Real-World Assessment of Interferon-ß-1b and Interferon-ß-1a Adherence Before and After the Introduction of the BETACONNECT® Autoinjector: A Retrospective Cohort Study.

BACKGROUND: Both interferon beta-1b (IFN-ß-1b) and interferon beta-1a (IFN-ß-1a) are immunomodulators that require regular subcutaneous self-administration by patients with multiple sclerosis (MS). However, no electronic autoinjector is available for IFN-ß-1a in the US. OBJECTIVE: This retrospective cohort study investigated adherence to two subcutaneous disease-modifying therapies, IFN-ß-1b and IFN-ß-1a, during two periods (before and after the introduction of the BETACONNECT® autoinjector for IFN-ß-1b). PATIENTS AND METHODS: Data were evaluated from the MarketScan database for adults in the US with an MS diagnosis and a medical claim for subcutaneous IFN-ß-1b or IFN-ß-1a, either before (October 2013-September 2015) or after the introduction of BETACONNECT (October 2016-September 2018). Patient populations were propensity-score matched by demographic and clinical characteristics. Persistence was recorded, and adherence was evaluated by medication possession ratio (MPR). RESULTS: The study included 196 IFN-ß-1b and 365 IFN-ß-1a people with MS (PwMS) (pre-BETACONNECT period), and 126 IFN-ß-1b and 223 IFN-ß-1a PwMS (post-BETACONNECT period). In the pre-BETACONNECT period, the proportion with at least 80% MPR was higher for IFN-ß-1a (90%) than for IFN-ß-1b (83%), but in the post-BETACONNECT period the proportion with ≥ 80% MPR was higher for IFN-ß-1b (92%) than for IFN-ß-1a (86%). In the pre-BETACONNECT period, median persistence (in days) was higher for IFN-ß-1a (199) than for IFN-ß-1b (152), while in post-BETACONNECT period persistence was higher for IFN-ß-1b (327) than for IFN-ß-1a (229). CONCLUSIONS: Following the introduction of BETACONNECT, this exploratory study suggested that PwMS taking IFN-ß-1b were more adherent compared with those taking IFN-ß-1a, with higher persistence, and more than 90% reached 80% MPR, a threshold commonly used to define good adherence.

Burden of Male Hypogonadism and Major Comorbidities, and the Clinical, Economic, and Humanistic Benefits of Testosterone Therapy: A Narrative Review.

Male hypogonadism and major comorbidities such as type 2 diabetes mellitus, obesity, cardiovascular disease, and osteoporosis appear closely connected, forming a vicious cycle that leads to further hypogonadism. This narrative review provides a comprehensive overview of the current literature on the overall burden of male hypogonadism alongside related comorbidities, and how this may be alleviated through testosterone therapy. Observational and clinical data demonstrate that the interaction of male hypogonadism and its related comorbidities is associated with increased mortality, cardiovascular event risk and reduced quality of life. Evidence from epidemiological and registry-based studies shows that this clinical and humanistic burden translates to increased economic burden on health-care systems, through increased physician visits, medical claims, and drug costs. Male hypogonadism can be managed with testosterone therapy, which is intended to normalize testosterone concentrations and thereby reduce both hypogonadism symptoms and risk of comorbidities. Clinical and observational data suggest that in males with hypogonadism, testosterone therapy rapidly and sustainably improves glycemia, reduces risk of progression to diabetes, leads to significantly reduced waist circumference and fat mass, while providing significant positive effects on cardiovascular event risk and bone density. Significant and sustained improvement in patient-reported erectile function, urinary function, and aging male symptoms have also been shown. Economic evaluations have estimated that reduced comorbidity risk following testosterone therapy may lead to cost-savings, with one study estimating yearly inpatient savings of £3732 for treating comorbidities after intervention. A major unmet need exists in the area of male hypogonadism, particularly related to common comorbidities. Options for treatment include testosterone therapy, which has been shown to alleviate the clinical, economic, and humanistic burden associated with these conditions. As the prevalence of male hypogonadism is likely to increase globally, and this condition may be currently underdiagnosed, cost-saving testosterone therapies should be increasingly considered to manage hypogonadism.

Longitudinal changes in risk status in pulmonary arterial hypertension.

