Five-Factor Prognostic Model for Survival of Post-Platinum Patients with Metastatic Urothelial Carcinoma Receiving PD-L1 Inhibitors.

PURPOSE: A prognostic model for overall survival of post-platinum patients with metastatic urothelial carcinoma receiving PD-1/PD-L1 inhibitors is necessary as existing models were constructed in the chemotherapy setting. MATERIALS AND METHODS: Patient level data were used from phase I/II trials evaluating PD-L1 inhibitors following platinum based chemotherapy for metastatic urothelial carcinoma. The derivation data set consisted of 2 phase I/II trials evaluating atezolizumab (405). Two phase I/II trials that evaluated avelumab (242) and durvalumab (198) comprised the validation data sets. Cox regression analyses evaluated the association of candidate prognostic factors with overall survival. Stepwise selection was used to select an optimal model using the derivation data set. Discrimination and calibration were assessed in the avelumab and durvalumab data sets. RESULTS: The 5 prognostic factors identified in the optimal model using the atezolizumab derivation data set were ECOG-PS (1 vs 0, HR 1.80, 95% CI 1.36-2.36), liver metastasis (HR 1.55, 95% CI 1.20-2.00), platelet count (HR 2.22; 95% CI 1.54-3.18), neutrophil-to-lymphocyte ratio (HR 1.94, 95% CI 1.57-2.40) and lactate dehydrogenase (HR 1.60, 95% CI 1.28-1.99). There was robust discrimination of survival between low, intermediate and high risk groups. The c-statistic was 0.692 in the derivation and 0.671 and 0.773 in the avelumab and durvalumab validation data sets, respectively. A web based interactive tool was developed to calculate the expected survival probabilities based on risk factors. CONCLUSIONS: A validated 5-factor model has satisfactory prognostic performance for survival across 3 PD-L1 inhibitors to treat metastatic urothelial carcinoma after platinum therapy and may assist in stratification, interpreting and designing trials incorporating PD-1/PD-L1 inhibitors in the post-platinum setting.

Impact of RSV: implications for managed care.

Severe RSV disease, manifested as bronchiolitis or pneumonia, is the leading cause of hospitalization of infants younger than 1 year of age in the United States. Infants born 35 weeks or less GA are particularly at high risk of severe RSV disease, which may result in frequent NICU admissions or long hospital stays and additional health care utilization over the first 12 months of life. This care is costly--infants 33 to 36 weeks GA with a history of RSV hospitalization incur costs that are nearly 5 times as much as costs for 33 to 36 weeks GA infants with no history of RSV hospitalization. Managed care payers should be cognizant of the potential ramifications of severe RSV disease in infants. Developing a proactive RSV management strategy can help improve health outcomes and reduce unnecessary hospital resource use.

Diagnostic virology practices for respiratory syncytial virus and influenza virus among children in the hospital setting: a national survey.

A survey was sent to the emergency room and laboratory directors of 400 randomly selected US hospitals to assess the diagnostic testing practices for respiratory syncytial virus and influenza virus in children. The results demonstrate that the majority of hospitals routinely perform viral testing for both viruses and use virology testing practices appropriate for the reasons reported for testing.

Evaluation of recent New Vaccine Surveillance Network data regarding respiratory syncytial virus hospitalization rates in US preterm infants.

In July 2014, the Committee on Infectious Diseases (COID) updated their guidance on the use of palivizumab, recommending against use in preterm infants 29 to 35 weeks' gestational age (wGA). A primary data source cited to support this significant change was the low respiratory syncytial virus (RSV) hospitalization rate observed in the subpopulation of preterm (<37 wGA) infants evaluated from 2000 to 2005 through the New Vaccine Surveillance Network (NVSN). Here we critically appraise the preterm infant data from the NVSN in the context of data regarding the use of palivizumab in this same time period. Data from the NVSN, an analysis of Florida Medicaid data, and a national survey of US in-hospital palivizumab administration demonstrated that during 2001 to 2007, palivizumab was administered to 59% to 83% of preterm infants born at <32 wGA and 21% to 27% of all preterm infants (<37 wGA). When the NVSN data regarding incidence of RSV hospitalization in preterm infant subgroups were evaluated as a function of chronologic age, preterm infants <32 wGA showed a paradoxical increase in RSV hospitalization with older age, with the highest risk of RSV hospitalization occurring at 18 to 23 months of age. This pattern is most consistent with a reduction in RSV hospitalizations in <32 wGA infants in the first 12 to 18 months of life due to high palivizumab use at these young ages. The NVSN data were not designed to and cannot accurately describe RSV disease burden in preterm infants given the small size of the analyzed subpopulation and the high use of palivizumab during the study period.

