Assessment of effectiveness and impact of universal prophylaxis with nirsevimab for prevention of hospitalizations due to respiratory syncytial virus in infants. The NIRSE-GAL study protocol.

Nirsevimab has been recently licensed for universal RSV prophylaxis in infants. NIRSE-GAL is a three-year population-based study initiated in Galicia in September 2023. It aims to evaluate nirsevimab effectiveness against RSV-related hospitalizations lower respiratory tract infections (LRTI), severe RSV, all-cause LRTI, and all-cause hospitalization. NIRSE-GAL also aims to estimate nirsevimab impact on primary healthcare use in the short and mid-term, children's wheezing and asthma, and medical prescriptions for RSV. The immunization campaigns will be scheduled based on the expected start week for the RSV season and will last the whole season. Immunization will be offered to: i) infants born during the campaign (seasonal), ii) infants < 6 months at the start of the campaign (catch-up), and iii) infants with high-risk factors, aged 6-24 months at the start of the campaign (high-risk). The follow-up period will start: i) the immunization date for all immunized infants, ii) the start of the campaign, for the non-immunized catch-up or high-risk groups, or iii) the birthdate for the non-immunized seasonal group. Infants will be followed up until outcome occurrence, death, or end of study. Nirsevimab effectiveness will be estimated using Poisson and Cox regression models. Sensitivity and stratified analyses will be undertaken. The number of averted cases and the number needed to immunize will be estimated. Immunization failure and nirsevimab safety will be monitored. NIRSE-GAL was approved by the ethics committee of Galicia (CEIC 2023-377) and registered in ClinicalTrials.gov (ID: NCT06180993). Findings will be mainly shared via peer-reviewed publications and scientific conferences.

Cost-utility analysis of palivizumab for preventing respiratory syncytial virus in preterm neonates and infants in Colombia.

AIM: Palivizumab has proven effective in reducing hospitalizations, preventing severe illness, improving health outcomes, and reducing healthcare costs for infants at risk of respiratory syncytial virus (RSV) infection. We aim to assess the value of palivizumab in preventing RSV infection in high-risk infants in Colombia, where RSV poses a significant threat, causing severe respiratory illness and hospitalizations. METHODS: We conducted a decision tree analysis to compare five doses of palivizumab with no palivizumab. The study considered three population groups: preterm neonates (≤ 35 weeks gestational age), infants with bronchopulmonary dysplasia (BPD), and infants with hemodynamically significant congenital heart disease (CHD). We obtained clinical efficacy data from IMpact-RSV and Cardiac Synagis trials, while we derived neonatal hospitalization risks from the SENTINEL-1 study. We based hospitalization and recurrent wheezing management costs on Colombian analyses and validated them by experts. We estimated incremental cost-effectiveness ratios and performed 1,000 Monte Carlo simulations for probabilistic sensitivity analyses. RESULTS: Palivizumab is a dominant strategy for preventing RSV infection in preterm neonates and infants with BPD and CHD. Its high efficacy (78% in preventing RSV in preterm infants), the substantial risk of illness and hospitalization, and the high costs associated with hospitalization, particularly in neonatal intensive care settings, support this finding. The scatter plots and willingness-to-pay curves align with these results. CONCLUSION: Palivizumab is a cost-saving strategy in Colombia, effectively preventing RSV infection in preterm neonates and infants with BPD and CHD by reducing hospitalizations and lowering healthcare costs.

Exploratory analysis of the economically justifiable price of nirsevimab for healthy late-preterm and term infants in Colombia.

INTRODUCTION: Respiratory syncytial virus infection is the leading cause of lower respiratory infection globally. Recently, nirsevimab has been approved to prevent respiratory syncytial virus (RSV) infection. This study explores the economically justifiable price of nirsevimab for preventing RSV infection in Colombia's children under 1 year of age. MATERIALS AND METHODS: A static model was developed using the decision tree microsimulation to estimate the quality-adjusted costs and life years of two interventions: a single intramuscular dose of nirsevimab versus not applying nirsevimab. This analysis was made during a time horizon of 1 year and from a societal perspective. RESULTS: The annual savings in Colombia associated with this cost per dose ranged from U$ 2.5 to 4.1 million. Based on thresholds of U$ 4828, U$ 5128, and U$ 19 992 per QALY evaluated in this study, we established economically justifiable drug acquisition prices of U$ 21.88, U$ 25.04, and U$ 44.02 per dose of nirsevimab. CONCLUSION: the economically justifiable cost for nirsevimab in Colombia is between U$ 21 to U$ 44 per dose, depending on the willingness to pay used to decide its implementation. This result should encourage more studies in the region that optimize decision-making processes when incorporating this drug into the health plans of each country.

Palivizumab en niños nacidos de 35 semanas o menos de gestación y menores de 6 meses de edad al inicio de la estación de riesgo de infección por virus sincitial respiratorio / Palivizumab in children born at 35 weeks or less of gestation and children under 6 months of age at the beginning of the season at risk for respiratory syncytial virus infection

