells/mm(3)) were studied. Sixteen patients received PACT (mainly valganciclovir). Patients who received PACT had lower CD4 cell counts and higher blood CMV DNA levels. The cumulative incidence of CMV EOD and death at one year was 44% and 21% in patients with and without PACT, respectively (p = 0.013). Both PACT and high blood CMV DNA levels were significantly associated with CMV EOD and death in unadjusted analysis. In adjusted analyses, only blood CMV DNA levels remained significantly associated with the risk of CMV EOD and death, whereas PACT was associated with a non-significant trend towards reduced CMV EOD or death (hazard ratio: 0.25, p = 0.13). Five patients with PACT experienced severe drug-related adverse events. In conclusion, the use of PACT in HIV-infected patients with CMV viraemia could improve outcome but is associated with significant toxicity.

Efectividad y seguridad de valganciclovir comparado con ganciclovir, valaciclovir y aciclovir, en pacientes receptores de trasplante de órganos sólidos / Effectiveness and safety of valganciclovir compared to ganciclovir, valaciclovir and acyclovir in patients receiving solid organ transplantation

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)

New algorithm for valganciclovir dosing in pediatric solid organ transplant recipients.

CMV infections are common after SOT. v-GCV is increasingly used in children. The aim of this study was to evaluate presently used dosing algorithms. Data from 104 pediatric SOT recipients (kidney, liver, and heart) aged 0.3-16.9 yr and receiving v-GCV once a day were used for model development and validation with the Pmetrics package for R. Monte Carlo simulations were performed to compare the probability of a GCV AUC 40-60 mg*h/L with the different algorithms across a range of ages, weights, and GFRs. GCV pharmacokinetics was well described by the non-parametric model. Clearance was dependent on GFR and Cockcroft-Gault estimates improved the model fit over Schwartz. Simulations showed that our new algorithm, where v-GCV dose is: Weight [kg]*(0.07*GFR [mL/min]+k), where k = 5 for GFR ≤ 30 mL/min, k = 10 for GFR > 30 mL/min and weight > 30 kg and k = 15 for GFR > 30 mL/min and weight ≤ 30 kg, outperformed the other algorithms. Thirty-three percent of all patients achieve an exposure above and 21% within the therapeutic window. We propose a simple algorithm for initial v-GCV dosing that standardizes plasma drug exposure better than current algorithms. Subsequent TDM is strongly suggested to achieve individual drug levels within the therapeutic window.

Eficácia e segurança de valganciclovir para prevenção da doença pelo citomegalovirus em pacientes transplantados / Efficacy and safety of valganciclovir for the prevention of cytomegalovirus disease in transplanted patients / Eficacia y seguridad de valganciclovir en la prevención de la enfermidad por citomegalovirus en los receptores de transplante

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)

[The evaluation of cost-effectiveness and cost-utility of valganciclovir for the prophylaxis of cytomegalovirus disease to 200 days after kidney transplantation]. / Ocena kosztowej efektywnosci i kosztowej uzytecznosci stosowania walgancyklowiru w profilaktyce wystapienia choroby cytomegalowirusowej do 200. dnia od przeszczepu nerki.

UNLABELLED: Standard procedure for cytomegalovirus disease (CMV) prophylaxis in kidney transplant patients was the administration of valganciclovir for up to 110 days after organ transplant. This prophylaxis has been extended up to 200 days in Poland since 2011. The decision was based on the results of clinical trials which showed significant clinical benefit in case of prolonged administration of the drug. The aim of the analysis was to provide the economic evaluation of extending the CMV prophylaxis with co-financed from public funds Valcyte (valganciclovirum; 60 tab. a 450 mg; Roche Polska Sp. z o.o.) from 110 to 200 days, in the high risk patients group after kidney transplant (seronegative recipient and infected donor, D+/R-). The analysis was performed from the Polish healthcare payer's perspective. MATERIAL AND METHODS: All methods used in the following study were consistent with the Requirements of the Polish HTA Agency (AHTAPOL). The cost-effectiveness and the cost-utility analysis were performed on the basis of a randomised study which was identified as a result of the systematic search of the medical databases, comparing 200 days valgancyclovir administration with 100 days drug use as a prophylaxis of CMV disease in the patients group mentioned above. The Markov model was developed, simulating the disease evolution over time considering a high risk patient after kidney transplant treated with valgancicloviras the CMV disease prophylaxis. The disease period was divided into health states that are the most probable for this condition and the transitions probabilities between them were identified and assigned. Based on the clinical trial results, registry database of health conditions usability and experts' opinion, all health states (i.e. death, kidney transplant, CMV disease) were attributed with utilities and costs. The direct costs, important from the Polish healthcare payer's perspective, were included in the analysis. Extension of the proposed model in the series of one month time cycles made it possible to assess long-term (assumed time horizon was median patient's life expectancy--23,5 years) costs and clinical effects of the compared technologies. RESULTS: The Incremental Cost-Effectiveness Ratio (ICER) was 39 669 008 PLN and The Incremental Cost-Utility Ratio (ICUR) was 48 008 PLN in the specified time horizon. The result is well below the accepted threshold of profitability in Poland (assuming tripled GDP per capita cost-utility threshold, i.e. 99 543 PLN), which means that the therapy is cost-effective. CONCLUSIONS: The results of the analysis confirmed that the 200 days use of valganciclovirin the prevention of CMV disease compared to standard 110 days therapy is economically justified from the Polish healthcare payer's perspective.

