Impact of Primary Letermovir Prophylaxis Versus Preemptive Antiviral Therapy for Cytomegalovirus on Economic and Clinical Outcomes after Hematopoietic Cell Transplantation.

Preemptive therapy (PET) historically has been the primary strategy to reduce early-onset cytomegalovirus (CMV) reactivation after allogeneic hematopoietic cell transplantation (HCT) but is associated with antiviral-associated toxicities and increases in healthcare resource utilization and cost. Despite its high cost, letermovir (LTV) prophylaxis has largely supplanted PET due to its effectiveness and tolerability. Direct comparisons between LTV and PET approaches on economic and clinical outcomes after allogeneic HCT remain limited. Objective: To compare total cost of care (inpatient and outpatient) between LTV prophylaxis and PET through day+180 after allogeneic HCT. Adult allogeneic CMV seropositive (R+) HCT recipients who initiated LTV <30 days after HCT between 01/01/18 and 12/31/18 were matched 1:1 to allogeneic CMV R+ HCT recipients between 01/01/15 and 12/31/17 (PET cohort). Patients were grouped into high-risk (HR) or standard-risk (SR) for CMV to compare the LTV and PET cohorts. Direct costs for each patient's index HCT admission and all subsequent inpatient and outpatient care through day+180 after HCT were determined and converted into 2021 US dollars and then to Medicare proportional dollars (MPD). A secondary analysis using 2019 average wholesale price was conducted to specifically evaluate anti-CMV medication costs. There were a total of 176 patients with 54 HR CMV pairs and 34 SR CMV pairs. No differences in survival between LTV and PET for both HR and SR CMV groups were observed. The rate of clinically significant CMV infection decreased for both HR CMV (11/54, 20.4% versus 38/54, 70.4%, P < .001) and SR CMV (1/34, 2.9% versus 12/34, 35.3%, P < .001) patients who were given LTV prophylaxis with corresponding reductions in val(ganciclovir) and foscarnet (HR CMV only) use. Among HR CMV patients, LTV prophylaxis was associated with reductions in CMV-related readmissions (3/54, 5.6% versus 18/54, 33.3%, P < .001) and outpatient visits within the first 100 days after HCT (20 versus 25, P = .002), and a decreased median total cost of care ($36,018 versus $75,525, P < .001) in MPD was observed. For SR CMV patients on LTV, a significant reduction in the median inpatient cost ($15,668 versus $27,818, P < .001) was found, but this finding was offset by a higher median outpatient cost ($26,145 versus $20,307, P = .030) that was not CMV-driven. LTV prophylaxis is highly effective in reducing clinically significant CMV reactivations for both HR and SR HCT recipients. In this study, LTV prophylaxis was associated with a decreased total cost of care for HR CMV patients through day+180. Specifically, reductions in CMV-related readmissions, exposure to CMV-directed antiviral agents, and outpatient visits in the first 100 days after HCT were observed. SR CMV patients receiving LTV prophylaxis benefited by having a reduced inpatient cost of care due to lowered room and pharmacy costs.

Cost-effectiveness of maribavir versus conventional antiviral therapies for post-transplant refractory cytomegalovirus infection with or without genotypic resistance: A US perspective.