AIMS: Low-risk status in pulmonary arterial hypertension (PAH) predicts better survival. The present study aimed to describe changes in risk status and treatment approaches over multiple clinical assessments in PAH, taking age and comorbidity burden into consideration. METHODS AND RESULTS: The study included incident patients from the Swedish PAH registry, diagnosed with PAH in 2008-2019. Group A (n = 340) were ≤75 years old with <3 comorbidities. Group B (n = 163) were >75 years old with ≥3 comorbidities. Assessments occurred at baseline, first-year (Y1) and third-year (Y3) follow-ups. The study used an explorative and descriptive approach. Group A: median age was 65 years, 70% were female, and 46% had no comorbidities at baseline. Baseline risk assessment yielded low (23%), intermediate (66%), and high risk (11%). Among patients at low, intermediate, or high risk at baseline, 51%, 18%, and 13%, respectively, were at low risk at Y3. At baseline, monotherapy was the most common therapy among low (68%) and intermediate groups (60%), while dual therapy was the most common among high risk (69%). In patients assessed as low, intermediate, or high risk at Y1, 66%, 12%, and 0% were at low risk at Y3, respectively. Of patients at intermediate or high risk at Y1, 35% received monotherapy and 13% received triple therapy. In low-risk patients at Y1, monotherapy (40%) and dual therapy (43%) were evenly distributed. Group B: median age was 77 years, 50% were female, and 44% had ≥3 comorbidities at baseline. At baseline, 8% were at low, 80% at intermediate, and 12% at high risk. Monotherapy was the most common therapy (62%) in Group B at baseline. Few patients maintained or reached low risk at follow-ups. CONCLUSIONS: Most patients with PAH did not meet low-risk criteria during the 3 year follow-up. The first year from diagnosis seems important in defining the longitudinal risk status.

Poor outcome of patients with pulmonary arterial hypertension with insufficient response to phosphodiesterase-5 inhibitors alone or in combination with other specific therapy: a registry-based study.

Phosphodiesterase-5 inhibitors are commonly used in pulmonary arterial hypertension but, as suggested by the RESPITE study, phosphodiesterase-5 inhibitor therapy (mono-/combination) does not always have a satisfactory treatment effect. This study aimed to investigate the clinical course of pulmonary arterial hypertension patients not at treatment goal after at least 90 days of treatment with phosphodiesterase-5 inhibitors, alone or in combination with other pulmonary arterial hypertension therapies. The study included 106 incident patients from the Swedish Pulmonary Arterial Hypertension Registry, treated with phosphodiesterase-5 inhibitors for ≥90 days, who were not at a pre-specified treatment goal, i.e. in World Health Organisation functional class III, with 6-min walking distance 165-440 m, and N-terminal prohormone of brain natriuretic peptide >300 ng/L. Changes in World Health Organisation functional class, 6-min walking distance, N-terminal prohormone of brain natriuretic peptide, and risk group between index and follow-up were assessed. Of patients with complete follow-up data, (n = 53) 77% were on combination therapy and risk assessment yielded 98% at intermediate risk at index. At follow-up, 11 patients transitioned from World Health Organisation functional class III to World Health Organisation functional class II, the median (Q1; Q3) change in 6-min walking distance was 6 (-30; 42) meters and in N-terminal prohormone of brain natriuretic peptide 47 (-410; 603) ng/L, while 89% remained at an intermediate risk. Of those without complete follow-up data, 11 patients died and 2 underwent lung transplantation. In conclusion, pulmonary arterial hypertension patients treated with phosphodiesterase-5 inhibitors, as single or combination therapy and not achieving the pre-specified treatment goals after ≥90 days have an unfavourable clinical course.

The impact of childhood varicella vaccination on the incidence of herpes zoster in the general population: modelling the effect of exogenous and endogenous varicella-zoster virus immunity boosting.

BACKGROUND: A controversy exists about the potential effect of childhood varicella vaccination on Herpes Zoster (HZ) incidence. Mathematical models projected temporary HZ incidence increase after vaccine introduction that was not confirmed by real-world evidence. These models assume that absence of contacts with infected children would prevent exogenous boosting of Varicella-Zoster-Virus (VZV) immunity and they do not include an endogenous VZV immunity-boosting mechanism following asymptomatic VZV reactivation. This study aims to explore the effect of various assumptions on exogenous and endogenous VZV immunity-boosting on HZ incidence in the general population after introduction of routine childhood varicella vaccination. METHODS: An age-structured dynamic transmission model was adapted and fitted to the seroprevalence of varicella in France in absence of vaccination using the empirical contact matrix. A two-dose childhood varicella vaccination schedule was introduced at 12 and 18 months. Vaccine efficacy was assumed at 65%/95% (dose 1/dose 2), and coverage at 90%/80% (dose 1/dose 2). Exogenous boosting intensity was based on assumptions regarding HZ-immunity duration, age-dependent boosting effect, and HZ reactivation rates fitted to observed HZ incidence. Endogenous boosting was the same as pre-vaccination exogenous boosting but constant over time, whilst exogenous boosting depended on the force of infection. Five scenarios were tested with different weightings of exogenous (Exo) - endogenous (Endo) boosting: 100%Exo-0%Endo, 75%Exo-25%Endo, 50%Exo-50%Endo, 25%Exo-75%Endo, 0%Exo-100%Endo. RESULTS: HZ incidence before varicella vaccination, all ages combined, was estimated at 3.96 per 1000 person-years; it decreased by 64% by year 80 post vaccine introduction, for all boosting assumptions. The 100%Exo-0%Endo boosting scenario, predicted an increase in HZ incidence for the first 21 years post vaccine introduction with a maximum increase of 3.7% (4.1/1000) at year 9. However, with 0%Exo-100%Endo boosting scenario an immediate HZ decline was projected. The maximum HZ incidence increases at 10, 3, and 2 years post vaccination were 1.8% (75%Exo-25%Endo), 0.8% (50%Exo-50%Endo) and 0.2% (25%Exo-75%Endo), respectively. CONCLUSIONS: Assuming modest levels of endogenous boosting, the increase in HZ incidence following childhood varicella vaccination was smaller and lasted for a shorter period compared with 100%Exo-0%Endo boosting assumption. Endogenous boosting mechanism could partly explain the divergence between previous HZ-incidence projections and real-world evidence.