INTRODUCCIÓN: Este informe de ETS-R se realizó a solicitud de la Dirección General de Intervenciones Estratégicas en Salud Pública del Ministerio de Salud (DGIESP / MINSA); la cual motivó la formulación de una pregunta PICO conjuntamente con representantes tanto de la Dirección de Intervenciones por Curso de Vida y Cuidado Integral de la DGIESP como del Centro de Evaluación de Tecnologías en Salud (CETS) del Instituto Nacional de Salud. La pregunta PICO formulada fue la siguiente: P: pacientes pediátricos con alto riesgo de enfermedad por virus sincitial respiratorio (VSR); I: palivizumab; C: placebo o no administración; O: mortalidad, hospitalización por VSR, eventos adversos y calidad de vida. Para la presente evaluación, se consideró la primera categoría de alto riesgo de la ficha técnica DIGEMID, que corresponde a la población de recién nacidos de 35 semanas o menos de gestación y menores de 6 meses de edad al inicio de la estación de riesgo de infección por VSR. No se consideró población pediátrica con comorbilidades asociadas, como enfermedad pulmonar crónica, displasia broncopulmonar o cardiopatía congénita. OBJETIVOS: Describir la evidencia científica disponible sobre la eficacia y seguridad de la Inmunoglobulina Intravenosa (IgIV) para el tratamiento de encefalitis autoinmune en pacientes pediátricos que no mejoran con respuesta a pulsos de metilprednisolona y/o plasmaféresis. METODOLOGÍA: Se realizó una búsqueda sistemática en Medline/PubMed, The Cochrane Library y LILACS utilizando la estrategia de búsqueda descrita en el Anexo 01. Ésta se complementó con la búsqueda de evidencia en páginas institucionales de agencias gubernamentales y buscadores genéricos. Se priorizó la identificación y selección de ensayos clínicos aleatorizados controlados (ECA), revisiones sistemáticas (RS) de ECA, estudios observacionales comparativos, guías de práctica clínica (GPC), evaluaciones de tecnología sanitaria (ETS) y evaluaciones económicas (EE) de América Latina. La calidad de la evidencia se valoró usando: AMSTAR 2 para revisiones sistemáticas, la herramienta de la colaboración Cochrane para ensayos clínicos, la escala Newcastle-Ottawa para estudios no aleatorizados incluyendo cohortes y estudios de casos y controles, y AGREE II para valorar el rigor metodológico de las GPC. RESULTADOS: Tras la búsqueda sistemática se identificaron 207 artículos de los cuales 11 pararon a revisión a texto completo. De estos 11 documentos solo uno (GPC) correspondió con la pregunta PICO de interés. No se identificaron ECA o estudios observacionales comparativos, evaluaciones económicas, ni ETS que respondieran a la pregunta PICO de interés. CONCLUSIONES: Se revisó la mejor evidencia disponible sobre la eficacia y seguridad de la IgIV más metilprednisolona en pacientes pediátricos con encefalopatía autoinmune no mejoran con respuesta a pulsos de metilprednisolona y/o plasmaféresis (población objetivo). Se identificó solo una GPC que brinda recomendaciones para la población objetivo basada únicamente en consenso de expertos. Esta guía recomienda tanto la intervención como el comparador (prolongar el uso de metilprednisolona). No se cuenta con evidencia procedente de estudios tipo ECA u observacionales comparativos que evalúen la eficacia y seguridad de IgIV más metilprednisolona en la población objetivo, incluso ni en el contexto de primera línea. No se disponen de ETS ni evaluaciones económicas que respondan a la pregunta PICO de la presente revisión. Se espera que los resultados de ensayos clínicos en curso puedan brindar nueva información que permita responder a la pregunta de la presente revisión.

Cost-effectiveness of nirsevimab and palivizumab for respiratory syncytial virus prophylaxis in preterm infants 29-34 6/7 weeks' gestation in the United States.

BACKGROUND: Respiratory syncytial virus (RSV) hospitalizations have increased since the 2014 guideline update recommended against the use of palivizumab for preterm infants born ≥29 0/7 weeks' gestational age (GA) without additional risk factors. A novel drug candidate, nirsevimab, has been developed for this population. We analyzed the cost-effectiveness of palivizumab/nirsevimab vs. no prophylaxis in this population. METHODS: A hybrid-Markov model predicted the RSV clinical course in the first year of life and sequelae in the subsequent four years for preterm infants from the healthcare and societal perspectives. Model parameters were derived from the literature. We calculated costs and quality-adjusted life-years (QALYs) to produce an incremental cost-effectiveness ratio (ICER) evaluated at a willingness-to-pay threshold of $150,000/QALY. Sensitivity analyses assessed model robustness. A threshold analysis examined nirsevimab pricing uncertainty. RESULTS: Compared to no prophylaxis, palivizumab costs $9572 and $9584 more from the healthcare and societal perspectives, respectively, with 0.0019 QALYs gained per patient over five years, resulting in ICERs >$5 million per QALY from each perspective. Results were robust to parameter uncertainties; probabilistic sensitivity analysis revealed that no prophylaxis had a 100% probability of being cost-effective. The threshold analysis suggested that nirsevimab is not cost-effective when compared to no prophylaxis if the price exceeds $1962 from a societal perspective. CONCLUSION: Palivizumab is dominated by no prophylaxis for preterm infants 29 0/7-34 6/7 weeks' GA with no additional risk factors. Relevant stakeholders should consider alternatives to palivizumab for this population that are both effective and economical.

Palivizumabe para prevenção da infecção pelo vírus sincicial respiratório em crianças prematuras com idade gestacional de 29 a 31 semanas e seis dias / Palivizumab for prevention of respiratory syncytial virus infection in premature babies with gestational age from 29 to 31 weeks and six days

INTRODUÇÃO: O vírus sincicial respiratório (VSR) é um dos principais agentes etiológicos das infecções que acometem o trato respiratório inferior entre lactentes e crianças menores de 2 anos de idade. Durante os períodos de sazonalidade é responsável por até 75% das bronquiolites e 40% das pneumonias. Lactentes com menos de seis meses de idade, em especial, os prematuros, crianças com doença pulmonar crônica da prematuridade e cardiopatas, compõem a população de maior risco para desenvolver infecção respiratória grave, necessitando de internação por desconforto respiratório agudo em 10% a 15% dos casos. Em dados atuais obtidos no período de temperaturas mais baixas nos Estados Unidos (novembro de 2022 a fevereiro de 2023), a taxa global de hospitalização associada ao VSR, teve um pico de 65,3 hospitalizações por 100.000 indivíduos na faixa etária de zero a quatro anos, com maior incidência na faixa de zero a seis meses (255 por 100 mil indivíduos). Não há terapêutica específica que possa reduzir o tempo de infecção ou resolver os sintomas. O tratamento estabelecido é de suporte. HISTÓRICO DE RECOMENDAÇÃO DA CONITEC: Em 2012, a pedido da Justiça Federal da 4ª região (seção judiciária do Rio Grande do Sul), p

A new cost-utility analysis assessing risk factor-guided prophylaxis with palivizumab for the prevention of severe respiratory syncytial virus infection in Italian infants born at 29-35 weeks' gestational age.

