Reply to Standaert, B. Comment on "Postma et al. Predicted Public Health and Economic Impact of Respiratory Syncytial Virus Vaccination with Variable Duration of Protection for Adults ≥60 Years in Belgium".

We have read the commentary from Baudouin Standaert [...].

Clinical burden of invasive Escherichia coli disease among older adult patients treated in hospitals in the United States.

BACKGROUND: Invasive extraintestinal pathogenic Escherichia coli disease (IED) can lead to severe outcomes, particularly among older adults. However, the clinical burden of IED in the U.S. has not been well characterized. METHODS: IED encounters among patients ≥ 60 years old were identified using the PINC AI™ Healthcare Database (10/01/2015-03/31/2020) by either a positive E. coli culture in blood or another normally sterile body site and ≥ 1 sign of systemic inflammatory response syndrome or signs of sepsis, or a positive E. coli culture in urine with urinary tract infection and signs of sepsis. Medical resource utilization, clinical outcomes, and E. coli isolate characteristics were descriptively reported during the first IED encounter and during the following year (observation period). RESULTS: Overall, 19,773 patients with IED were included (mean age: 76.8 years; 67.4% female; 78.5% with signs of sepsis). Most encounters involved community-onset IED (94.3%) and required hospitalization (96.5%; mean duration: 6.9 days), with 32.4% of patients being admitted to the intensive care unit (mean duration: 3.7 days). Most E. coli isolates were resistant to ≥ 1 antibiotic category (61.7%) and 34.4% were resistant to ≥ 3 antibiotic categories. Following their first IED encounter, 34.8% of patients were transferred to a skilled nursing/intermediate care facility, whereas 6.8% had died. During the observation period, 36.8% of patients were rehospitalized, 2.4% had IED recurrence, and in-hospital death increased to 10.9%. CONCLUSIONS: IED is associated with substantial clinical burden at first encounter with considerable long-term consequences. Findings demonstrate the need for increased IED awareness and highlight potential benefits of prevention.

Enhancement and external validation of algorithms using diagnosis codes to identify invasive Escherichia coli disease.

OBJECTIVE: To assess the predictive accuracy of code-based algorithms for identifying invasive Escherichia coli (E. coli) disease (IED) among inpatient encounters in US hospitals. METHODS: The PINC AI Healthcare Database (10/01/2015-03/31/2020) was used to assess the performance of six published code-based algorithms to identify IED cases among inpatient encounters. Case-confirmed IEDs were identified based on microbiological confirmation of E. coli in a normally sterile body site (Group 1) or in urine with signs of sepsis (Group 2). Code-based algorithm performance was assessed overall, and separately for Group 1 and Group 2 based on sensitivity, specificity, positive and negative predictive value (PPV and NPV) and F1 score. The improvement in performance of refinements to the best-performing algorithm was also assessed. RESULTS: Among 2,595,983 encounters, 97,453 (3.8%) were case-confirmed IED (Group 1: 60.9%; Group 2: 39.1%). Across algorithms, specificity and NPV were excellent (>97%) for all but one algorithm, but there was a trade-off between sensitivity and PPV. The algorithm with the most balanced performance characteristics included diagnosis codes for: (1) infectious disease due to E. coli OR (2) sepsis/bacteremia/organ dysfunction combined with unspecified E. coli infection and no other concomitant non-E. coli invasive disease (sensitivity: 56.9%; PPV: 56.4%). Across subgroups, the algorithms achieved lower algorithm performance for Group 2 (sensitivity: 9.9%-61.1%; PPV: 3.8%-16.0%). CONCLUSIONS: This study assessed code-based algorithms to identify IED during inpatient encounters in a large US hospital database. Such algorithms could be useful to identify IED in healthcare databases that lack information on microbiology data.

Economic burden of invasive Escherichia coli disease among older adult patients treated in hospitals in the United States.