Burden of Herpes Zoster in the Japanese Population with Immunocompromised/Chronic Disease Conditions: Results from a Cohort Study Claims Database from 2005-2014.

INTRODUCTION: The aim of this study is to describe the disease burden and costs of herpes zoster (HZ) in the general adult Japanese population or patients with immunocompromised (IC) conditions or chronic disorders. METHODS: A retrospective cohort study of individuals aged 18-74 years was conducted using January 2005 to December 2014 records from the Japan Medical Data Center claims database. Twenty-eight IC conditions and chronic disorders were defined by diagnosis codes and/or procedures/treatments. HZ and its related complications were identified. Incidence rates (IR), frequency of HZ-related complications, healthcare resource utilization (HRU), and direct medical costs were estimated. HRU and costs were estimated on a subcohort of HZ cases occurring April 2012-January 2014. RESULTS: The overall IR of HZ in the total cohort of 2,778,476 adults was 4.92/1000 person-years (PY) [95% confidence interval (CI): 4.86-4.98] and increased with age. The IR in the IC cohort (51,818 subjects) was 8.87/1000 PY (95% CI: 8.29-9.48), ranging from 5.55/1000 PY (95% CI: 4.26-7.09) in psoriasis to 151.68/1000 PY (95% CI: 111.45-201.71) in hematopoietic stem cell transplant recipients; most IRs were in the range 6-10/1000 PY. The IRs in individuals with chronic disorders were also relatively high, in the range 5.40-12.90/1000 PY. The frequency of postherpetic neuralgia was 4.01% (95% CI: 3.72-4.33) in the total cohort and 11.73% (95% CI: 9.01-14.93) in the IC cohort. The mean [standard deviation (SD)] number of outpatient visits was 3.4 (4.9) and 5.0 (5.7), respectively, and the proportion of HZ patients hospitalized was 2.20% and 6.70%, respectively. The mean (SD) direct medical cost per HZ episode was ¥34,664 (¥54,433) and ¥55,201 (¥92,642) in the total and IC cohort, respectively. CONCLUSIONS: The elevated burden of HZ in Japanese individuals harboring IC conditions and chronic disorders documented in our study underlines the need for prevention of HZ in people with these conditions. FUNDING: GlaxoSmithKline Biologicals SA.

The Potential Public Health Impact of Herpes Zoster Vaccination of People Aged ≥ 50 Years in Japan: Results of a Markov Model Analysis.

INTRODUCTION: The aim of this study was to compare the public health impact of introducing two herpes zoster (HZ) vaccines into the vaccination programs for the Japanese population aged ≥ 50 years: a single-dose Varicella Vaccine Live (VVL) or a two-dose adjuvanted Recombinant Zoster Vaccine (RZV). METHODS: A multi-cohort static Markov model was developed to follow age cohorts (50-59, 60-69, 70-79 and ≥ 80 years) over their remaining lifetime. Japan-specific data inputs for the model were obtained from Japanese data sources. Age-stratified vaccine efficacy and waning rates were based on published clinical trial data. In the base-case analysis, vaccine coverage was assumed to be 40% for both vaccines, and compliance with second-dose of the RZV vaccine was set to 95%. RESULTS: Vaccination with RZV was projected to prevent approximately 3.3 million HZ cases, 692,000 cases of postherpetic neuralgia (PHN), and 281,000 cases of other complications, compared with the prevention of 0.8 million HZ cases, 216,000 PHN cases, and 57,000 other complications with vaccination with VVL. The number of individuals needed to vaccinate in order to prevent one HZ case ranged from 6 to 14 using RZV (depending on age and assumed second-dose compliance) and from 21 to 138 depending on age using VVL. By preventing a higher number of HZ cases and its complications, RZV vaccination led to fewer outpatient visits and hospitalizations than vaccination with VVL. CONCLUSION: Both vaccines had a positive public health impact compared to no vaccination, but due to its higher vaccine efficacy, RZV demonstrated a superior public health impact compared with VVL. FUNDING: GlaxoSmithKline Biologicals SA.