Since the last Italian cost-utility assessment of palivizumab in 2009, new data on the burden of respiratory syncytial virus (RSV) and an International Risk Scoring Tool (IRST) have become available. The objective of this study was to provide an up-to-date cost-utility assessment of palivizumab versus no prophylaxis for the prevention of severe RSV infection in otherwise healthy Italian infants born at 29-31 weeks' gestational age (wGA) infants and those 32-35wGA infants categorized as either moderate- or high-risk of RSV-hospitalization (RSVH) by the IRST. A decision tree was constructed in which infants received palivizumab or no prophylaxis and then could experience: i) RSVH; ii) emergency room medically-attended RSV-infection (MARI); or, iii) remain uninfected/non-medically attended. RSVH cases that required intensive care unit admission could die (0.43%). Respiratory morbidity was considered in all surviving infants up to 18 years of age. Hospitalization rates were derived from Italian data combined with efficacy from the IMpact-RSV trial. Palivizumab costs were calculated from vial prices (50mg: €490.37 100mg: €814.34) and Italian birth statistics combined with a growth algorithm. A lifetime horizon and healthcare and societal costs were included. The incremental cost-utility ratio (ICUR) was €14814 per quality-adjusted life year (QALY) gained in the whole population (mean: €15430; probability of ICUR being <€40000: 0.90). The equivalent ICURs were €15139 per QALY gained (€15915; 0.89) for 29-31wGA infants and €14719 per QALY gained (€15230; 0.89) for 32-35wGA infants. The model was most sensitive to rates of long-term sequelae, utility scores, palivizumab cost, and palivizumab efficacy. Palivizumab remained cost-effective in all scenario analyses, including a scenario wherein RSVH infants received palivizumab without a reduction in long-term sequelae and experienced a 6-year duration of respiratory morbidity (ICUR: €27948 per QALY gained). In conclusion, palivizumab remains cost-effective versus no prophylaxis in otherwise healthy Italian preterm infants born 29-35wGA. The IRST can help guide cost-effective use of palivizumab in 32-35wGA infants.

The increasing age of respiratory syncytial virus-related hospitalisation during COVID-19 pandemic in Lyon was associated with reduced hospitalisation costs.

BACKGROUND: Preventive measures applied during the COVID-19 pandemic have modified the age distribution, the clinical severity and the incidence of Respiratory Syncytial Virus (RSV) hospitalisations during the 2020/21 RSV season. The aim of the present study was to estimate the impact of these aspects on RSV-associated hospitalisations (RSVH) costs stratified by age group between pre-COVID-19 seasons and 2020/21 RSV season. METHODS: We compared the incidence, the median costs, and total RSVH costs from the national health insurance perspective in children < 24 months of age during the COVID-19 period (2020/21 RSV season) with a pre-COVID-19 period (2014/17 RSV seasons). Children were born and hospitalised in the Lyon metropolitan area. RSVH costs were extracted from the French medical information system (Programme de Médicalisation des Systémes d'Information). RESULTS: The RSVH-incidence rate per 1000 infants aged < 3 months decreased significantly from 4.6 (95 % CI [4.1; 5.2]) to 3.1 (95 % CI [2.4; 4.0]), and increased in older infants and children up to 24 months of age during the 2020/21 RSV season. Overall, RSVH costs for RSVH cases aged below 2 years old decreased by €201,770 (31 %) during 2020/21 RSV season compared to the mean pre-COVID-19 costs. CONCLUSIONS: The sharp reduction in costs of RSVH in infants aged < 3 months outweighed the modest increase in costs observed in the 3-24 months age group. Therefore, conferring a temporal protection through passive immunisation to infants aged < 3 months should have a major impact on RSVH costs even if it results in an increase of RSVH in older children infected later in life. Nevertheless, stakeholders should be aware of this potential increase of RSVH in older age groups presenting with a wider range of disease to avoid any bias in estimating the cost-effectiveness of passive immunisation strategies.

Impact of using the International Risk Scoring Tool on the cost-utility of palivizumab for preventing severe respiratory syncytial virus infection in Canadian moderate-to-late preterm infants.

BACKGROUND AND OBJECTIVE: To assess the cost-utility of palivizumab versus no prophylaxis in preventing severe respiratory syncytial virus (RSV) infection in Canadian moderate-to-late preterm (32-35 weeks' gestational age) infants using an (i) International Risk Scoring Tool (IRST) and (ii) Canadian RST (CRST). METHODS: A decision tree was developed to assess cost-utility. Infants assessed at moderate- and high-risk of RSV-related hospitalization (RSVH) by the IRST or CRST received palivizumab or no prophylaxis and then progressed to either (i) RSVH; (ii) emergency room/outpatient medically attended RSV-infection (MARI) or (iii) were uninfected/non-medically attended. Infants admitted to intensive care could incur mortality (0.43%). Respiratory morbidity was accounted in all uninfected surviving infants for 6 years or 18 years (RSVH/MARI). Palivizumab efficacy (72.2% RSVH reduction) and hospital outcomes were from the Canadian CARESS, PICNIC and RSV-Quebec studies. Palivizumab costs (50 mg: CAN$752; 100 mg: $1,505) were calculated from Canadian birth statistics combined with a growth algorithm. Healthcare/payer and societal costs (May 2022; 1.5% discounting) were included. RESULTS: Cost per quality-adjusted life year (QALY) was $29,789 with the IRST (0.79 probability of being <$50,000) and $15,833 with the CRST (0.96 probability). The model was most sensitive to utility scores, long-term sequelae and palivizumab cost. Vial sharing improved the incremental cost-utility ratio (IRST: $22,319; CRST: $9,231). CONCLUSIONS: Palivizumab was highly cost-effective (vs no prophylaxis) in Canadian moderate-to-late preterm infants using either the IRST or CRST. The IRST has fewer risk factors than the CRST (3 vs 7, respectively), captures more potential RSVHs (85% vs 54%) and provides another option to guide cost-effective RSV prophylaxis in Canada.

