Resource Use and Financial Impact of Oral Step-Down Therapy for Resistant Cytomegalovirus in Solid Organ Transplant Recipients.

BACKGROUND: Cytomegalovirus (CMV) infections are common opportunistic infections in solid organ transplants (SOT) with increased health care resource USE and costs. Costs are further increased with ganciclovir-resistance (GR). This study aimed to evaluate the real-world impact of conversion to oral step-down therapy on duration of foscarnet and hospital length of stay (LOS) for treatment of GR-CMV infections in SOT. METHODS: This study included adult recipients of kidney or lung transplants who received foscarnet for genotypically documented GR-CMV while admitted at the University of Wisconsin Hospital from October 1, 2015, to January 31, 2022. Patients in the oral step-down group were converted from standard of care (SOC; foscarnet) to maribavir or letermovir; patients in the historical control group were treated with SOC. RESULTS: Twenty-six patients met the inclusion criteria: 5 in the intervention group and 21 in the SOC group. The median viral load at foscarnet initiation was 11,435 IU/mL. Patients who received oral step-down conversion had shorter mean foscarnet duration than those who received SOC (7 ± 4 vs 37 ± 25 days, P = .017). Mean hospital LOS in the oral step-down group (16 ± 3 days) was shorter than the SOC group (33 ± 21 days; P < .001). In the SOC group, 9 patients lost their graft, and 9 patients died; 2 deaths were attributed to CMV. There were 2 deaths in the oral step-down group, neither of which was attributed to CMV. CONCLUSION AND RELEVANCE: In this real-world case series of patients receiving treatment for GR-CMV infection, oral step-down conversion decreased foscarnet therapy duration and hospital LOS. Future studies are needed to evaluate better the effect of oral step-down in treating GR-CMV infection on treatment duration and cost-savings.

Cytomegalovirus related hospitalization costs among hematopoietic stem cell and solid organ transplant recipients treated with maribavir versus investigator-assigned therapy: A US-based study.

BACKGROUND: Cytomegalovirus (CMV) infections among hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients impose a significant health care resource utilization (HCRU)-related economic burden. Maribavir (MBV), a novel anti-viral therapy (AVT), approved by the United States Food and Drug Administration for post-transplant CMV infections refractory (with/without resistance) to conventional AVTs has demonstrated lower hospital length of stay (LOS) versus investigator-assigned therapy (IAT; valgancilovir, ganciclovir, foscarnet, or cidofovir) in a phase 3 trial (SOLSTICE). This study estimated the HCRU costs of MBV versus IAT. METHODS: An economic model was developed to estimate HCRU costs for patients treated with MBV or IAT. Mean per-patient-per-year (PPPY) HCRU costs were calculated using (i) annualized mean hospital LOS in SOLSTICE, and (ii) CMV-related direct costs from published literature. Probabilistic sensitivity analysis with Monte-Carlo simulations assessed model robustness. RESULTS: Of 352 randomized patients receiving MBV (n = 235) or IAT (n = 117) for 8 weeks in SOLSTICE, 40% had HSCT and 60% had SOT. Mean overall PPPY HCRU costs of overall hospital-LOS were $67,205 (95% confidence interval [CI]: $33,767, $231,275) versus $145,501 (95% CI: $62,064, $589,505) for MBV and IAT groups, respectively. Mean PPPY ICU and non-ICU stay costs were: $32,231 (95% CI: $5,248, $184,524) versus $45,307 (95% CI: $3,957, $481,740) for MBV and IAT groups, and $82,237 (95% CI: $40,397, $156,945) MBV versus $228,329 (95% CI: $94,442, $517,476) for MBV and IAT groups, respectively. MBV demonstrated cost savings in over 99.99% of simulations. CONCLUSIONS: This analysis suggests that Mean PPPY HCRU costs were 29%-64% lower with MBV versus other-AVTs.

Cytomegalovirus infection and disease in pediatric liver transplantation: Burden of disease under a preemptive therapy approach.