Impact of Herpes Zoster and Post-Herpetic Neuralgia on Health-Related Quality of Life in Japanese Adults Aged 60 Years or Older: Results from a Prospective, Observational Cohort Study.

BACKGROUND AND OBJECTIVES: Herpes zoster (HZ) and its most frequent complication, post-herpetic neuralgia (PHN), have been shown to considerably impact quality of life (QoL). This has not yet been demonstrated in Japan. METHODS: QoL in HZ and PHN patients was evaluated using the Zoster Brief Pain Inventory (ZBPI), EuroQoL-5 Dimension (EQ-5D), Short-Form 12 version 2.0, and short-form McGill Pain Questionnaire up to 270 days after rash onset as part of a prospective, observational, cohort study conducted in Kushiro, Hokkaido, Japan. RESULTS: This study involved 412 adults ≥ 60 years of age diagnosed with HZ, 38 of whom developed PHN. QoL in daily activity performance and emotional and physical functioning was impaired at Day 0 (rash onset) and almost resolved by Day 90. Although the mean ZBPI worst pain score for HZ patients without PHN improved from 4.1 at Day 0 to 0.1 at Day 90, the score for HZ patients with PHN at Day 90 was comparable to that for HZ patients without PHN at Day 0. While the EQ-5D score in HZ without PHN improved, on average, from 0.755 to 0.949, the score for HZ with PHN was dependent on PHN duration and did not improve until PHN disappearance. CONCLUSIONS: HZ impaired QoL in daily activity performance and emotional and physical functioning. The negative impact on QoL was more prevalent in patients with a longer PHN duration compared with HZ without PHN. ClinicalTrials.gov identifier: NCT01873365.

Impact of rotavirus vaccination on the burden of acute gastroenteritis in Nagoya city, Japan.

BACKGROUND: In Nagoya city, Japan, rotavirus (RV) vaccination has been available since 2011 with estimated coverage reaching 92% by 2015 after the introduction of a public subsidy in 2012. This study assessed the impact of vaccination on the RV gastroenteritis (RVGE) burden in children aged <5 years old (y) by comparing RVGE hospitalizations and outpatient visits during pre-vaccination (2007-2011), transition (2011-2012) and subsidization (2012-2016) periods. METHODS: All hospitalizations and outpatient visits in children aged <5 y from 2 administrative districts of Nagoya city were identified from the hospital-based electronic databases of 4 hospitals. RVGE cases were identified by diagnostic code and/or positive results of diagnostic kits. RESULTS: Compared to the pre-vaccination period, there was a decrease in RVGE hospitalizations for children <5 y from 5.59 per 1000 person-year (kPY) to 3.65/kPY in the subsidization period (i.e. 34.69%). In children <1 y, the incidence of RVGE hospitalizations decreased continuously from 6.62/kPY in the pre-vaccination period to 1.84/kPY in the subsidization period (i.e. 72.19%). The highest decrease was observed in the subsidization season i.e. when high coverage was reached: 69% and 75.57% in the 2013/2014 season for 2-3 y and 3-4 y, and 74.03% in the 2014/2015 season for 4-5 y, respectively. Proportion of RVGE outpatient visits decreased by 87.44% for children <1 y and 57.05% for <5 y from the pre-vaccination to the subsidization period. This decrease started the first year of subsidization for children <1 y, 1-2 y and 2-3 y (78.89%, 18.86% and 5.80%) and the second year (2013/2014 season) for children 3-4 y and 4-5 y (87.73% and 51.78%). CONCLUSIONS: Although yearly fluctuations have been observed, the introduction of vaccination significantly decreased pediatric RVGE hospitalizations and outpatient visits, especially in the age group eligible for vaccination. During the second and third year of subsidization, we observed a herd protection effect on other age groups <5 y who were not eligible for vaccination. Clinicaltrial.gov.registered#:NCT01733862.

Economic Burden of Herpes Zoster and Post-Herpetic Neuralgia in Adults 60 Years of Age or Older: Results from a Prospective, Physician Practice-Based Cohort Study in Kushiro, Japan.