Cost of childhood RSV management and cost-effectiveness of RSV interventions: a systematic review from a low- and middle-income country perspective.

BACKGROUND: Approximately 97% of global deaths due to RSV occur in low- and middle-income countries (LMICs). Until recently, the only licensed preventive intervention has been a shortacting monoclonal antibody (mAb), palivizumab (PVZ) that is expensive and intensive to administer, making it poorly suited for low-resource settings. Currently, new longer acting RSV mAbs and maternal vaccines are emerging from late-stage clinical development with promising clinical effectiveness. However, evidence of economic value and affordability must also be considered if these interventions are to be globally accessible. This systematic review's objective was to summarise existing evidence on the cost-of-illness (COI) and cost-effectiveness of RSV prevention interventions in LMICs. METHODS: We conducted a systematic literature review using the Embase, MEDLINE, and Global Index Medicus databases for publications between Jan 2000 and Jan 2022. Two categories of studies in LMICs were targeted: cost-of-illness (COI) of RSV episodes and cost-effectiveness analyses (CEA) of RSV preventive interventions including maternal vaccines and long-acting mAbs. Of the 491 articles reviewed, 19 met the inclusion criteria. RESULTS: COI estimates varied widely: for severe RSV, the cost per episode ranged from $92 to $4114. CEA results also varied-e.g. evaluations of long-acting mAbs found ICERs from $462/DALY averted to $2971/DALY averted. Study assumptions of input parameters varied substantially and their results often had wide confidence intervals. CONCLUSIONS: RSV represents a substantial disease burden; however, evidence of economic burden is limited. Knowledge gaps remain regarding the economic value of new technologies specifically in LMICs. Further research is needed to understand the economic burden of childhood RSV in LMICs and reduce uncertainty about the relative value of anticipated RSV prevention interventions. Most CEA studies evaluated palivizumab with fewer analyses of interventions in development that may be more accessible for LMICs.

Cost-effectiveness of Respiratory Syncytial Virus Disease Prevention Strategies: Maternal Vaccine Versus Seasonal or Year-Round Monoclonal Antibody Program in Norwegian Children.

BACKGROUND: Every winter, respiratory syncytial virus (RSV) disease results in thousands of cases in Norwegian children under 5 years of age. We aim to assess the RSV-related economic burden and the cost-effectiveness of upcoming RSV disease prevention strategies including year-round maternal immunization and year-round and seasonal monoclonal antibody (mAb) programs. METHODS: Epidemiological and cost data were obtained from Norwegian national registries, while quality-adjusted life-years (QALYs) lost and intervention characteristics were extracted from literature and phase 3 clinical trials. A static model was used and uncertainty was accounted for probabilistically. Value of information was used to assess decision uncertainty. Extensive scenario analyses were conducted, including accounting for long-term consequences of RSV disease. RESULTS: We estimate an annual average of 13 517 RSV cases and 1572 hospitalizations in children under 5, resulting in 79.6 million Norwegian kroner (~€8 million) treatment costs. At €51 per dose for all programs, a 4-month mAb program for neonates born in November to February is the cost-effective strategy for willingness to pay (WTP) values up to €40 000 per QALY gained. For higher WTP values, the longer 6-month mAb program that immunizes neonates from October to March becomes cost-effective. Sensitivity analyses show that year-round maternal immunization can become a cost-effective strategy if priced lower than mAb. CONCLUSIONS: Assuming the same pricing, seasonal mAb programs are cost-effective over year-round programs in Norway. The timing and duration of the cost-effective seasonal program are sensitive to the pattern of the RSV season in a country, so continued RSV surveillance data are essential.

Respiratory syncytial virus nosocomial outbreak in neonatal intensive care: A review of the incidence, management, and outcomes.

BACKGROUND: The main objective was to determine the incidence, management, and outcomes of respiratory syncytial virus nosocomial infection (RSVNI) outbreaks in neonatal intensive care units. METHODS: A comprehensive search of RSVNI in 9 databases was conducted from January 1, 2000 to May 1, 2021, of which the Cochrane Library comprised the Cochrane central register of controlled trials and the Cochrane database of systematic reviews. Two hundred and twenty-eight articles were retrieved and 17 were retained. A descriptive analysis was performed, and frequencies are reported as mean, median, and range where pertinent. RESULTS: One hundred and seventeen infants were analyzed and comprised preterms (88.1%) and those with pre-existing co-morbidities. The estimated proportional incidence of RSVNI was 23.8% (177/744) infants. Outbreaks were principally managed by conventional protective measures, neonatal intensive care unit closure, and visitor restriction. Palivizumab was used to control RSVNI in 10 studies. RSVNI-related mortality was 8.5% (15/177) and 8.0% (7/87) among infants where infection control was solely employed. CONCLUSION: RSVNI is associated with significant morbidity and mortality. The use of palivizumab should be a multidisciplinary decision, based on rapidly spreading infection. Prospective studies are essential to determine the cost-benefit of palivizumab versus standard prevention control for an RSVNI outbreak.