This study evaluated the cost-effectiveness of maribavir versus investigator-assigned therapy (IAT; valganciclovir/ganciclovir, foscarnet, or cidofovir) for post-transplant refractory cytomegalovirus (CMV) infection with or without resistance. A two-stage Markov model was designed using data from the SOLSTICE trial (NCT02931539), real-world multinational observational studies, and published literature. Stage 1 (0-78 weeks) comprised clinically significant CMV (csCMV), non-clinically significant CMV (n-csCMV), and dead states; stage 2 (78 weeks-lifetime) comprised alive and dead states. Total costs (2022 USD) and quality-adjusted life years (QALYs) were estimated for the maribavir and IAT cohorts. An incremental cost-effectiveness ratio was calculated to determine cost-effectiveness against a willingness-to-pay threshold of $100 000/QALY. Compared with IAT, maribavir had lower costs ($139 751 vs $147 949) and greater QALYs (6.04 vs 5.83), making it cost-saving and more cost-effective. Maribavir had higher acquisition costs compared with IAT ($80 531 vs $65 285), but lower costs associated with administration/monitoring ($16 493 vs $27 563), adverse events (AEs) ($11 055 vs $16 114), hospitalization ($27 157 vs $33 905), and graft loss ($4516 vs $5081), thus making treatment with maribavir cost-saving. Maribavir-treated patients spent more time without CMV compared with IAT-treated patients (0.85 years vs 0.68 years), leading to lower retreatment costs for maribavir (cost savings: -$42 970.80). Compared with IAT, maribavir was more cost-effective for transplant recipients with refractory CMV, owing to better clinical efficacy and avoidance of high costs associated with administration, monitoring, AEs, and hospitalizations. These results can inform healthcare decision-makers on the most effective use of their resources for post-transplant refractory CMV treatment.

Assessment of patients' characteristics associated with the efficacy and safety of oral valganciclovir treatment for infants with symptomatic congenital cytomegalovirus disease.

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.

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.

In vitro assessment of the combined effect of letermovir and sirolimus on cytomegalovirus replication.

OBJECTIVE: Letermovir (LMV) is used for prophylaxis of cytomegalovirus (CMV) reactivation and end-organ disease in adult CMV-seropositive allogeneic hematopoietic stem cell transplant recipients (allo-HSCT). In turn, sirolimus (SLM) which displays in vitro anti-CMV activity, is frequently employed for prophylaxis of Graft vs. Host disease in allo-HSCT. Here, we aimed at assessing whether LMV and SLM used in combination may act synergistically in vitro on inhibiting CMV replication. METHODS: The antiviral activity of LMV and SLM alone or in combination was evaluated by a checkerboard assay, using ARPE-19 cells infected with CMV strain BADrUL131-Y. LMV and SLM were used at concentrations ranging from 24 nM to 0.38 nM and 16 nM to 0.06 nM, respectively. RESULTS: The mean EC50 for LMV and SLM was 2.44 nM (95% CI, 1.66-3.60) and 1.40 nM (95% CI, 0.41-4.74), respective. LMV and SLM interaction yielded mainly additive effects over the range of concentrations tested. CONCLUSIONS: The additive nature of the combination of LMV and SLM against CMV may have relevant clinical implications in management of CMV infection in allo-HSCT recipients undergoing prophylaxis with LMV.

Epidemiology, treatment patterns, and disease burden of cytomegalovirus in hematopoietic cell transplant recipients in selected countries outside of Europe and North America: A systematic review.

BACKGROUND: Cytomegalovirus (CMV) disease impacts morbidity and mortality in hematopoietic cell transplant (HCT) recipients. This systematic review summarized data on the epidemiology, management, and burden of CMV post-HCT outside of Europe and North America. METHODS: The MEDLINE, Embase, and Cochrane databases were searched for observational studies and treatment guidelines in HCT recipients across 15 selected countries from Asia-Pacific, Latin America, and Middle East (search period: 1 January 2011-17 September 2021). Outcomes included incidence of CMV infection/disease, recurrence, risk factors, CMV-related mortality, treatments, refractory, resistant CMV, and burden. RESULTS: Of 2708 references identified, 68 were eligible (67 studies and one guideline; 45/67 studies specific to adult allogeneic HCT recipients). The rates of CMV infection and disease within 1 year of allogeneic HCT were 24.9%-61.2% (23 studies) and 2.9%-15.7% (10 studies), respectively. Recurrence occurred in 19.8%-37.9% of cases (11 studies). Up to 10% of HCT recipients died of CMV-related causes. In all countries, first-line treatment for CMV infection/disease involved intravenous ganciclovir or valganciclovir. Conventional treatments were associated with serious adverse events such as myelosuppression (10.0%) or neutropenia only (30.0%, 39.8%) and nephrotoxicity (11.0%) (three studies), frequently leading to treatment discontinuation (up to 13.6%). Refractory CMV was reported in 2.9%, 13.0%, and 28.9% of treated patients (three studies) with resistant CMV diagnosed in 0%-10% of recipients (five studies). Patient-reported outcomes and economic data were scarce. CONCLUSION: The incidence of CMV infection and disease post-HCT is high outside of North America and Europe. CMV resistance and toxicity highlight a major unmet need with current conventional treatments.