BACKGROUND: CMV remains a frequent complication after liver transplantation. Few studies exist in children reporting the epidemiology and outcomes of CMV after LT with current prevention strategies. Our goal is to report the incidence of CMV infection and disease in pediatric LT recipients under preemptive therapy, identify risk factors, complications, and adverse reactions to treatment. METHODS: All pediatric LT recipients from a single center (1998-2018) were included. Antigenemia pp65 (1998-2003) and QNAT or both were used to inform preemptive therapy. Cutoff value for starting treatment was Agpp65 > 10 + cells/200 000 or QNAT >1500 copies/ml or any value in high-risk recipients (D+/R-). RESULTS: One hundred eighteen LT were analyzed. CMV infection was detected in 67% of patients, only 44 (37%) required treatment, and 5 (4%) developed CMV disease. All patients responded well to treatment, and no graft or patients were lost to CMV effects. There were no differences in mortality, CMV indirect effects, or other complications between those who required treatment and those who did not. Thirty-two percent of the patients who received antivirals developed an adverse hematological reaction. Risk factors associated with CMV infection requiring treatment were D+/R- (OR 13.9, p = .01) and fulminant hepatitis (OR 4.8, p = .02). CONCLUSIONS: Preemptive therapy for CMV in children is safe and effective, yields low CMV infection rates that require treatment, and minimal rates of CMV disease, without increasing CMV-related complications. Using this strategy, 63% of our patients did not receive treatment. Therefore, drug exposure, adverse reactions, and resistance risk were minimized.

Low-Dose Valganciclovir Prophylaxis Is Safe and Cost-Saving in CMV-Seropositive Kidney Transplant Recipients.

Introduction: Observational studies suggest that low-dose valganciclovir prophylaxis (450 mg daily for normal renal function) is as effective as and perhaps safer than standard-dose valganciclovir (900 mg daily) in preventing CMV infection among kidney transplant recipients. However, this practice is not supported by current guidelines due to concerns for breakthrough infection from resistant CMV, mainly in high-risk CMV donor-seropositive/recipient-seronegative kidney transplant recipients. Standard-dose valganciclovir is costly and possibly associated with higher incidence of neutropenia and BKV DNAemia. Our institution adopted low-dose valganciclovir prophylaxis for intermediate-risk (seropositive) kidney transplant recipients in January 2018. Research Question: To analyze the efficacy (CMV DNAemia), safety (BK virus DNAemia, neutropenia, graft loss, and death), and cost savings associated with this change. Design: We retrospectively compared the above outcomes between CMV-seropositive kidney transplant recipients who received low-dose and standard-dose valganciclovir, transplanted within our institution, between 1/19/2014 and 7/15/2019, using propensity score-adjusted competing risk analyses. We also compared cost estimates between the two dosing regimens, for 3 months of prophylaxis, and for different percentage of patient-weeks with normal renal function, using the current average wholesale price of valganciclovir. Results: We studied 179 CMV-seropositive kidney transplant recipients, of whom 55 received low-dose and 124 standard-dose valganciclovir. The majority received nonlymphocyte depleting induction (basiliximab). Low-dose valganciclovir was at least as effective and safe as, and more cost-saving than standard-dose valganciclovir. Conclusion: This single-center study contributes to mounting evidence for future guidelines to be adjusted in favor of low-dose valganciclovir prophylaxis in CMV-seropositive kidney transplant recipients.

Intracerebral Administration of Autologous Mesenchymal Stem Cells as HSV-TK Gene Vehicle for Treatment of Glioblastoma Multiform: Safety and Feasibility Assessment.

Widespread investigation has revealed the promising ability of suicidal genes in the treatment of glioma tumors; nevertheless, promoting their effects relies on the ability to apply suitable vehicles and techniques. In this study, the safety and feasibility of using bone marrow-derived mesenchymal stem cells (MSCs) in combination with prodrug for treatment of patients with primary and secondary glioblastoma multiform (GBM) was assessed. Five GBM patients were recruited. Following gross total resection of the tumor and adjuvant radiotherapy and chemotherapy, intracerebral injection of autologous MSCs transduced with lentivirus containing herpes simplex virus thymidine kinase (HSV-TK) was performed followed by intravenous administration of ganciclovir for 2 weeks. The treatment was well tolerated by all patients. Mild-to-moderate fever, headache, and cerebrospinal fluid leukocytosis were evident in three, two, and one patient, respectively. The progression-free survival (PFS) and overall survival (OS) of patients were 95.79 ± 51.40 and 128.85 ± 48.81 weeks, respectively. The 1-year PFS and OS were 60% and 100%, respectively, among our patients, and two patients had more than 3 years of OS and more than 2 years of PFS. It seems that intracerebral administration of bone marrow MSC containing the HSV-TK gene in combination with intravenous ganciclovir would be safe and feasible in the treatment of patients with GBM.

Cost-effectiveness of Preemptive Therapy Versus Prophylaxis in a Randomized Clinical Trial for the Prevention of Cytomegalovirus Disease in Seronegative Liver Transplant Recipients With Seropositive Donors.