BACKGROUND: Although invasive Escherichia coli disease (IED) can lead to severe clinical outcomes, little is known about the associated medical resource use and cost burden of IED in US hospitals. OBJECTIVE: To comprehensively describe medical resource use and costs associated with IED during the initial IED event and over the subsequent 12 months. METHODS: Patients aged 60 years or older with 1 or more IED encounters were identified from the PINC AI Healthcare US hospital database (October 1, 2015, to March 31, 2020). The index encounter was defined as the first encounter with a positive E coli culture in a normally sterile site (group 1 IED) or positive E coli culture in urine with signs of sepsis (group 2 IED). Encounters with a positive culture from other bacteria or fungal pathogens were excluded. Outcomes were descriptively reported between admission and discharge for the index encounter and more than 1 - year post-index discharge. Medical resource use and costs included inpatient admissions and outpatient hospital services; costs were reported from a hospital's perspective (ie, charged amount) in 2021 USD. RESULTS: A total of 19,773 patients were identified (group 1 IED = 51.8%; group 2 IED = 48.2%). Mean age was 76.8 years, 67.4% were female, and 82.1% were White. Most index encounters were community-onset (94.3%) and led to hospitalization (96.5%) (mean inpatient days = 6.9 days). During the 1 - year post-index, 36.8% of patients had 1 or more all-cause hospitalizations. Mean [median] total all-cause hospital costs (as captured through the PINC AI Healthcare database) amounted to $16,760 [$11,340] during the index encounter and $10,942 [$804] during the 1 - year post-index; these costs were higher in the presence of sepsis and multidrug resistance and among hospital-onset IED. CONCLUSIONS: IED is associated with a substantial medical resource use and economic burden both during the initial encounter and over the following year in older adults. This highlights the critical need and potential benefits of preventive measures that may reduce the incidence of IED and associated economic burden. DISCLOSURES: This study was funded by Janssen Global Services, LLC. Dr Hernandez-Pastor is an employee of Janssen Pharmaceutica NV. Dr Geurtsen is an employee of Janssen Vaccines & Prevention BV. Dr Baugh is an employee of Janssen Research & Development, LLC. Dr El Khoury is an employee of Janssen Global Services, LLC. Dr Kalu and Dr Krishnarajah are employees of Janssen Scientific Affairs, LLC. Dr Gauthier-Loiselle, Ms Bungay, and Mr Cloutier are employees of Analysis Group, Inc., a consulting company that provided paid consulting services to Janssen Global Services, LLC. Dr Saade received consultation and speaker fees from Janssen.

Predicted Public Health and Economic Impact of Respiratory Syncytial Virus Vaccination with Variable Duration of Protection for Adults ≥60 Years in Belgium.

Respiratory syncytial virus (RSV) is a leading cause of acute respiratory infection (ARI) in older adults. This study used a static, cohort-based decision-tree model to estimate the public health and economic impact of vaccination against RSV in Belgians aged ≥60 years compared with no vaccination for different vaccine duration of protection profiles from a healthcare payer perspective. Three vaccine protection durations were compared (1, 3, and 5 years), and several sensitivity and scenario analyses were performed. Results showed that an RSV vaccine with a 3-year duration of protection would prevent 154,728 symptomatic RSV-ARI cases, 3688 hospitalizations, and 502 deaths over three years compared to no vaccination in older adults and would save EUR 35,982,857 in direct medical costs in Belgium. The number needed to vaccinate to prevent one RSV-ARI case was 11 for the 3-year duration profile, while it was 28 and 8 for the 1- and 5-year vaccine duration profiles, respectively. The model was generally robust in sensitivity analyses varying key input values. This study suggested that vaccination could substantially decrease the public health and economic burden of RSV in adults ≥60 years in Belgium, with benefits increasing with a longer duration of vaccine protection.

Targeted Literature Review of the Burden of Respiratory Syncytial Infection among High-Risk and Elderly Patients in Asia Pacific Region.

INTRODUCTION: The burden of respiratory syncytial virus (RSV), which causes acute respiratory illness, is well recognized among the pediatric population but also imposes a significant risk to the elderly (age ≥ 60) and those with underlying comorbidities. The study aimed to review the most recent data on epidemiology and burden (clinical and economic) of RSV in the elderly/high-risk populations in China, Japan, South Korea, Taiwan, and Australia. METHODS: A targeted review was conducted of English, Japanese, Korean, and Chinese language articles published from 1 January 2010 to 7 October 2020 relevant for the purpose. RESULTS: A total of 881 studies were identified, and 41 were included. The median proportion of elderly patients with RSV in all adult patients with acute respiratory infection (ARI) or community acquired pneumonia was 79.78% (71.43-88.12%) in Japan, 48.00% (3.64-80.00%) in China, 41.67% (33.33-50.00%) in Taiwan, 38.61% in Australia, and 28.57% (22.76-33.33%) in South Korea. RSV was associated with a high clinical burden on those patients with comorbidities such as asthma and chronic obstructive pulmonary disease. In China, inpatients with ARI showed a significantly higher rate of RSV-related hospitalization than outpatients (13.22% versus 4.08%, p < 0.01). The median length of hospital stay among elderly patients with RSV was longest in Japan (30 days) and shortest in China (7 days). Mortality data varied by region with some studies reporting rates as high as 12.00% (9/75) in hospitalized elderly patients. Finally, data on the economic burden was only available for South Korea, with the median cost of a medical admission for an elderly patient with RSV being US dollar (USD) 2933. CONCLUSION: RSV infection is a major source of disease burden among elderly patients, especially in regions with aging populations. It also complicates the management of those with underlying diseases. Appropriate prevention strategies are required to reduce the burden among the adult, especially the elderly, population. Data gaps regarding economic burden of RSV infection in the Asia Pacific region indicates the need for further research to increase our understanding on the burden of this disease in this region.