Epidemiology, management, and burden of cytomegalovirus in solid organ transplant recipients in selected countries outside of Europe and North America: A systematic review.

BACKGROUND: Cytomegalovirus (CMV) is a frequent infectious complication following solid organ transplantation (SOT). Considering significant differences in healthcare systems, a systematic review was conducted to describe the epidemiology, management, and burden of CMV post-SOT in selected countries outside of Europe and North America. METHODS: MEDLINE, Embase, and Cochrane databases were searched for observational studies in SOT recipients across 15 countries in the regions of Asia, Pacific, and Latin America (search period: January 1, 2011 to September 17, 2021). Outcomes included incidence of CMV infection/disease, recurrence, risk factors, CMV-related mortality, treatment patterns and guidelines, refractory and/or resistant CMV, patient-reported outcomes, and economic burden. RESULTS: Of 2708 studies identified, 49 were eligible (n = 43/49; 87.8% in adults; n = 34/49, 69.4% in kidney recipients). Across studies, selection of CMV preventive strategy was based on CMV serostatus. Overall, rates of CMV infection (within 1 year) and CMV disease post-SOT were respectively, 10.3%-63.2% (9 studies) and 0%-19.0% (17 studies). Recurrence occurred in 35.4%-41.0% cases (3 studies) and up to 5.3% recipients died of CMV-associated causes (11 studies). Conventional treatments for CMV infection/disease included ganciclovir (GCV) or valganciclovir. Up to 4.4% patients were resistant to treatment (3 studies); no studies reported on refractory CMV. Treatment-related adverse events with GCV included neutropenia (2%-29%), anemia (13%-48%), leukopenia (11%-37%), and thrombocytopenia (13%-24%). Data on economic burden were scarce. CONCLUSION: Outside of North America and Europe, rates of CMV infection/disease post-SOT are highly variable and CMV recurrence is frequent. CMV resistance and treatment-associated adverse events, including myelosuppression, highlight unmet needs with conventional therapy.

Cost-effectiveness of screening and valacyclovir-based treatment strategies for first-trimester cytomegalovirus primary infection in pregnant women in France.

OBJECTIVE: To assess the effectiveness, cost and cost-effectiveness of four screening strategies for first-trimester (T1) cytomegalovirus (CMV) primary infection (PI) in pregnant women in France. METHODS: In a simulated pregnant population of 800 000 (approximate number of pregnancies each year in France), using costs based on the year 2022, we compared four CMV maternal screening strategies: Strategy S1, no systematic screening (current public health recommendations in France); Strategy S2, screening of 25-50% of the pregnant population (current screening practice in France); Strategy S3, universal screening (current medical recommendations in France); Strategy S4, universal screening (as in Strategy S3) in conjunction with valacyclovir in case of T1 PI. Outcomes were total cost, effectiveness (number of congenital infections, number of diagnosed infections) and incremental cost-effectiveness ratio (ICER). Two ICERs were calculated, comparing Strategies S1, S2 and S3 in terms of euros (€) per additional diagnosis, and comparing Strategies S1 and S4 in € per avoided congenital infection. RESULTS: Compared with Strategy S1, Strategy S3 enabled diagnosis of 536 more infected fetuses and Strategy S4 prevented 375 congenital infections. Strategy S1 was the least expensive strategy (€98.3m total lifetime cost), followed by Strategy S4 (€98.6m), Strategy S2 (€106.0m) and Strategy S3 (€118.9m). In the first analysis, Strategy S2 was dominated and Strategy S3 led to an additional €38 552 per additional in-utero diagnosis, compared with Strategy S1. In the second analysis, Strategy S4 led to an additional €893 per avoided congenital infection compared with Strategy S1, and was cost-saving compared with Strategy S2. CONCLUSIONS: In France, current screening practice for CMV PI during pregnancy is no longer acceptable in terms of cost-effectiveness because this strategy was dominated by universal screening. Moreover, universal screening in conjunction with valacyclovir treatment would be cost-effective compared with current recommendations and is cost-saving compared with current practice. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