BACKGROUND AND OBJECTIVE: Herpes zoster has a high incidence rate among people aged ≥ 60 years and can lead to serious complications such as post-herpetic neuralgia. There are currently no data on the economic burden of herpes zoster and post-herpetic neuralgia in Japan, and the objective of this study was to address this gap. METHODS: A total of 412 patients aged ≥ 60 years diagnosed with herpes zoster were recruited. Demographic, clinical, and healthcare resource utilization data on patients with herpes zoster or post-herpetic neuralgia collected via case report forms were used to estimate direct medical cost. Data obtained from a questionnaire survey among patients with herpes zoster/post-herpetic neuralgia were used to estimate transportation cost and productivity loss. RESULTS: The mean number of outpatient visits was 5.7. Prescription medications were the main cost driver accounting for 60% of the direct medical cost. The mean direct medical and total herpes zoster-related costs per patient were ¥43,925 and ¥57,112, respectively, and were higher in patients with post-herpetic neuralgia than in those with herpes zoster without complications. Direct medical cost represented 77%, productivity loss 19%, and transportation cost 4% of the total. CONCLUSIONS: This is the first study of the economic burden of herpes zoster and post-herpetic neuralgia in Japan and it demonstrated substantial direct medical cost as a result of the multiple outpatient visits and prescription medications required. These findings provide baseline data for possible future economic evaluations of new herpes zoster/post-herpetic neuralgia interventions. TRIAL REGISTRATION: This cost analysis is part of a prospective, physician practice-based cohort study conducted between June 2013 and February 2015 in Kushiro, Japan (Clinicaltrials.gov identifier NCT01873365, registered on 6 June, 2013).

Burden of herpes zoster and postherpetic neuralgia in Japanese adults 60 years of age or older: Results from an observational, prospective, physician practice-based cohort study.

Approximately one in three persons will develop herpes zoster during their lifetime, and it can lead to serious complications such as postherpetic neuralgia. However, evidence on burden of herpes zoster and postherpetic neuralgia in Japan is limited. This prospective, observational, multicenter, physician practice-based cohort study was conducted in Kushiro, Hokkaido, Japan (Clinicaltrials.gov identifier NCT01873365) to assess the incidence and hospitalization rates of herpes zoster, and the proportion, clinical burden and risk factors for postherpetic neuralgia in adults aged 60 years or more. Within the study area, 800 subjects developed herpes zoster and 412 were eligible for the study. Herpes zoster incidence was 10.2/1000 person-years and higher among women and older subjects. Subjects with herpes zoster required on average 5.7 outpatient consultations. Herpes zoster-associated hospitalization rate was 3.4% (27/800). The proportion of postherpetic neuralgia and other complications was 9.2% (38/412) and 26.5% (109/412), respectively. Statistically significant association with the development of postherpetic neuralgia was male sex (odds ratio [OR], 2.51; 95% confidence interval [CI], 1.17-5.38), age of 70-74 years (OR, 3.51; 95% CI, 1.09-11.3), immunosuppressive therapy (OR, 6.44; 95% CI, 1.26-32.9), severe herpes zoster pain at first consultation (OR, 3.08; 95% CI, 1.10-8.62) and rash on upper arms (vs no rash on upper arms; OR, 3.46; 95% CI, 1.10-10.9). Considerable herpes zoster and postherpetic neuralgia burden exists among elderly in Japan, and there may be predictive factors at the first visit which could be indicative of the risk of developing postherpetic neuralgia.

Coverage, efficacy or dosing interval: which factor predominantly influences the impact of routine childhood vaccination for the prevention of varicella? A model-based study for Italy.

BACKGROUND: Varicella is a highly infectious disease with a significant public health and economic burden, which can be prevented with childhood routine varicella vaccination. Vaccination strategies differ by country. Some factors are known to play an important role (number of doses, coverage, dosing interval, efficacy and catch-up programmes), however, their relative impact on the reduction of varicella in the population remains unclear. This paper aims to help policy makers prioritise the critical factors to achieve the most successful vaccination programme with the available budget. METHODS: Scenarios assessed the impact of different vaccination strategies on reduction of varicella disease in the population. A dynamic transmission model was used and adapted to fit Italian demographics and population mixing patterns. Inputs included coverage, number of doses, dosing intervals, first-dose efficacy and availability of catch-up programmes, based on strategies currently used or likely to be used in different countries. The time horizon was 30 years. RESULTS: Both one- and two-dose routine varicella vaccination strategies prevented a comparable number of varicella cases with complications, but two-doses provided broader protection due to prevention of a higher number of milder varicella cases. A catch-up programme in susceptible adolescents aged 10-14 years old reduced varicella cases by 27-43 % in older children, which are often more severe than in younger children. Coverage, for all strategies, sustained at high levels achieved the largest reduction in varicella. In general, a 20 % increase in coverage resulted in a further 27-31 % reduction in varicella cases. When high coverage is reached, the impact of dosing interval and first-dose vaccine efficacy had a relatively lower impact on disease prevention in the population. Compared to the long (11 years) dosing interval, the short (5 months) and medium (5 years) interval schedules reduced varicella cases by a further 5-13 % and 2-5 %, respectively. Similarly, a 10 % increase in first-dose efficacy (from 65 to 75 % efficacy) prevented 2-5 % more varicella cases, suggesting it is the least influential factor when considering routine varicella vaccination. CONCLUSIONS: Vaccination strategies can be implemented differently in each country depending on their needs, infrastructure and healthcare budget. However, ensuring high coverage remains the critical success factor for significant prevention of varicella when introducing varicella vaccination in the national immunisation programme.