BACKGROUND: The relative costs of preemptive therapy (PET) or prophylaxis for the prevention of cytomegalovirus (CMV) disease in high-risk donor CMV-seropositive/recipient-seronegative (D+/R-) liver transplant recipients have not been assessed in the context of a randomized trial. METHODS: A decision tree model was constructed based on the probability of outcomes in a randomized controlled trial that compared valganciclovir as PET or prophylaxis for 100 days in 205 D+/R- liver transplant recipients. Itemized costs for each site were obtained from a federal cost transparency database. Total costs included costs of implementation of the strategy and CMV disease treatment-related costs. Net cost per patient was estimated from the decision tree for each strategy. RESULTS: PET was associated with a 10% lower absolute rate of CMV disease (9% vs 19%). The cost of treating a case of CMV disease in our patients was $88 190. Considering cost of implementation of strategy and treatment-related cost for CMV disease, the net cost-savings per patient associated with PET was $8707 compared to prophylaxis. PET remained cost-effective across a range of assumptions (varying costs of monitoring and treatment, and rates of disease). CONCLUSIONS: PET is the dominant CMV prevention strategy in that it was associated with lower rates of CMV disease and lower overall costs compared to prophylaxis in D+/R- liver transplant recipients. Costs were driven primarily by more hospitalizations and higher CMV disease-associated costs due to delayed onset postprophylaxis disease in the prophylaxis group.

In vitro efficacy of ganciclovir against feline herpesvirus type 1 and assessment of ocular tolerability in healthy cats.

OBJECTIVES: Feline herpesvirus-1 (FHV-1) is a prevalent cause of ocular disease in cats and limited topical options for treatment currently exist. The first objective of this study was to confirm the efficacy of ganciclovir against FHV-1 in vitro. The second objective was to assess the safety and ocular tolerability of topically applied ganciclovir eye gel (GEG) in healthy cats. METHODS: FHV-1 was used to infect tissue culture wells covered in maximally confluent Crandall-Rees feline kidney cells prior to the addition of three molarities of ganciclovir (8.9 µM, 17.8 µM and 89 µM) before being incubated for 48 h. Ganciclovir efficacy in vitro was then assessed using standard plaque reduction assay. Commercially available GEG (0.15%) was applied q8h to one randomly chosen eye of four healthy cats for 7 days. Commercially available lubricating eye gel (LEG) was applied to the opposite eye q8h. Complete blood counts (CBCs), blood chemistry panels (CHEM) and urinalysis (UA) were performed on all cats before and after the study period. Ocular lesions were assessed daily using a standardized scheme. RESULTS: Ganciclovir led to a significant reduction in FHV-1 plaque number, area and diameter at all tested molarities in vitro. The highest molarity assessed (89 µM) caused a 100% reduction in viral plaque number. There was no significant difference in ocular lesion scores between eyes receiving GEG and LEG. Animals remained healthy throughout the study period with CBC, CHEM and UA showing no clinically significant alterations. CONCLUSIONS AND RELEVANCE: Based on the in vitro results, ganciclovir appears to be effective against FHV-1 in vitro. When applied q8h as a commercial 0.15% gel to a small group of cats with normal eyes, this medication was well tolerated. Taken together, these data suggest this medication warrants further investigation in cats with ocular disease caused by FHV-1.

Informe diário de evidências COVID-19: busca realizada em 6 de agosto de 2020 / Daily evidence report COVID-19: Search conducted on August 6, 2020

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referentes ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 11 artigos e 10 protocolos.

Informe diário de evidências COVID-19: busca realizada em 17 de julho de 2020 / COVID-19 daily evidence report: search conducted on July 17, 2020

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referentes ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 14 artigos e 13 protocolos.

Population Pharmacokinetics of Ganciclovir in Critically Ill Patients.