The cost-effectiveness of maternal and neonatal screening for congenital cytomegalovirus infection in Japan.

Congenital cytomegalovirus infection is the most common congenital infection. Using a decision tree model, cost-effectiveness of maternal screening with subsequent prenatal valacyclovir treatment and newborn screening with neonatal valganciclovir treatment was evaluated. The incremental cost-effectiveness ratio (ICER) was calculated for (1) universal maternal antibody screening with prenatal valacyclovir treatment compared to targeted newborn screening, and (2) universal newborn screening with postnatal valganciclovir treatment compared to targeted newborn screening. We performed a one-way sensitivity analysis. Compared to targeted newborn screening, the ICERs for universal newborn screening and maternal screening were 2 966 296 Japanese Yen (JPY) (21 188 USD) and 1 026 984 JPY (7336 USD), respectively. In all scenarios in the one-way sensitivity analysis, the ICERs of the maternal screening and the universal newborn screening strategies were less than three gross domestic product per capita compared with the targeted newborn screening strategy. Both maternal and universal newborn screening strategies may be cost-effective than a targeted newborn screening program. The potential utility of the maternal screening with valacyclovir treatment strategy, while potentially cost effective in regions with lower baseline seroprevalence rates, requires further study as the modeling was based on limited evidence.

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.

Letermovir para profilaxia de infecção e doença causadas pelo citomegalovírus (CMV) em adultos receptores soropositivos para CMV (R+) submetidos ao transplante de células-tronco hematopoiéticas alogênico / Letermovir for prophylaxis of cytomegalovirus (CMV) infection and disease in CMV (R+) seropositive adult recipients undergoing allogeneic hematopoietic stem cell transplantation