Incidence of acute otitis media in children below 6 years of age seen in medical practices in five East European countries.

BACKGROUND: Although acute otitis media (AOM) remains a major public health problem worldwide and brings economic burden on health care system and caregivers, little information is available about its epidemiology in Eastern Europe. METHODS: We conducted an epidemiological, prospective, observational, multi-centre cohort study (NCT01365390) in five East European countries (Estonia, Lithuania, Poland, Romania and Slovenia) between June 2011 and January 2013 to determine the incidence and clinical characteristics of AOM among children aged < 6 years during 1 year. RESULTS: AOM incidence was 160.7 cases (95 % confidence interval [CI]: 144.7-177.9) per 1000 person-years (PY) being the lowest in the < 1 year age group (92.3 cases [95 % CI: 59.7-136.2] per 1000 PY) and the highest in the 3- < 4 years age group (208.9 cases [95 % CI: 165.1-260.7] per 1000 PY). AOM incidence was similar across the countries, with the exception of Slovenia (340.3 cases [95 % CI: 278.3-412.0] per 1000 PY). There was a lower risk in breastfed children and a higher risk in those attending school/childcare or with allergies. AOM required 521 visits to the doctor. Antibiotics were prescribed for 276 (74.8 %) episodes with the lowest prescription rate in Estonia (51.4 %) and the highest in Romania (83.7 %). Complications were rare and hospitalisations occurred in 2 % of the cases. CONCLUSIONS: The disease burden of AOM in Eastern Europe is relevant and public health initiatives to reduce it should be considered. TRIAL REGISTRATION: ClinicalTrial.gov NCT01365390 .

Post-Marketing Benefit-Risk Assessment of Rotavirus Vaccination in Japan: A Simulation and Modelling Analysis.

INTRODUCTION: Rotarix™, GSK's live attenuated rotavirus vaccine, was introduced in Japan in 2011. A recent trend in reduction of rotavirus gastroenteritis (RVGE) due to this vaccine was described. However, an observed/expected analysis showed a temporal association with intussusception within 7 days post dose 1. OBJECTIVE: In this paper, we compare the benefit and risk of vaccination side-by-side in a benefit-risk analysis. METHODS: The number of vaccine-preventable RVGE-associated hospitalizations and deaths (benefit) and intussusception-associated hospitalizations and deaths (risk) following two doses of Rotarix™ in Japan was compared using simulations. Source data included peer-reviewed clinical and epidemiological publications, Japanese governmental statistics (Statistics Bureau, Ministry of Internal Affairs and Communications), and market survey data. RESULTS: For a birth cohort of 1 million vaccinated Japanese children followed for 5 years, the benefit-risk analysis suggested that the vaccine would prevent ~17,900 hospitalizations and ~6.3 deaths associated with RVGE. At the same time, vaccination would be associated with about ~50 intussusception hospitalizations and ~0.017 intussusception deaths. Therefore, for every intussusception hospitalization caused by vaccination and for one intussusception-associated death, 350 (95 % CI 69-2510) RVGE-associated hospitalizations and 366 (95 % CI 59-3271) RVGE-associated deaths are prevented, respectively, by vaccination. CONCLUSIONS: The benefit-risk balance for Rotarix™ is favorable in Japan. From a public health perspective, the benefits in terms of prevented RVGE hospitalizations and deaths for the vaccinated population far exceed the estimated risks due to intussusception.

The burden of bacteremia and invasive diseases in children aged less than five years with fever in Italy.

BACKGROUND: Invasive diseases (ID) caused by Streptococcus pneumoniae (S. pneumoniae), Haemophilus influenzae (H. influenzae), and Neisseria meningitidis are a major public health problem worldwide. Comprehensive data on the burden of bacteremia and ID in Italy, including data based on molecular techniques, are needed. METHODS: We conducted a prospective, multi-centre, hospital-based study (GSK study identifier: 111334) to assess the burden of bacteremia and ID among children less than five years old with a fever of 39 °C or greater. Study participation involved a single medical examination, collection of blood for polymerase chain reaction (PCR) and blood culture, and collection of an oropharyngeal swab for colonization analysis by PCR. RESULTS: Between May 2008 and June 2009, 4536 patients were screened, 944 were selected and 920 were enrolled in the study. There were 225 clinical diagnoses of ID, 9.8 % (22) of which were bacteremic. A diagnosis of sepsis was made for 38 cases, 5.3 % (2) of which were bacteremic. Among the 629 non-ID diagnoses, 1.6 % (10) were bacteremic. Among the 34 bacteremic cases, the most common diagnoses were community-acquired pneumonia (15/34), pleural effusion (4/34) and meningitis (4/34). S. pneumoniae was the most frequently detected bacteria among bacteremic cases (29/34) followed by H. influenzae (3/34). Ninety percent (27/30) of bacteremic patients with oropharyngeal swab results were colonized with the studied bacterial pathogens compared to 46.1 % (402/872) of non-bacteremic cases (p < 0.001). PCV7 (7-valent pneumococcal conjugate vaccine) vaccination was reported for 55.9 % (19/34) of bacteremic cases. S. pneumoniae serotypes were non-vaccine serotypes in children who had been vaccinated. Mean duration of hospitalization was longer for bacteremic cases versus non-bacteremic cases (13.6 versus 5.8 days). CONCLUSIONS: These results confirm that S. pneumoniae is one of the pathogens frequently responsible for invasive disease.