Targeted literature review of the burden of extraintestinal pathogenic Escherichia Coli among elderly patients in Asia Pacific regions.

BACKGROUND: Extraintestinal Pathogenic Escherichia coli (ExPEC) is a leading cause of invasive disease, including bacteremia and sepsis. Invasive ExPEC disease (IED) has the potential to complicate the clinical treatment of other conditions and is associated with an increased mortality, hospitalization, and worse outcomes. Older adults and individuals with comorbid conditions are at higher risk of IED. ExPEC is of particular concern in the Asia Pacific region due to aging populations and rising antimicrobial resistance. OBJECTIVES: This study aimed to synthesize most recent data on the epidemiology, clinical and economic burden of IED in the elderly/high risk populations in China, Japan, South Korea, Taiwan, and Australia. METHODS: A targeted literature review was conducted using Embase, Medline, as well as local scientific databases. We included studies published in English and local languages published from January 1, 2010 to October 7, 2020 that were relevant to the research objectives. Studies were narratively synthesized. RESULTS: A total of 1,047 studies were identified and 34 of them were included in this review. ExPEC accounted for 46.0% (1,238/2,692) of bacteria-related invasive diseases in patients aged above 60 years in South Korea, followed by China (44.4% (284/640)), Taiwan (39.0% (1,244/3,194)), and Japan (18.1% (581/3,206)), while Australia reported ExPEC out of all pathogens (54.7% (4,006/7,330)) in general adults. Comorbidities such as diabetes or cancer were common in these patients. Studies reported increases in length-of-stay, and in-hospital 30-day all-cause mortality related to ExPEC associated bacteremia was between 9% to 12%. From a cost perspective, a 3-fold increase in sepsis-associated cost was reported in South Korea between 2005 and 2012. In Australia, antimicrobial resistance contributed to an additional cost of AUD $5.8 million per year (95% uncertainty interval [UI], $2.2-$11.2 million) in the treatment of bloodstream infections (BSIs). CONCLUSION: ExPEC was a major cause of blood stream infection across China, Japan, South Korea, Taiwan, and Australia. Both the clinical and economic burden associated to ExPEC infections as well as the antimicrobial resistance observed in the elderly call for preventive and curative actions in these regions.

Extraintestinal Pathogenic Escherichia coli (ExPEC) is a leading cause of invasive disease, including bacteremia and sepsis.A targeted literature review included the most recent data from 34 published studies on the epidemiology and clinical and economic burden of IED in the elderly/high risk populations in China, Japan, South Korea, Taiwan, and Australia.ExPEC accounted for 46.0% (1,238/2,692) of bacteria-related invasive diseases in patients aged above 60 years in South Korea, followed by China (44.4% (284/640)), Taiwan (39.0% (1,244/3,194)), and Japan (18.1% (581/3,206)), while Australia reported ExPEC out of all pathogens (54.7% (4,006/7,330)) in general adults. Studies reported increases in length-of-stay and in-hospital 30-day all-cause between 9% to 12%. These factors, along with antimicrobial resistance observed in the elderly, call for preventive and curative actions in these regions.Data for costs associated with ExPEC induced BSI or sepsis in this region are limited, but evidence shows increasing expenditures.

Development and performance characteristics of novel code-based algorithms to identify invasive Escherichia coli disease.