INTRODUÇÃO: A infecção clinicamente significativa por citomegalovírus (ICS-CMV) é um importante fator associado a mortalidade em pacientes submetidos ao transplante de células tronco hematopoiéticas (TCTH). Estima-se que a incidência de ICS-CMV no período pós TCTH seja de 30% a 70% nos indivíduos transplantados. Diante disso, a ICS-CMV é considerada uma complicação no TCTH alogênico, que pode desencadear doenças agudas e tardias. Atualmente, como forma de prevenir a doença pelo CMV (DCMV), é empregada a terapia preemptiva com o medicamento ganciclovir, que é indicado quando o receptor IgG positivo desenvolve evidências de infecção por CMV. No entanto, o uso desse medicamento é limitado pelo risco de neutropenia, uma complicação que pode comprometer a estabilidade do TCTH. PERGUNTA DE PESQUISA: Letermovir como profilaxia da infecção e doença por CMV é eficaz, efetivo, seguro e custo-efetivo, em pacientes adultos receptores de TCTH alogênico R+, frente a qualquer comparador? EVIDÊNCIAS CLÍNICAS: O demandante apresentou pergunta PICO para revisão de literatura, que incluiu revisões sistemáticas com ou sem metanálise e ensaios clínicos randomizados. A busca incluiu o ensaio clínico randomizado (ECR) de fase III (Marty et al., 2017) e dois estudos de extensão deste ECR. Foi realizada uma nova busca em literatura com reformulação do PICO, contemplando revisões sistemáticas, ensaios clínicos randomizados e estudos observacionais sem restrição de comparador. Ao final, foram incluídos 18 estudos, entre experimentais e observacionais. De modo geral, o ECR demonstra a eficácia do letermovir na redução da incidência de ICS-CMV. No entanto, não foi verificada diferença estatisticamente significativa na mortalidade por todas as causas e na sobrevida global relacionada ao letermovir. Os estudos observacionais, em geral, apresentam resultados semelhantes aos encontrados no ECR pivotal. AVALIAÇÃO ECONÔMICA: Uma nova análise econômica foi construída, uma vez que o horizonte temporal de acompanhamento dos pacientes, pelo demandante, foi extrapolado de dois a 15 anos após o transplante. A nova análise foi estimada com o acompanhamento de um ano, considerando a história natural da doença. O demandante apresentou um modelo de árvore de decisão para avaliar a razão de custo-efetividade incremental (RCEI) e a razão de custo-utilidade incremental (RCUI) do uso profilático de letermovir em relação à não profilaxia em pessoas R+ para CMV submetidas a TCTH. O modelo considerou a probabilidade de desenvolvimento de ICS-CMV e, consequentemente, DCMV e complicações. Após análise crítica, e diante dos problemas e das inconsistências identificadas no modelo econômico do demandante, considerou-se mais prudente a elaboração de uma nova avaliação econômica, em um modelo de árvore de decisão, comparando a profilaxia com letermovir e placebo (sem profilaxia), levando em consideração os principais desfechos da doença em horizonte temporal de um ano. A nova análise resultou em custo de R$ 84.451,73 para a profilaxia com letermovir e R$27.416,06 sem realização de profilaxia em um ano pós TCTH. O uso de letermovir implicou em custo incremental de R$57.035,67 e em efetividade incremental de 0,0525 anos, aproximadamente 18 dias de vida ganhos, com RCEI de R$1.086.063,38 por ano de vida ganho. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: A partir dos parâmetros adotados no modelo da avaliação econômica, foi recalculada a análise de impacto orçamentário incremental na perspectiva do Sistema Único de Saúde e com horizonte temporal de cinco anos. Foram projetados dois cenários, o primeiro, atual, sem a incorporação de letermovir (cenário referência) e o segundo com a incorporação do medicamento para a profilaxia de infecção por citomegalovírus (CMV) em pacientes adultos provenientes do transplante alogênico de células hematopoiéticas (TCTH) (cenário alternativo). Ao final, os valores recalculados geraram uma estimativa de impacto orçamentário incremental de R$100.075.649, enquanto o demandante estimou um valor maior para o mesmo cenário de difusão gradativa, de R$100.950.787. Para o cenário de difusão mais acelerada, o valor de impacto estimado foi de R$271.969.304, enquanto o valor estimado pelo demandante foi menor, totalizando R$233.978.508. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Na análise foi identificada uma tecnologia potencial para compor o esquema terapêutico e de profilaxia da infecção e doença causadas pelo CMV em adultos receptores de transplantes de células tronco hematopoiéticas alogênico e soropositivos ao CMV (R+). Esta tecnologia é uma terapia pronta para ser administrada por via intravenosa que compreende parcialmente antígeno leucocitário humano (HLA) - linfócitos T alogênicos específicos compatíveis, para o potencial tratamento intravenoso de infecções causadas por agentes virais, incluindo CMV. Foram detectados cinco estudos que estão avaliando a eficácia e a segurança dessa terapia, com previsão de conclusão para 2023. Contudo, o seu mecanismo de ação ainda não está estabelecido. CONSIDERAÇÕES FINAIS: O uso profilático de letermovir em pacientes R+ para CMV pós TCTH alogênico demonstra resultados benéficos na prevenção de ICS-CMV, conforme relatos do ECR e dos estudos observacionais incluídos neste Relatório. Apesar disso, o medicamento não demostra diferenças estatisticamente significantes nos eventos de doença do enxerto contra hospedeiro, neutropenia, doença renal aguda e mortalidade em 48 semanas. Quanto à segurança, observou-se que ainda são escassas as informações a respeito dos eventos adversos relacionados ao medicamento. A avaliação econômica resultou em custo incremental de R$ 57.035,67 com efetividade incremental de 0,0525 anos, aproximadamente 18 dias de vida ganhos, com RCEI de R$1.086.063,38 por ano de vida ganho. O impacto orçamentário não demonstra resultados de economia para o SUS, quando comparado ao tratamento atual. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros presentes na 111ª Reunião Ordinária, no dia 03 de agosto de 2022, deliberaram, por unanimidade, encaminhar o tema para consulta pública com recomendação preliminar desfavorável a incorporação do letermovir para profilaxia de infecção e doença causadas pelo citomegalovírus (CMV) em adultos receptores positivos para CMV (R+) de transplante de células-tronco hematopoiéticas (TCTH) alogênico. Considerou-se a ausência de redução na mortalidade por todas as causas com o uso do letermovir; os custos significativos por anos de vida ganhos na avaliação econômica e os valores estimados no impacto orçamentário com uma possível incorporação do letermovir. CONSULTA PÚBLICA: A consulta pública (CP) nº 60/2022 foi realizada entre os dias 13/09/2022 e 03/10/2022. Foram recebidas 80 contribuições, sendo 59 pelo formulário para contribuições técnico-científico e 21 pelo formulário pra contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. As contribuições abordaram a eficácia, a efetividade e a segurança do letermovir. Sobre as contribuições técnicas, não se identificou nenhuma evidência científica adicional que pudesse modificar o entendimento preliminar da Conitec sobre a tecnologia. A empresa demandante apresentou uma nova proposta comercial, especificamente para a apresentação de letermovir 240 mg, caixa com 28 comprimidos, com redução de 17,8% do preço inicialmente proposto. A análise de custo-efetividade, considerando o novo preço, resultou em RCEI de R$ 973.629,01 por ano de vida ganho, em um ano de acompanhamento. O impacto orçamentário em cenário de difusão gradativa passou a ser R$ 90.365.646,83 e, em cenário de difusão acelerada, R$ 249.467.644,99. Nas contribuições de experiência ou opinião, todos os 20 participantes manifestaram-se favoráveis à incorporação da tecnologia avaliada e, portanto, em discordância com a recomendação preliminar da Conitec. RECOMENDAÇÃO FINAL DA CONITEC: Os membros presentes na 114ª Reunião Ordinária, no dia 10 de novembro de 2022, deliberaram, por unanimidade, recomendar a não incorporação do letermovir para profilaxia de infecção e doença causadas pelo citomegalovírus (CMV) em adultos soropositivos para CMV (R+) receptores de transplante de células-tronco hematopoiéticas (TCTH) alogênico. Considerou-se os valores significativos da avaliação econômica e do impacto orçamentário. Foi assinado o Registro de Deliberação nº 782/2022. DECISÃO: Não incorporar, no âmbito do Sistema Único de Saúde - SUS, o letermovir para profilaxia de infecção e doença causadas pelo citomegalovírus (CMV) em adultos soropositivos para CMV (R+) receptores de transplante de células-tronco hematopoiéticas (TCTH) alogênico, conforme protocolo estabelecido pelo Ministério da Saúde, conforme a Portaria nº 170, publicada no Diário Oficial da União nº 230, seção 1, página 295, em 8 de dezembro de 2022.