Disease burden of respiratory syncytial virus infection in the pediatric population in Japan.

INTRODUCTION: Respiratory syncytial virus (RSV) is one of the most common causes of lower respiratory tract infections in children aged <5 years and is associated with long-term respiratory morbidities such as recurrent wheezing and asthma, decreased lung function, and allergic sensitization. The objective of this review was to evaluate the epidemiology and burden of RSV infection in the pediatric population in Japan. METHODS: Studies indexed in PubMed and ICHUSHI databases during January 2010-December 2020 were manually reviewed. Data on proportion of RSV infections, seasonality, length of stay (LoS), mortality, medical expenses, and palivizumab use were extracted from the selected articles. RESULTS: Ninety-three articles were included (PubMed, 64; ICHUSHI, 29). The proportion of patients/samples with an RSV infection was 5.5%-66.7%, and 6.0%-29.9% in the inpatient and outpatient departments, respectively. RSV infections generally occurred during autumn/winter; however, recently the peak has shifted to summer. The LoS was variable and depended on factors such as age, infection severity, wheezing, and RSV subgroups. Mortality rates varied from <1% to 19% depending on the infection severity. The average daily hospitalization and intensive care unit cost was JPY 34,548 while intensive care unit incurred an additional cost of JPY 541,293. Palivizumab was indicated for high-risk infants and 0%-3% of patients required hospitalization despite palivizumab use. CONCLUSIONS: RSV imposes a significant burden on the Japanese healthcare system, suggesting a need to create awareness among caregivers of children, pregnant women and healthcare professionals to ensure early recognition of infection and adequate treatment or prophylaxis.

Eficacia y seguridad de palivizumab en la prevención de la enfermedad grave causada por el virus sincitial respiratorio en niños con displasia broncopulmonar y antecedente de prematuridad / Efficacy and safety of palivizumab in the prevention of severe respiratory syncytial virus disease in children with bronchopulmonary dysplasia and a history of prematurity