The Impact of Childhood Acute Otitis Media on Parental Quality of Life in a Prospective Observational Cohort Study.

BACKGROUND AND OBJECTIVES: Acute otitis media (AOM) not only affects childhood quality of life (QoL), but can also affect parental QoL. We adapted a previously published questionnaire on the effect of childhood recurrent ear, nose and throat infections on parental QoL for use with AOM and used it in an observational, multicentre, prospective study of children with AOM. METHODS: The AOM-specific parental QoL questionnaire grouped 15 items into emotional, daily disturbance, total and overall parental QoL impact scores. The questionnaire was assessed using item-convergent and item-discriminant validity criteria and internal consistency reliability; and then used with parents of children aged <6 years diagnosed with AOM at 73 practices in Germany, Italy, Spain, Sweden and the UK. Bivariate analyses explored the differences in mean parental QoL impact scores by various characteristics. RESULTS: The questionnaire demonstrated good to excellent internal consistency reliability for the various components (Cronbach's α 0.82-0.97). There were 1419 AOM episodes among 5882 healthy children over 1 year, of which 1063 episodes (74.9%) among 852 children had a questionnaire. Parents reported interrupted sleep (68.4%), worry (51.0%), altered daily schedule (44.6%) and less leisure time (41.5%) with a score ≥ 3 (1 = least to 5 = most impact). Factors that adversely affected parental QoL included: increased parental perception of AOM severity, younger child age and multiple AOM episodes. CONCLUSIONS: The AOM-specific parental QoL questionnaire demonstrated good performance across five European countries. Parental QoL was affected by childhood AOM proportionally to severity, number of episodes and younger child age.

Human papillomavirus prevalence and type-distribution in cervical glandular neoplasias: Results from a European multinational epidemiological study.

Cervical glandular neoplasias (CGN) present a challenge for cervical cancer prevention due to their complex histopathology and difficulties in detecting preinvasive stages with current screening practices. Reports of human papillomavirus (HPV) prevalence and type-distribution in CGN vary, providing uncertain evidence to support prophylactic vaccination and HPV screening. This study [108288/108290] assessed HPV prevalence and type-distribution in women diagnosed with cervical adenocarcinoma in situ (AIS, N = 49), adenosquamous carcinoma (ASC, N = 104), and various adenocarcinoma subtypes (ADC, N = 461) from 17 European countries, using centralised pathology review and sensitive HPV testing. The highest HPV-positivity rates were observed in AIS (93.9%), ASC (85.6%), and usual-type ADC (90.4%), with much lower rates in rarer ADC subtypes (clear-cell: 27.6%; serous: 30.4%; endometrioid: 12.9%; gastric-type: 0%). The most common HPV types were restricted to HPV16/18/45, accounting for 98.3% of all HPV-positive ADC. There were variations in HPV prevalence and ADC type-distribution by country. Age at diagnosis differed by ADC subtype, with usual-type diagnosed in younger women (median: 43 years) compared to rarer subtypes (medians between 57 and 66 years). Moreover, HPV-positive ADC cases were younger than HPV-negative ADC. The six years difference in median age for women with AIS compared to those with usual-type ADC suggests that cytological screening for AIS may be suboptimal. Since the great majority of CGN are HPV16/18/45-positive, the incorporation of prophylactic vaccination and HPV testing in cervical cancer screening are important prevention strategies. Our results suggest that special attention should be given to certain rarer ADC subtypes as most appear to be unrelated to HPV.

Post-marketing monitoring of intussusception after rotavirus vaccination in Japan.