Current management of CMV infection in cancer patients (solid tumors). Epidemiology and therapeutic strategies.

Little evidence is available regarding the incidence of CMV disease in patients with solid cancers. Latest data show that approximately 50 % of these patients with CMV PCR positivity developed clinically relevant CMV-viremia, and would require specific therapy. In the clinical arena, CMV reactivation is an important differential diagnosis in the infectological work up of these patients, but guidelines of management on this subject are not yet available. CMV reactivation should be considered during differential diagnosis for patients with a severe decline in lymphocyte counts when receiving chemoradiotherapy or immunochemotherapy with lymphocyte-depleting or blocking agents. Monitoring of CMV reactivation followed by the implementation of preemptive strategies or the establishment of early antiviral treatment improves the prognosis and reduces the morbidity and mortality of these patients.

Real-World Treatment Patterns of Antiviral Prophylaxis for Cytomegalovirus Among Adult Kidney Transplant Recipients: A Linked USRDS-Medicare Database Study.

Limited data exist on cytomegalovirus (CMV) antiviral treatment patterns among kidney transplant recipients (KTRs). Using United States Renal Database System registry data and Medicare claims (1 January 2011-31 December 2017), we examined CMV antiviral use in 22,878 KTRs who received their first KT from 2011 to 2016. Three-quarters of KTRs started CMV prophylaxis (85.8% of high-, 82.4% of intermediate-, and 32.1% of low-risk KTRs). Median time to prophylaxis discontinuation was 98, 65, and 61 days for high-, intermediate-, and low-risk KTRs, respectively. Factors associated with receiving CMV prophylaxis were high-risk status, diabetes, receipt of a well-functioning kidney graft, greater time on dialysis before KT, panel reactive antibodies ≥80%, and use of antithymocyte globulin, alemtuzumab, and tacrolimus. KTRs were more likely to discontinue CMV prophylaxis if they developed leukopenia/neutropenia, had cardiovascular disease, or received their kidney from a deceased donor. These findings suggest that adherence to the recommended duration of CMV-prophylaxis for high and intermediate-risk patients is suboptimal, and CMV prophylaxis is overused in low-risk patients.

Assessment of UL56 Mutations before Letermovir Therapy in Refractory Cytomegalovirus Transplant Recipients.

De novo mutations in the UL56 terminase subunit and its associated phenotypes were studied in the context of cytomegalovirus (CMV) transplant recipients clinically resistant to DNA-polymerase inhibitors, naive to letermovir. R246C was the only UL56 variant detected by standard and deep sequencing, located within the letermovir-resistance-associated region (residues 230-370). R246C emerged in 2/80 transplant recipients (1 hematopoietic and 1 heart) since first cytomegalovirus replication and responded transiently to various alternative antiviral treatments in vivo. Recombinant phenotyping showed R246C conferred an advanced viral fitness and was sensitive to ganciclovir, cidofovir, foscarnet, maribavir, and letermovir. These results demonstrate a low rate (2.5%) of natural occurring polymorphisms within the letermovir-resistant-associated region before its administration. Identification of high replicative capacity variants in patients not responding to treatment or experiencing relapses could be helpful to guide further therapy and dosing of antiviral molecules. IMPORTANCE We provide comprehensive data on the clinical correlates of both CMV genotypic follow-up by standard and deep sequencing and the clinical outcomes, as well as recombinant phenotypic results of this novel mutation. Our study emphasizes that the clinical follow-up in combination with genotypic and phenotypic studies is essential for the assessment and optimization of patients experiencing HCMV relapses or not responding to antiviral therapy. This information may be important for other researchers and clinicians working in the field to improve the care of transplant patients since drug-resistant CMV infections are an important emerging problem even with the new antiviral development.

Changes in Valganciclovir Use Among Infants with Congenital Cytomegalovirus Diagnosis in the United States, 2009-2015 and 2016-2019.

From 2009-2015 to 2016-2019, the proportion of infants in the US with congenital cytomegalovirus treated with valganciclovir roughly doubled for infants enrolled with employer-sponsored insurance (from 16% to 29%) and Medicaid (from 16% to 36%). The proportion treated with valganciclovir increased for all congenital cytomegalovirus disease severity groups.