Cost analysis in favor of a combined approach for cytomegalovirus after kidney transplantation: a single-center experience.

BACKGROUND: In kidney transplant recipients, cytomegalovirus (CMV) can cause significant morbidity, mortality, and costs, which can be prevented by universal antiviral prophylaxis or preemptive therapy. METHODS: With the aim to improve our understanding of the advantages and disadvantages of these interventions, we documented resource use for 101 consecutive kidney transplant recipients in our center receiving preemptive therapy and estimated resource use for 2 alternative scenarios. RESULTS: At 100 days after transplantation, the mean total costs of our preemptive strategy including monitoring and treatment with intravenous ganciclovir was €2545 per patient. At €4853 per patient, these costs were highest for the CMV-positive donor/CMV-negative recipient (D+/R-) patient subgroup (n = 28), who frequently require recurrent treatment. A treatment scenario with valganciclovir prophylaxis for D+/R- and R+ patients, in which we ignored late-onset disease after discontinuation of prophylaxis, resulted in an estimated cost of €1892 per patient. A combined approach using valganciclovir prophylaxis in the D+/R- group and a preemptive strategy in the R+ groups would result in the lowest mean and median costs per patient (€1701). CONCLUSION: Our study suggests that a combined approach, using valganciclovir prophylaxis in D+/R- patients and preemptive treatment in R+ patients, may result in the lowest cost. This approach seems reasonable as it restricts expensive prophylactic drug therapy to those who would benefit the most, whereas it limits the risk for drug toxicity and late-onset disease in those at lower risk for CMV.

Universal prophylaxis is cost effective in cytomegalovirus serology-positive kidney transplant patients.

BACKGROUND: The economic merit of universal prophylaxis and preemptive therapy in the management of cytomegalovirus (CMV) infection for serology positive (R+) kidney transplant patients remains undefined. We performed cost effectiveness and cost utility modeling comparing these two approaches. METHODS: The incidence of CMV infection under universal prophylaxis and preemptive therapy was determined among 653 R+ patients from our institution and 416 R+ patients from various clinic trials, respectively. Standardized decision tree analysis and Markov transitional models were used to calculate cost and quality-adjusted life years (QALYs) from the prototypical clinical data and published literature. Incremental cost effectiveness and cost utility were calculated as dollars for one case of infection avoided and one QALY gained over 10 years, respectively. One- and two-way sensitivity analyses were performed. RESULTS: The incidence of CMV infection was 4.1% and 55.5% within the first year after transplant for universal prophylaxis and preemptive therapy, respectively. Compared with preemptive therapy, universal prophylaxis incurred $1464 more in direct cost while saving $7309 in indirect cost, and resulted in a net gain of 0.209 in QALYs per patient over a 10-year period. Thus, universal prophylaxis dominates over preemptive therapy with a cost saving of $27,967 for 1 QALY gained. This cost saving was sensitive to the variation in the rate of CMV infection and disease with each approach. CONCLUSION: Universal prophylaxis in CMV R+ kidney transplant patients is clinically effective and cost saving. It should be considered as the preferred approach.

Prolonged prophylaxis with valganciclovir is cost effective in reducing posttransplant cytomegalovirus disease within the United States.