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad de palivizumab para prevenir la enfermedad grave causada por el VSR en niños con DBP que hayan recibido tratamiento para la DBP en los últimos seis meses y tengan antecedente de haber nacido a las 29 semanas o menos de gestación. A nivel mundial, el virus sincitial respiratorio (VSR) es una de las principales causas de infección del tracto respiratorio inferior en niños. En Perú, el VSR ha sido detectado en el 86 % de niños menores de un año y en el 76 % de niños de uno a cuatro años, con infecciones respiratorias agudas. La displasia broncopulmonar (DBP) y la prematuridad son factores de riesgo para el desarrollo de enfermedad grave por VSR y están asociadas con mayores tasas de hospitalización, 388/1000 en niños con DBP y 57/1000 en niños prematuros, y muerte, tasas de casos fatales que van del 3.5 % al 23 % en niños con DBP y del 1.2 % al 6.1 % en niños prematuros. Un aspecto importante de la epidemiología del VSR es que difiere de acuerdo con las condiciones meteorológicas de las regiones. Por ejemplo, en las regiones tropicales y subtropicales, como es el caso de Perú, las infecciones por VSR se distribuyen de manera uniforme a lo largo de todo el año, con algunos aumentos variables. Actualmente, no se cuenta con un tratamiento antiviral efectivo para las infecciones por VSR, por lo que las medidas profilácticas toman gran importancia. Palivizumab, un anticuerpo monoclonal, es usado como una medida para prevenir el desarrollo de la enfermedad grave causada por el VSR, que requiera hospitalización, en niños susceptibles a desarrollar enfermedad. En el contexto de EsSalud, no se cuenta con una medida profiláctica frente a la enfermedad grave causada por el VSR. Los especialistas de EsSalud consideran que palivizumab ayudaría a prevenir la hospitalización, mortalidad y morbilidad causadas por la infección por VSR, en pacientes con alto riesgo de desarrollar enfermedad grave. En ese sentido, el presente dictamen expone la evaluación de la eficacia y seguridad de palivizumab, comparado con placebo, en la prevención de la enfermedad grave causada por el VSR en niños con DBP, que hayan recibido tratamiento para la DBP en los últimos seis meses, y con antecedente de haber nacido a las 29 semanas, o menos, de gestación. METODOLOGÍA: La búsqueda de la literatura se realizó con el objetivo de identificar evidencia sobre la eficacia y seguridad de palivizumab, en comparación con placebo, para prevenir la enfermedad grave causada por el VSR en niños con DBP que hayan recibido tratamiento para la DBP en los últimos seis meses, con antecedente de haber nacido a las 29 semanas o menos de gestación. La búsqueda de la evidencia se realizó en las bases de datos bibliográficas: PubMed, LILACS y The Cochrane Library. Adicionalmente, se amplió la búsqueda revisando la evidencia generada por grupos internacionales que realizan revisiones sistemáticas, evaluaciones de tecnologías sanitarias y guías de práctica clínica, tales como The National Institute for Health and Care Excellence (NICE), The Canadian Agency for Drugs and Technologies in Health (CADTH), Centro Nacional de Excelencia Tecnológica en Salud (CENETEC), Scottish Intercollegiate Guidelines Network (SIGN), Institute for Quality and Efficiency in Health Care (IQWiG), Scottish Medicines Consortium (SMC), Agency for Healthcare Research and Quality's (AHRQ), National Health and Medical Research Council (NHMRC), New Zealand Guidelines Group (NZGG), Canadian Medical Association (CMA), American College of Physicians Clinical Practice Guidelines y Registered Nurses Association of Ontario (RNAO). Adicionalmente, se realizó una búsqueda manual en las bases The Guidelines International Network (G-I-N), eGuidelines, y el portal de la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA). Finalmente, se realizó una búsqueda manual en el portal ClinicalTrials.gov del National Institutes of Health (NIH) para identificar ensayos clínicos en desarrollo o cuyos resultados aún no hayan sido publicados en una revista científica. RESULTADOS: Se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad. CONCLUSIONES: En el presente documento, se evaluó la mejor evidencia científica disponible hasta agosto del 2021, en relación con la eficacia y seguridad de palivizumab en la prevención de la enfermedad grave causada por el VSR, que requiere hospitalización, en niños con DBP que hayan recibido tratamiento para la DBP en los últimos seis meses, con antecedente de haber nacido a las 29 semanas o menos de gestación. En EsSalud no se cuenta con una medida profiláctica frente al desarrollo de enfermedad grave causada por el VSR, que requiera hospitalización, para niños con alto riesgo; enmarcándose en un contexto de vacío terapéutico. La búsqueda sistemática de la evidencia culminó con la selección de dos GPC (Castaños y Rodríguez 2019; Ralston et al. 2014), dos ETS (Ministerio de Salud de Chile 2017; DIGEMID 2016), y el ECA de fase III IMPACT (The IMpact-RSV Study Group 1998). Las guías de Castaños y Rodríguez, y de Ralston et al., coinciden en recomendar la profilaxis con palivizumab en niños con DBP y prematuridad; aunque difieren en el rango de EG del paciente prematuro y el grado de DBP. Ambas guías tomaron en consideración los resultados del ECA IMPACT para emitir sus recomendaciones. Las dos ETS, del Ministerio de Salud de Chile y la DIGEMID de Perú, brindan recomendaciones opuestas sobre el uso profiláctico de palivizumab en niños con DBP y prematuridad. El Ministerio de Salud de Chile aprobó la ampliación de uso de palivizumab en pacientes prematuros menores a 36 semanas con patologías o condiciones de riesgo asociadas. En cambio, la DIGEMID de Perú decide no incluir a palivizumab en el PNUME para su uso en neonatos con EG de 29 a 32 semanas con DBP y edad corregida menor o igual a 3 meses al inicio de la profilaxis. Ambas ETS tomaron en cuenta los resultados del ECA IMPACT. El ECA IMPACT, evaluó el uso de palivizumab versus placebo en niños prematuros con edad menor o igual a seis meses, y niños con DBP y edad menor o igual a dos años. El ECA reportó la reducción de la incidencia de hospitalizaciones por VSR en los niños que recibieron palivizumab en comparación con placebo; un menor número de ingresos a UCI a favor de palivizumab. No se observaron diferencias en la incidencia de ventilación mecánica, duración de ventilación mecánica, mortalidad y el reporte de EA, entre el uso de placebo y palivizumab. El ECA IMPACT (estudio de fase III, doble ciego y pivotal de palivizumab) es el único ECA disponible que evalúa la eficacia comparativa de palivizumab. Las limitaciones del ECA IMPACT afectan la validez y precisión de sus resultados. Tomando en cuenta estas limitaciones, el uso de palivizumab sería eficaz en reducir la incidencia de hospitalización solo en el subgrupo de pacientes de 6 meses de edad o menos y prematuridad (EG menor o igual a 35 semanas). El contexto de vacío terapéutico y la evidencia disponible sugieren que el uso de palivizumab podría tener un impacto significativo en la incidencia de hospitalizaciones por VSR en la población objetivo del presente dictamen (pacientes con DBP y antecedente de prematuridad). Por lo expuesto, el IETSI aprueba el uso de palivizumab para la prevención de la enfermedad grave causada por el VSR en niños con DBP que hayan recibido tratamiento para la DBP en los últimos seis meses, con antecedente de haber nacido a las 29 semanas o menos de gestación, según lo establecido en el Anexo N°1. La vigencia del presente dictamen preliminar es de un año a partir de la fecha de publicación. Así, la continuación de dicha aprobación estará sujeta a la evaluación de los resultados obtenidos y de mayor evidencia que pueda surgir en el tiempo.

Unintended Consequences Following the 2014 American Academy of Pediatrics Policy Change for Palivizumab Prophylaxis among Infants Born at Less than 29 Weeks' Gestation.

OBJECTIVE: The aim of this study is to compare outpatient respiratory syncytial virus (RSV) immunoprophylaxis (IP) use and relative RSV hospitalization (RSVH) rates for infants <29 weeks' gestational age (wGA) versus term infants before and after the 2014 American Academy of Pediatrics (AAP) policy change. STUDY DESIGN: Infants were identified in the MarketScan Commercial and Multi-State Medicaid databases. Outpatient RSV IP receipt and relative <29 wGA/term hospitalization risks in 2012 to 2014 and 2014 to 2016 were assessed using rate ratios and a difference-in-difference model. RESULTS: Outpatient RSV IP receipt by infants <29 wGA and aged <3 months in the Commercial and Medicaid populations and those aged 3 to <6 months in the Medicaid population declined after 2014. Relative RSVH risks for infants <29 wGA were numerically greater after 2014, with infants aged <3 months and Medicaid infants experiencing the greatest increases. Difference-in-difference results indicated a significantly increased relative risk of RSVH for infants <29 wGA versus term (both cohorts aged 0 to <6 months) in the Medicaid-insured population (1.68, p = 0.0054). A nonsignificant increase of similar magnitude occurred in the commercially insured population (1.57, p = 0.2867). CONCLUSION: The 2014 policy change was associated with a decrease in RSV IP use and an increase in RSVH risk among otherwise healthy infants <29 wGA.

RSV Lower Respiratory Tract Illness in Infants of Low- and Middle-income Countries.