PURPOSE: Rotarix(TM) was launched in November 2011 in Japan to prevent rotavirus gastroenteritis. Some studies suggest that Rotarix(TM) may have a temporal association with a risk of intussusception (IS). We assessed a possible association between IS and Rotarix(TM) vaccination in Japan. METHODS: All IS cases spontaneously reported post-vaccination (Brighton collaboration levels 1, 2, and 3) were extracted from the GlaxoSmithKline spontaneous report database on the 11th of January 2013. Expected numbers of IS cases were estimated using the number of vaccine doses distributed and the Japanese incidence rate of IS stratified by month of age. The observed versus expected analysis considered the IS cases for each risk period (7 and 30 days post-vaccination) and for each vaccine dose (two doses). RESULTS: Before January 2013, approximately 601 000 Rotarix(TM) doses were distributed in Japan. For a risk period of 7 days post-dose 1 and post-dose 2, 10 and five IS cases were observed, whereas 3.4 and 7.6 were expected, providing an observed-to-expected ratio of 2.96 (95% confidence interval [CI]: 1.42; 5.45) and 0.66 (95% CI: 0.21; 1.53), respectively. For a risk period of 30 days post-dose 1 and post-dose 2, 14 and eight cases were observed, whereas 14.5 and 32.7 were expected, providing an observed-to-expected ratio of 0.97 (95% CI: 0.53; 1.62) and 0.24 (95% CI: 0.11; 0.48), respectively. CONCLUSION: A statistically significant excess of IS cases was observed within 7 days post-dose 1, but not post-dose 2. These results are consistent with previous observations in large post-marketing safety studies in other world regions.

HPV-type distribution and reproducibility of histological diagnosis in cervical neoplasia in Poland.

This study was performed to assess attribution of high grade cervical intraepithelial neoplasia (HG-CIN) and invasive cervical cancer (ICC) to human papillomavirus (HPV) genotypes and secondarily to assess reproducibility of HG-CIN/ICC diagnosis obtained in Poland. Formaldehyde fixed, paraffin embedded blocks of HG-CIN/ICC from two distant institutions were sent to a central laboratory together with original histological diagnoses. Central/expert review of histopathological specimens was performed and agreement between local and central/expert diagnoses was calculated. HPV detection and genotyping in the samples was carried out with the use of SPF10-LiPA25 technology. Results were analyzed for 205 HG-CIN and 193 ICC cases with centrally confirmed diagnoses. Kappa coefficients and 95 % confidence intervals for HG-CIN and ICC diagnoses were: 0.13 (0.09;0.17) and 0.19 (0.11;0.26) respectively. Cohen's kappa coefficients for lesions with representative number of samples ranged from 0.01 for cervical intraepithelial neoplasia grade 2 to 0.75 for adenocarcinoma. HPV DNA was detected in 96.1 and 91.2 % of the confirmed HG-CIN and ICC specimens respectively. HPV positive HG-CIN was most commonly attributed to HPV types: 16 (62.8), 33 (7.8), 31 (6.6), 52 (3.7), 45 (2.6) and 58 (2.6 %). HPV positive ICC was most commonly attributed to HPV types: 16 (72.1), 18 (10.8), 33 (5.7), 45 (3.4) and 31 (1.7 %). Reproducibility of histological diagnosis of HG-CIN/ICC obtained in Poland generally increases with the severity of lesion and is lowest for cervical intraepithelial neoplasia grade 2 and highest for adenocarcinoma. Over 80 % of ICC cases are vaccine-preventable in Poland.

Hospital-based surveillance to estimate the burden of rotavirus gastroenteritis in children below five years of age in Romania.

INTRODUCTION: Rotavirus (RV) is a leading cause of acute gastroenteritis (AGE), affecting 95% of children below five years of age. METHODS: In this prospective, multi-center study, children below five years of age who were hospitalized or those who visited the emergency room (ER) due to AGE or who developed AGE at least 48 hours after hospitalization (nosocomial infection) and had a RV-positive stool sample were included (n=1,222). RV-positive samples were genotyped by reverse-transcriptase polymerase chain reaction. RESULTS: RV test results were available for 1,212 children (hospitalizations [n=677], ER visits [n=398] and nosocomial AGE cases [n=137]). Proportions of rotavirus gastroenteritis (RVGE) hospitalizations and ER visits were 51.70% (350/677; 95%CI: 47.86-55.52) and 36.18% (144/398; 95%CI: 31.45-41.12), respectively. Overall, 45.95% (494/1075) of all community-acquired AGE cases were due to RV. High numbers of RVGE cases were recorded between January and March. Most common genotypes were G9P[8] (34.27%) followed by G4P[8] (25.83%) and G1P[8] (23.02%). Of all community-acquired RVGE cases, the highest number of cases was observed in children aged 12-23 months. Median duration of hospitalization among RV-positive subjects was six days (range: 2-31 days). Incidence of nosocomial RVGE was 0.52 (95%CI: 0.45-0.60) cases per 1,000 child-days hospitalization. Median duration for additional hospitalization due to nosocomial RVGE was five days (range: 1-10). The highest burden of nosocomial RVGE was observed in children aged 12-23 months (42.34%, 58/137). Our findings confirm a high burden of acute RVGE disease in Romania and provide useful data to support the implementation of RV vaccination in Romania. TRIAL REGISTRATION: NCT01253967.