PURPOSE: Evaluation of novel code-based algorithms to identify invasive Escherichia coli disease (IED) among patients in healthcare databases. METHODS: Inpatient visits with microbiological evidence of invasive bacterial disease were extracted from the Optum© electronic health record database between January 1, 2016 and June 30, 2020. Six algorithms, derived from diagnosis and drug exposure codes associated to infectious diseases and Escherichia coli, were developed to identify IED. The performance characteristics of algorithms were assessed using a reference standard derived from microbiology data. RESULTS: Among 97 194 eligible records, 25 310 (26.0%) were classified as IED. Algorithm 1 (diagnosis code for infectious invasive disease due to E. coli) had the highest positive predictive value (PPV; 96.0%) and lowest sensitivity (60.4%). Algorithm 2, which additionally included patients with diagnosis codes for infectious invasive disease due to an unspecified organism, had the highest sensitivity (95.5%) and lowest PPV (27.8%). Algorithm 4, which required patients with a diagnosis code for infectious invasive disease due to unspecified organism to have no diagnosis code for non-E. coli infections, achieved the most balanced performance characteristics (PPV, 93.6%; sensitivity, 78.1%; F1 score, 85.1%). Finally, adding exposure to antibiotics in the treatment of E. coli had limited impact on performance algorithms 5 and 6. CONCLUSION: Algorithm 4, which achieved the most balanced performance characteristics, offers a useful tool to identify patients with IED and assess the burden of IED in healthcare databases.

Budget impact analysis of first-line treatment with pazopanib for advanced renal cell carcinoma in Spain.

BACKGROUND: Due to economic constraints, cancer therapies are under close scrutiny by clinicians, pharmacists and payers alike. There is no published pharmacoeconomic evidence guiding the choice of first-line therapy for advanced renal cell carcinoma (RCC) in the Spanish setting. We aimed to develop a model describing the natural history of RCC that can be used in healthcare decision-making. We particularly analyzed the budget impact associated with the introduction of pazopanib compared to sunitinib under the Spanish National Healthcare System (NHS) perspective. METHODS: We developed a Markov model to estimate the future number of cases of advanced RCC (patients with favorable or intermediate risk) resulting either from initial diagnosis or disease progression after surgery. The model parameters were obtained from the literature. We assumed that patients would receive either pazopanib or sunitinib as first-line therapy until disease progression. Pharmacological costs and costs associated with the management of adverse events (AE) were considered. A univariate sensitivity analysis was undertaken in order to test the robustness of the results. RESULTS: The model predicted an adult RCC prevalence of 7.5/100,000 (1-year), 20.7/100,000 (3-year) and 32.5/100,000 (5-year). These figures are very close to GLOBOCAN reported RCC prevalence estimates of 7.6/100,000, 20.2/100,000 and 31.1/100,000, respectively. The model predicts 1,591 advanced RCC patients with favorable or intermediate risk in Spain in 2013. Annual per patient pharmacological costs were €32,365 and €39,232 with pazopanib and sunitinib, respectively. Annual costs associated with the management of AE were €662 and €974, respectively. Overall annual per patient costs were €7,179 (18%) lower with pazopanib compared to sunitinib. For every point increase in the percentage of patients treated with pazopanib, the NHS would save €67,236. If all the 1,591 patients predicted were treated with pazopanib, the NHS would save €6,723,622 in 2013. Results were robust according to the sensitivity analysis. CONCLUSIONS: We developed a model that accurately reproduces the natural history of RCC and can be thus used in healthcare decision-making. When applied to the Spanish case, the introduction of pazopanib results in savings for the NHS, as a consequence of both reduced pharmacological costs and lower costs associated with the management of AE compared to sunitinib.

Safety and treatment patterns of angiogenesis inhibitors in patients with advanced renal cell carcinoma in Spain.

OBJECTIVE: To examine real-world safety and treatment patterns of angiogenesis inhibitors for advanced renal cell carcinoma (aRCC) using observational data from two Spanish hospitals. METHODS: A retrospective medical record review was performed for 93 patients with a histological diagnosis of aRCC who received sunitinib, sorafenib, bevacizumab or temsirolimus as first-line angiogenesis inhibitor therapy, between January 2005 and September 2010 at two Spanish hospitals. Data were collected on adverse events (AEs), dosing to calculate relative dose intensity (RDI), treatment modifications and reasons for modifications. RESULTS: Sixty patients received sunitinib, 23 received sorafenib, 6 received bevacizumab, 1 received temsirolimus and 3 received a bevacizumab-temsirolimus combination. 91.7 and 100.0% of patients receiving sunitinib and sorafenib, respectively, experienced ≥ 1 AE; 40.0% and 43.5% had ≥ 1 grade 3/4 AE. Mean RDI for sunitinib and sorafenib were 0.866 (standard deviation (std) = 0.903) and 0.798 (std = 2.154), respectively. Among patients receiving sunitinib, 15.0% discontinued treatment, 43.3% had an interruption and 33.3% had a reduction due to AEs. For sorafenib, these rates were 4.3, 56.5 and 34.8%, respectively. CONCLUSIONS: High rates of AEs were observed which resulted in high rates of treatment interruptions and dose reductions. These results suggest the need for additional treatment options for aRCC with improved tolerability.