This review addresses differences in respiratory syncytial virus (RSV) lower respiratory tract illness (LRTI) between industrialized and developing countries and provides observations associated with the dissimilar consequences of viral infection in both environments. RSV LRTI is an important cause of morbidity and mortality in infants worldwide. Its burden is highest in developing countries, where most hospitalizations and mortality occur. Palivizumab has been approved for disease prevention in premature infants in numerous countries but its cost and requirement for several doses hampers its routine use. The significant gap between low- and high-income countries in mortality rates stresses the need to identify specific risk factors for RSV LRTI prevention in different populations. CONCLUSION: RSV LTRI continues to be a serious problem for industrialised and developing countries, although mortality occurs preferentially in the latter. Several vaccines and monoclonal antibodies to prevent severe disease are advancing steadily in late phase trials. The next decade may witness a change in the landscape of RSV infections in young infants.

Updated cost-effectiveness analysis of palivizumab (Synagis) for the prophylaxis of respiratory syncytial virus in infant populations in the UK.

AIMS: Respiratory syncytial virus (RSV) is a common cause of respiratory infection in infants and severe infection can result in hospitalization. The passive immunization, palivizumab, is used as prophylaxis against RSV, however, use in the UK is restricted to populations at high risk of hospitalization. This study assesses the cost-effectiveness (CE) of palivizumab in premature infants with and without risk factors for hospitalization (congenital heart disease [CHD], bronchopulmonary dysplasia [BPD]). METHODS: A decision tree model, based on earlier CE analyses, was updated using data derived from targeted literature reviews and advice gained from a Round Table meeting. All costs were updated to 2019 prices. One-way and probabilistic sensitivity analyses were performed to assess the degree of uncertainty surrounding the results. RESULTS: Palivizumab is dominant (i.e. clinically superior and cost saving) when used in premature infants born ≤35 weeks gestational age (wGA) without CHD or BPD and aged <6 months at the start of the RSV season, infants aged <24 months with CHD and infants aged <24 months requiring treatment for BPD within the last 6 months. LIMITATIONS: One-way sensitivity analysis suggests that these results are highly sensitive to the efficacy of prophylaxis, number of doses, impact of long-term respiratory sequalae, rate of hospitalization and mortality due to RSV. A conservative approach has been taken toward long-term respiratory sequalae due to uncertainty around epidemiology and etiology and a lack of recent cost and utility data. CONCLUSIONS: Palivizumab prophylaxis is cost-effective in preventing severe RSV infection requiring hospital admission in a wider population than currently recommended in UK guidelines. Prophylaxis in premature infants born <29 wGA, 29-32 wGA and 33-35 wGA without CHD or BPD aged <6 months at the start of the RSV season is not funded under current guidance, however, prophylaxis has been demonstrated to be cost-effective in this analysis.

Réévaluation des critères d'admissibilité au palivizumab (SynagisMC) pour la prévention des infections graves par le virus respiratoire syncytial chez l'enfant / Reassessment of palivizumab eligibility criteria (Synagis™) for the prevention of serious viral infections respiratory syncytial in children