Health Care Resource Utilization and Economic Burden Associated With Congenital Cytomegalovirus Infection: A Longitudinal Analysis of Data From Clinical Practice at a Large Health Care Provider in Israel.

PURPOSE: Congenital cytomegalovirus infection (cCMVi) is the leading cause of nonhereditary sensorineural hearing loss and can cause other long-term neurodevelopmental disabilities; however, data on the economic burden of cCMVi during early childhood are scarce. The primary objective of the study was to describe longitudinal patterns of health care resource utilization (HCRU) and direct medical costs among infants with cCMVi compared to infants unexposed to cCMVi. METHODS: A retrospective cohort study was performed using data on infants born between 2013 and 2017, as captured in the database of Maccabi Healthcare Services, a 2.5 million-member health care organization in Israel. cCMVi cases were identified by physician diagnosis and/or dispensed valganciclovir within 90 days after birth. Infants born to mothers CMV-seronegative throughout pregnancy were selected for comparison (unexposed controls). Infants were retrospectively followed up through December 31, 2018, or 4 years of age (Y4). HCRU included physician visits, hospital admissions, audiology tests/procedures, imaging, and valganciclovir treatment. Direct medical costs, in US dollars per person per year (USD PPPY) were calculated from the health-system perspective. To compare costs of cCMVi cases and controls, direct medical costs were estimated using a generalized linear model with a log link function and γ distribution after adjustment for patient characteristics. FINDINGS: A total of 351 cCMVi cases and 11,733 control infants with continuous follow-up during their first year of life (Y1) were included in the study. In Y1, cases were more likely to have a hospital admission (8.5% cases vs 4.5% control; P < 0.001) and higher numbers of pediatrician visits (median, 18 vs 15), audiology visits and tests, and cranial ultrasounds (all, P < 0.05). Longitudinally, incremental costs associated with cases were highest in Y1 (1686.7 USD PPPY; cost ratio = 2.6; P < 0.001) and remained elevated through Y4. IMPLICATIONS: cCMVi was associated with substantial increases in HCRU and economic burden during early childhood, and particularly during the first year of life.

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.

Absorption, Metabolism, Distribution, and Excretion of Letermovir.

BACKGROUND: Letermovir is approved for prophylaxis of cytomegalovirus infection and disease in cytomegalovirus-seropositive hematopoietic stem-cell transplant (HSCT) recipients. OBJECTIVE: HSCT recipients are required to take many drugs concomitantly. The pharmacokinetics, absorption, distribution, metabolism, and excretion of letermovir and its potential to inhibit metabolizing enzymes and transporters in vitro were investigated to inform on the potential for drug-drug interactions (DDIs). METHODS: A combination of in vitro and in vivo studies described the absorption, distribution, metabolism, and routes of elimination of letermovir, as well as the enzymes and transporters involved in these processes. The effect of letermovir to inhibit and induce metabolizing enzymes and transporters was evaluated in vitro and its victim and perpetrator DDI potentials were predicted by applying the regulatory guidance for DDI assessment. RESULTS: Letermovir was a substrate of CYP3A4/5 and UGT1A1/3 in vitro. Letermovir showed concentration- dependent uptake into organic anionic transporting polypeptide (OATP)1B1/3-transfected cells and was a substrate of P-glycoprotein (P-gp). In a human ADME study, letermovir was primarily recovered as unchanged drug and minor amounts of a direct glucuronide in feces. Based on the metabolic pathway profiling of letermovir, there were few oxidative metabolites in human matrix. Letermovir inhibited CYP2B6, CYP2C8, CYP3A, and UGT1A1 in vitro, and induced CYP3A4 and CYP2B6 in hepatocytes. Letermovir also inhibited OATP1B1/3, OATP2B1, OAT3, OCT2, BCRP, BSEP, and P-gp. CONCLUSION: The body of work presented in this manuscript informed on the potential for DDIs when letermovir is administered both intravenously and orally in HSCT recipients.

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.