BACKGROUND: Cytomegalovirus (CMV) disease in transplant patients is known to have a substantial clinical and economic burden, and its prevention is expected to have long-term benefits. Evidence from the Improved Protection Against CMV in Transplant trial proved that prolonged prophylaxis of 200 days with valganciclovir compared with 100 days significantly reduces the incidence of CMV in high-risk kidney transplant seropositive donors/seronegative recipients. The aim of this study was to develop a cost-effectiveness model to evaluate prolonged prophylaxis of 200 days with valganciclovir and its long-term economic impact. METHODS: An economic model was designed to simulate long-term costs and outcomes of prolonged prophylaxis with valganciclovir (200 vs. 100 days) in a cohort of 10,000 high-risk renal transplant patients over 5 and 10 years. The first year of the model was based on the results of the Improved Protection Against CMV in Transplant trial and the extension to the long-term periods (5 and 10 years); and quality of life data were based on evidence retrieved through a systematic literature search. This analysis was conducted from the US healthcare payer perspective. RESULTS: For the 5-year time horizon, the incremental cost-effectiveness ratio of US $14,859/quality-adjusted life year (QALY) suggests that 200-day valganciclovir prophylaxis is cost effective over the 100-day regimen considering a threshold of US $50,000/QALY. The 10-year analysis revealed the 200-day prophylaxis as cost saving with a 2380 QALY gain and simultaneously lower cost. CONCLUSION: Prolonged prophylaxis with valganciclovir reduces the incidence of events associated with CMV infection in high-risk kidney transplant recipients and is a cost-effective strategy in CMV disease management.

Can preemptive cytomegalovirus monitoring be as effective as universal prophylaxis when implemented as the standard of care in patients at moderate risk?

BACKGROUND: Cytomegalovirus (CMV) is a significant cause of morbidity, mortality, and cost in solid organ transplant recipients. This study was conducted to measure both the clinical efficacy and the pharmacoeconomic impact of implementing, as standard of care, an abbreviated preemptive monitoring strategy compared with universal prophylaxis in a large teaching hospital. METHODS: This prospective observational study included only recipients at moderate risk for CMV infection, specifically recipients who were CMV seropositive before transplant. Recipients transplanted between February 2006 and December 2006 received prophylactic valganciclovir for 90 days after transplant, and those transplanted between January 2007 and December 2007 were enrolled in a preemptive monitoring strategy that included no anti-CMV prophylaxis but instead used serial CMV polymerase chain reactions in weeks 4, 6, 8, 10, 12, 16, 20, and 24 to monitor the development of CMV DNAemia. Costs were analyzed from a societal perspective. RESULTS: A total of 130 patients were included in this study. Baseline and transplant demographics are well matched between groups. CMV syndrome occurred in three patients in each group, and one patient in the preemptive group developed CMV disease. Thirty-seven percent of patients in the preemptive group developed CMV DNAemia, 68% of these patients received antiviral therapy. Personnel and laboratory monitoring costs were significantly higher in the preemptive group, whereas medication cost was significantly higher in the prophylaxis group. CONCLUSIONS: Although outcomes and the overall cost of (1) universal prophylaxis and (2) preemptive monitoring are similar, universal prophylaxis places the cost burden on the patient whereas preemptive monitoring shifts the cost burden to the healthcare system.

Six-month prophylaxis is cost effective in transplant patients at high risk for cytomegalovirus infection.

The risk of late-onset cytomegalovirus (CMV) infection remains a concern in seronegative kidney and/or pancreas transplant recipients of seropositive organs despite the use of antiviral prophylaxis. The optimal duration of prophylaxis is unknown. We studied the cost effectiveness of 6- versus 3-mo prophylaxis with valganciclovir. A total of 222 seronegative recipients of seropositive kidney and/or pancreas transplants received valganciclovir prophylaxis for either 3 or 6 mo during two consecutive time periods. We assessed the incidence of CMV infection and disease 12 mo after completion of prophylaxis and performed cost-effectiveness analyses. The overall incidence of CMV infection and disease was 26.7% and 24.4% in the 3-mo group and 20.9% and 12.1% in the 6-mo group, respectively. Six-month prophylaxis was associated with a statistically significant reduction in risk for CMV disease (HR, 0.35; 95% CI, 0.17 to 0.72), but not infection (HR, 0.65; 95% CI, 0.37 to 1.14). Cost-effectiveness analyses showed that 6-mo prophylaxis combined with a one-time viremia determination at the end of the prophylaxis period incurred an incremental cost of $34,362 and $16,215 per case of infection and disease avoided, respectively, and $8,304 per one quality adjusted life-year gained. Sensitivity analyses supported the cost effectiveness of 6-mo prophylaxis over a wide range of valganciclovir and hospital costs, as well as variation in the incidence of CMV disease. In summary, 6-mo prophylaxis with valganciclovir combined with a one-time determination of viremia is cost effective in reducing CMV infection and disease in seronegative recipients of seropositive kidney and/or pancreas transplants.