INTRODUCTION: En vue d'optimiser l'usage du palivizumab et de déterminer ensuite le budget à y attribuer, le MSSS a demandé à l'INESSS de réviser les critères d'admissibilité du programme québécois d'immunoprophylaxie par le palivizumab. Le palivizumab (SynagisMC) est un agent d'immunisation passive, plus précisément un anticorps monoclonal humain (IgG1κ), qui agit en neutralisant le VRS et en inhibe la fusion avec la cellule. Il est commercialisé sous forme de solution pour injection par voie intramusculaire. Il est indiqué pour la « prévention d'affections graves des voies respiratoires inférieures causées par le virus respiratoire syncytial (VRS) chez les enfants hautement susceptibles de contracter une infection par le VRS. Soulignons que le palivizumab n'empêche pas la transmission du VRS; il influe plutôt sur le risque de voir une infection par le VRS s'aggraver au point d'entraîner une hospitalisation de l'enfant qui en est atteint. Le VRS est la principale cause d'affections des voies respiratoires inférieures, notamment la bronchiolite et la pneumonie, chez les jeunes enfants. Leur incidence est à son pic chez les nourrissons âgés de 2 à 6 mois et il infecte presque tous les enfants avant l'âge de 2 ans, lors d'épidémies annuelles sévissant généralement, au Québec, de la mi-novembre à la fin avril. Le traitement des enfants qui en sont atteints consiste principalement à soulager les symptômes. La primo-infection ne confère pas une immunité protectrice et, donc, une réinfection est possible durant la même saison ou les saisons subséquentes. Environ 1 à 2 % des enfants atteints de bronchiolite seront malades au point de devoir être hospitalisés afin de recevoir de l'oxygénothérapie ou des soins d'appoint. Les frais d'hospitalisation représentent plus de la moitié du fardeau économique associé au VRS chez les enfants âgés de moins de 4 ans. La documentation scientifique rapporte que certaines populations d'enfants risquent plus que d'autres d'être hospitalisées, de séjourner plus longtemps à l'hôpital ou d'être admises dans une unité de soins intensifs. Il s'agit notamment de certains bébés prématurés, d'enfants atteints de dysplasie bronchopulmonaire, de maladie pulmonaire chronique du nouveau-né ou d'une cardiopathie congénitale dont les conséquences hémodynamiques sont cliniquement significatives. Parmi les enfants hospitalisés, certains peuvent avoir des séquelles à long terme. Toutefois, les décès sont rares. Un programme d'immunoprophylaxie est en vigueur au Québec depuis plusieurs années. Il cible les populations pédiatriques jugées les plus à risque de complications en cas d'infection des voies respiratoires par le VRS. L'objectif du présent rapport est de faire état des recommandations de l'INESSS concernant la mise à jour des critères d'admissibilité à ce programme en vue de la saison 2020-2021 et des modalités d'administration du palivizumab, en tenant compte de l'évolution de la science et de la pratique clinique. MÉTHODOLOGIE: L'INESSS a procédé à des travaux relatifs à la réévaluation des critères d'admissibilité au palivizumab pour la prévention des infections graves des voies respiratoires par le VRS chez l'enfant. À cette fin, le cadre d'évaluation retenu s'inspire de celui établi relativement à l'évaluation des médicaments aux fins d'inscription sur les listes des médicaments assurés au Québec. En effet, il inclut les volets de la valeur thérapeutique, de la justesse du prix et du rapport entre le coût et l'efficacité du produit, des conséquences sur la santé de la population et sur les autres composantes du système de santé et des services sociaux et celui des autres considérations, notamment de nature éthique ou sociétale. Il s'agit d'une démarche rigoureuse qui permet de formuler des recommandations fondées sur des données scientifiques, en plus des données expérientielles des cliniciens et des parents d'enfants. Ainsi, cela augmente les chances que la communauté médicale adhère à ces recommandations et que la population soit réceptive aux changements, le cas échéant. JUSTESSE DU PRIX: Le prix de vente d'une fiole de 50 mg et de 100 mg de palivizumab est respectivement de 752,30 $ et de 1 504,50 $. En considérant une administration tous les mois pour une saison d'une durée de 5 mois, le coût de traitement du palivizumab est de 4 739 $ pour un bébé de 4,2 kg, soit le poids moyen des bébés inscrits au registre canadien du palivizumab (registre CARESS) pour les saisons 2013-2014 et 2014-2015. À noter que les pertes en médicament n'ont pas été considérées, compte tenu du fait qu'en pratique, les cliniciens administrent la prophylaxie en groupe chez les bébés afin d'éviter ces pertes. RAPPORT ENTRE LE COÛT ET L'EFFICACITÉ: Du point de vue pharmacoéconomique, compte tenu du fait que l'INESSS recommande le maintien de l'abrogation du critère d'admissibilité au palivizumab pour les bébés prématurés nés de 33 à 35 SG, à la suite de l'évaluation réalisée par les membres du groupe d'experts et du CSEMI, l'évaluation de l'efficience du produit n'a pas été réalisée. En ce qui concerne les autres critères d'admissibilité, lesquels portent notamment sur la population d'enfants du Nunavik nés à terme, ils sont tous maintenus. Il est important de souligner que lors de la réévaluation des critères d'admissibilité au palivizumab en août 2016, il n'avait pas été possible d'évaluer l'efficience de ce produit chez ces différentes populations. Cela s'expliquait notamment par la faiblesse ou l'absence de preuves cliniques suffisamment robustes pour être introduites dans le modèle pharmacoéconomique. À noter qu'en raison de constats similaires quant à la qualité des études analysées dans les présents travaux, il n'a pas été davantage possible d'évaluer l'efficience du palivizumab. CONCLUSION: Le mode d'évaluation qu'adopte usuellement l'INESSS pour les médicaments à inscrire sur les listes des médicaments présente des défis dans le cas d'un produit comme le palivizumab. Il s'est avéré que les études répertoriées sont, en grande majorité, des études rétrospectives de faible niveau de preuve, dont la plupart incluent un faible nombre de patients. De surcroît, l'usage du palivizumab n'est pas documenté en ce qui concerne certaines populations pédiatriques. L'INESSS, conformément à ses modalités d'évaluation des médicaments [INESSS 2018], a procédé à l'évaluation des données scientifiques à l'aide d'un groupe d'experts, et en considérant les données expérientielles rapportées par les parents. Parmi les recommandations finales résumées au début du rapport, l'INESSS souhaite, pour conclure, mettre l'accent sur les points suivants: La revue systématique indique une absence de données cliniques concernant certaines des populations ciblées, de même que la présence d'un très faible nombre d'études de qualité. La grande majorité des études répertoriées sont rétrospectives et de faible niveau de preuve; elles ont été effectuées à partir de dossiers médicaux ou de données de facturation. La plupart de ces études incluent un petit nombre de patients dont l'AG à la naissance est très variable. L'abrogation du critère concernant les bébés prématurés nés de 33 à 35 SG doit être maintenue. L'étude analysée, réalisée au Québec, présente trop de limites pour permettre de recommander la réintroduction d'un critère d'admissibilité pour ces enfants. Le critère d'admissibilité ciblant les enfants du Nunavik nés à terme doit être maintenu. Ce maintien doit s'accompagner d'améliorations du fonctionnement global du système : des ressources supplémentaires doivent être déployées afin d'assurer l'inclusion et l'acceptation des populations ciblées, d'optimiser l'implantation et l'adhésion au traitement, sans affecter les ressources dédiées aux autres programmes de santé publique. De plus, le financement dédié à l'évaluation de l'efficacité du palivizumab chez cette population devrait être prolongé. L'évaluation des répercussions personnelles et financières sur les familles et sur le système de santé (hospitalisations et transferts) est souhaitable. Par ailleurs, une meilleure coordination avec les membres des communautés devrait être mise de l'avant, de façon à optimiser la prophylaxie. L'INESSS préconise le maintien des modalités d'administration du palivizumab en vigueur, notamment la poursuite des mesures ayant pour but de favoriser l'efficacité du palivizumab. Compte tenu de la recommandation de maintien des critères d'admissibilité du palivizumab et de la qualité insuffisante des données répertoriées dans les présents travaux, il n'y a pas lieu d'effectuer une évaluation du rapport entre le coût et l'efficacité chez les différentes populations d'intérêt. L'impact financier net demeure nul puisque les coûts d'acquisition du palivizumab sont déjà engagés.