BACKGROUND: The pharmacokinetic (PK) data of ganciclovir (GCV), a first-line antiviral treatment for cytomegalovirus infections, in critically ill patients are limited. This study aimed at characterizing GCV population PK and interindividual variability (IIV) in intensive care unit (ICU) patients. Secondary objectives were to identify patient characteristics responsible for IIV and simulate GCV exposure for different dosing regimens. METHOD: In this retrospective observational study, clinical data and serum GCV levels were collected from ICU patients on intravenous GCV. PK modeling, covariate analyses, and explorative Monte Carlo dosing simulations (MCS) were performed using nonlinear mixed-effects modeling. Bootstrap and visual predictive checks were used to determine model adequacy. RESULTS: In total, 128 GCV measurements were obtained from 34 patients. GCV PK conformed to a 1-compartment model with first-order elimination. After multivariate analyses, only the estimated glomerular filtration rate calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula (P < 0.001) was included as a covariate. In the final model, the estimated clearance (CL) and volume of distribution (V1) were 2.3 L/h and 42 L, respectively, for a patient with the median CKD-EPI of the population (65 mL/min per 1.73 m). The association between CKD-EPI and CL decreased the residual variability from 0.56 to 0.43 and V1-IIV from 114% to 80%, whereas CL-IIV changed from 43% to 47%. MCS revealed that a substantial number of patients may not achieve the GCV PK/pharmacodynamic target trough level (>1.5 mg/L) when administering the label-recommended dose reductions for patients with CKD-EPI <50 mL/min. CONCLUSIONS: A large IIV was observed in GCV PK among ICU patients. CKD-EPI could partially explain the IIV, although a large part of the variability remains unclear. MCS suggested that recommended dose reductions for CKD-EPI <50 mL/min may lead to subtherapeutic plasma GCV levels in these patients.

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.

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.

[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.

Compassionate use: a story of ethics and science in the development of a new drug.

This history chronicles the unusual development of the antiviral drug ganciclovir. The first compound with activity against human cytomegalovirus (CMV), ganciclovir was so clearly efficacious that a placebo-controlled clinical trial could not ethically be done, and the FDA rejected the first application to market the drug. Used to treat a blinding eye infection in patients with AIDS, the story of ganciclovir paralleled the spread of the AIDS epidemic. Both ganciclovir and AIDS caught the federal government off guard. Caught in a Catch-22 situation, the pharmaceutical company developing ganciclovir gave the drug away free for five years under compassionate use guidelines. The problems encountered in the development of ganciclovir provide guidance on how future drugs to treat life-threatening diseases can be developed.

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.

[Clinical assessment of oral ganciclovir capsules on the treatment of herpes simplex keratitis].

OBJECTIVE: To evaluate the clinical values of oral ganciclovir on the treatment of herpes simplex keratitis (HSK). METHODS: A randomized, controlled, single-blind and prospective study was carried out from May in 2008 to June in 2009 at Department of Ophthalmology, Eye Ear Nose and Throat Hospital of Fudan University. 60 patients (60 eyes) with HSK, including stromal keratitis and corneal endotheliitis, were enrolled in the study and were randomly arranged into two groups in average. Oral ganciclovir was orally administered 1000 mg 3 times per day for 8 weeks, 0.15% ganciclovir ophthalmic gel, 4 times per day, and 0.1% fluorometholone eye drops, 3 times per day, in the test group, meanwhile, the control group was adopted the same ophthalmic gel and eye drops without the oral capsules. The symptoms and signs were evaluated before and after the therapy 1st week, 2nd week, 4th week, 6th week and 8th day respectively with the side effects observed. RESULTS: There was no significant difference between the control and test group in the mean scores of symptoms (control 10.70 ± 3.61, test 11.87 ± 3.47) and signs (control 13.83 ± 3.74, test 15.27 ± 3.83) respectively before the treatment (Z = -1.269 and -1.419; P > 0.05). After the administration, the total scores of symptoms and signs in the test group were 8.37 ± 4.31, 2.70 ± 2.65, 0.70 ± 1.44, 0.33 ± 0.92 and 0.17 ± 0.65 respectively at each follow-up time point, which were obviously lower than those in the control group, 13.63 ± 7.64, 10.53 ± 7.18, 7.83 ± 6.49, 5.37 ± 5.33 and 4.37 ± 5.11 respectively (Z = -2.801, -4.895, -5.260, -4.758, and -4.292; P < 0. 05). The efficacy rates in the test group were all 100.0% after the administration, but those in the control group were 50.0%, 73.3%, 86.7%, 93.3% and 96.6%. Furthermore, the cure rates in the test group were 0.0%, 36.7%, 76.7%, 90.0% and 93.3% respectively at each follow-up time point, which were significantly higher than those in the control group with 0.0%, 3.3%, 16.7%, 30.0% and 43.3% respectively (χ(2) = 20.00, 16.433, 22.571, 22.636 and 17.330; P < 0. 001). There was no obvious discomfortableness and adverse reaction observed in the test group. Unfortunately, 5 patients in the control group and 3 patients in the test group underwent the recurrence of HSK after the course of treatment, but there was no significant difference between the groups in the recurrence rate. CONCLUSIONS: Oral ganciclovir can effectively assist to relieve the symptoms and signs and shorten the pathogenesis of herpes simplex stromal keratitis and corneal endotheliitis. And short-term oral ganciclovir has confirmed good safety.