An assessment of herpesvirus co-infections in patients with CMV disease: correlation with clinical and virologic outcomes.

The effect of herpesvirus co-infections (HHV-6, HHV-7) on cytomegalovirus (CMV) disease and its response to therapy is unknown. We prospectively analyzed herpesvirus co-infections in transplant recipients with CMV disease. All patients received 3 weeks of antiviral therapy. Samples were collected at baseline (day 0) and then day 3, 7, 14 and 21 poststart of therapy. Viral load testing for CMV, HHV-6 and HHV-7 was done using quantitative PCR assays in 302 patients of whom 256 had documented symptomatic CMV viremia. In this subset, day 0 HHV-6 co-infection was present in 23/253 (9.1%) and HHV-7 in 17/253 (6.7%). Including those positive at any time point raised the prevalence to 79/256 (30.9%) for HHV-6 and 75/256 (29.3%) for HHV-7. Viral co-infection did not influence the response of CMV disease to antiviral therapy. Baseline CMV viral loads, time to eradication and risk of recurrence were similar in patients with and without HHV-6 or HHV-7 co-infection. Ganciclovir and valganciclovir had no clear effect on HHV-6 and HHV-7 viremia. In conclusion, herpesvirus co-infections are common in patients with CMV disease but with standard antiviral therapy, no clear clinical effects are discernable. Routine monitoring for viral co-infection in patients with CMV disease is not indicated.

Pharmacokinetic and pharmacodynamic assessment of oral valganciclovir in the treatment of symptomatic congenital cytomegalovirus disease.

BACKGROUND: Intravenous ganciclovir administered for 6 weeks improves hearing outcomes in infants with symptomatic congenital cytomegalovirus (CMV) disease involving the central nervous system. METHODS: Twenty-four subjects received antiviral therapy for 6 weeks. Serial pharmacokinetic assessments were performed after administration of valganciclovir oral solution and of intravenous ganciclovir. RESULTS: On the basis of a previous pharmacokinetic study of the use of intravenous ganciclovir in this population, a target AUC12 (area under the concentration-time curve over a 12-h period) of 27 mg x h/L was defined. The median dose of oral valganciclovir administered in the present trial was 16 mg/kg, which produced a geometric mean AUC12 of 27.4 mg x h/L. The bioavailability of valganciclovir was 41.1%. Of the 18 subjects who had detectable CMV in whole blood at baseline or during therapy, 11 had <4 log viral DNA copies/mL at baseline, and 7 had > or =4 log viral DNA copies/mL at baseline; subjects who started the study with the higher viral burden experienced greater decreases in viral load but did not clear virus during the 42-day course of therapy. Neutropenia of grade 3 or 4 developed in 38% of subjects. CONCLUSIONS: In neonates with symptomatic congenital CMV disease, valganciclovir oral solution provides plasma concentrations of ganciclovir comparable to those achieved with administration of intravenous ganciclovir. The results of the present study cannot be extrapolated to extemporaneously compounded liquid formulations of valganciclovir.

Valacyclovir prophylaxis versus preemptive valganciclovir therapy to prevent cytomegalovirus disease after renal transplantation.

Both preemptive therapy and universal prophylaxis are used to prevent cytomegalovirus (CMV) disease after transplantation. Randomized trials comparing both strategies are sparse. Renal transplant recipients at risk for CMV (D+/R-, D+/R+, D-/R+) were randomized to 3-month prophylaxis with valacyclovir (2 g q.i.d., n = 34) or preemptive therapy with valganciclovir (900 mg b.i.d. for a minimum of 14 days, n = 36) for significant CMV DNAemia (>/=2000 copies/mL by quantitative PCR in whole blood) assessed weekly for 16 weeks and at 5, 6, 9 and 12 months. The 12-month incidence of CMV DNAemia was higher in the preemptive group (92% vs. 59%, p < 0.001) while the incidence of CMV disease was not different (6% vs. 9%, p = 0.567). The onset of CMV DNAemia was delayed in the valacyclovir group (37 +/- 22 vs. 187 +/- 110 days, p < 0.001). Significantly higher rate of biopsy-proven acute rejection during 12 months was observed in the preemptive group (36% vs. 15%, p = 0.034). The average CMV-associated costs per patient were $5525 and $2629 in preemptive therapy and valacyclovir, respectively (p < 0.001). However, assuming the cost of $60 per PCR test, there was no difference in overall costs. In conclusion, preemptive valganciclovir therapy and valacyclovir prophylaxis are equally effective in the prevention of CMV disease after renal transplantation.