Cost-effectiveness of ranibizumab compared with pegaptanib in neovascular age-related macular degeneration.

OBJECTIVE: To assess the cost-effectiveness of ranibizumab compared with pegaptanib in the treatment of patients with minimally classic/occult neovascular age-related macular degeneration (AMD), from a societal perspective in Spain. METHODS: We constructed a Markov model with five states defined by visual acuity (VA) in the better-seeing eye (Snellen scale): VA >20/40, < or =20/40 to >20/80, < or =20/80 to >20/200, < or =20/200 to >20/400, < or =20/400, and an additional death state. Two cohorts of patients were distributed along the VA states, and treated with either ranibizumab or pegaptanib. Transition probabilities assigned for movement between these states with both drugs were obtained from published randomized clinical trials. Medical costs related to AMD treatment and follow-up, medical costs related to AMD comorbidities, and non-medical-related costs were taken into account. Costs (2008 Euro), health outcomes (Quality-adjusted life years--QALYs), both discounted at a 3.5% annual rate, and incremental cost-effectiveness ratios (ICER: euro/QALY), were determined for a lifetime horizon in the base case analysis. Sensitivity analyses were conducted to explore different scenarios and assumptions in the model. RESULTS: Treating patients with varying degrees of visual impairment with monthly ranibizumab instead of pegaptanib was 71,206 euro more costly and provided 2.437 additional QALYs (29,224 euro/QALY). When administered on an as-needed basis, as in the Prospective Optical Coherence Tomography Imaging of Patients with Neovascular AMD Treated with Intraocular Ranibizumab (PrONTO) trial, the cost per QALY gained with ranibizumab was reduced to 4,623 euro. CONCLUSIONS: The cost per QALY gained with monthly ranibizumab compared with pegaptanib in the minimally classic/occult neovascular AMD population is just below the 30,000 euro threshold below which new drugs are sometimes regarded as cost-effective strategies in Spain. In this model, the key variables with greater impact on the cost-effectiveness results were the selected time horizon and the chosen extrapolation method, the source for data on pegaptanib efficacy and the number of ranibizumab injections. When administered on an as-needed basis, ranibizumab was a cost-effective strategy compared to pegaptanib in this population.

Ranibizumab for neovascular age-related macular degeneration.

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, safety, pharmacoeconomics, and place in therapy of ranibizumab are reviewed. SUMMARY: Ranibizumab is the humanized fragment of the murine monoclonal antibody that binds all the active forms of the vascular endothelial growth factor, leading to the inhibition of the neovascular process underlying age-related macular degeneration (AMD). In animal studies, intravitreal administration of ranibizumab resulted in penetration of the drug into all layers of the retina and subsequent slow absorption into the systemic circulation. Improvement in visual acuity by 15 or more letters has been observed in 33.8-40.3% of patients treated with ranibizumab in pivotal clinical trials, compared with 5% of patients treated with sham injections and photodynamic therapy (PDT). The addition of PDT to ranibizumab has not been shown to offer any benefit in terms of efficacy and has been found to worsen ocular adverse reactions. The most common adverse ocular reactions reported in patients receiving ranibizumab during clinical trials include conjunctival hemorrhage, eye pain, vitreous floaters, increased intraocular pressure, and intraocular inflammation. Ranibizumab's efficacy in the treatment of neovascular AMD is well established; however, questions remain regarding the drug's optimal dosing strategy, duration of therapy, and combined therapy with other agents. While ranibizumab has been defined as the best available weapon against AMD, it is also the most expensive. CONCLUSION: The efficacy of ranibizumab in the treatment of AMD is well established, but more studies are needed to determine ranibizumab's optimal dosage interval, duration of therapy, and combined use with other agents.

Cost-effectiveness of ranibizumab compared with photodynamic treatment of neovascular age-related macular degeneration.

OBJECTIVE: This study compared the cost-effectiveness of ranibizumab with that of photodynamic therapy (PDT) in the treatment of predominantly classic choroidal neovascularization secondary to age-related macular degeneration (AMD) from the perspective of a third-party payer in a Spanish setting. METHODS: We constructed a Markov model with 5 states defined by visual acuity (VA) in the better-seeing eye (Snellen scale), as follows: VA >20/40, 20/80, 20/200, 20/400, and