Modeling the Potential Impact of the 2014 American Academy of Pediatrics Respiratory Syncytial Virus Prophylaxis Guidance on Preterm Infant RSV Outcomes.

INTRODUCTION: The American Academy of Pediatrics (AAP) Committee on Infectious Diseases issued updated guidance on respiratory syncytial virus (RSV) prophylaxis in 2014. This report models the potential impact of the new guidance on RSV outcomes in preterm infants 29-34 weeks' gestational age (wGA) without chronic lung disease in the United States. METHODS: The number of preterm infants was estimated using 2012 natality data. Palivizumab utilization prior to the 2014 guidance update was estimated using 2013-2014 specialty pharmacy utilization data. Low, moderate, and high RSV hospitalization (RSVH) rates as well as average hospital length of stay, intensive care unit (ICU) admissions and mechanical ventilation (MV) frequencies were derived from published observational studies. Palivizumab efficacy was derived from two randomized clinical trials. RSV events that would be attributable to the 2014 guidance change were calculated for preterm infants 29-31 and 32-34 wGA. RESULTS: Annual number of infants 29-34 wGA surviving the neonatal period was estimated at 123,687. Of these, an estimated 44,712 (37%) would receive palivizumab based on the 2012 guidance. The annual number of RSVH among infants 29-34 wGA would increase from 3580 under the 2012 guidance to 6166 under the 2014 guidance based on moderate rates. This would result in an additional 24,440 hospitalization days, 1162 ICU admissions, and 584 MV events among this population. CONCLUSIONS: Based on published historical and contemporary data on RSVH rates in preterm infants 29-34 wGA, the 2014 AAP guidance is expected to result in additional burden to the healthcare system and families of preterm infants. The impact of the new guidance will be difficult to detect among the overall infant population, particularly in settings without routine testing for RSV, but the impact will be substantial for the small high-risk population affected by the changes. FUNDING: AstraZeneca.

Rationale for full-season dosing for passive antibody prophylaxis of respiratory syncytial virus.

Palivizumab monthly injections throughout the RSV season prevent severe respiratory syncytial virus (RSV) disease in preterm infants ≤ 35 wGA. However, some RSV guidelines currently recommend stopping palivizumab after 3 months of age in the midst of the RSV season. This article evaluates the need for full-season dosing by reviewing the pharmacokinetic properties of palivizumab and RSV hospitalization (RSVH) risk as a function of chronologic age. Precise human palivizumab protective levels are not established. Clinical trials show significant interpatient variability in palivizumab serum trough concentrations. Partial season dosing is associated with increased risk of RSVH. For late-preterm infants, data suggest that the risk of RSVH remains elevated through at least 6 months of age. Monthly, full-season palivizumab dosing provides the only empirically proven protection from RSVH. In conclusion, late-preterm infants are at significant risk for RSVH through at least 6 months of age and would benefit from dosing throughout the RSV season.

Randomized, Double-Blind Study of the Safety of the Liquid Versus Lyophilized Formulation of Palivizumab in Premature Infants and Children with Chronic Lung Disease of Prematurity.

INTRODUCTION: To avoid the need for reconstitution required by lyophilized palivizumab, a liquid formulation was developed. This study assessed the safety and antidrug antibodies (ADA) of the liquid formulation of palivizumab compared with the lyophilized formulation. METHODS: This phase 4, randomized, double-blind, multicenter study included children with chronic lung disease of prematurity who were ≤24 months of age and children born prematurely with a gestational age of ≤35 weeks who were ≤6 months of age at randomization. Subjects were randomized 1:1 to 15 mg/kg of either liquid or lyophilized palivizumab administered via intramuscular injection every 30 days for a total of 5 injections. Safety was assessed based on serious adverse events (SAEs). ADA to palivizumab was assessed using blood collected at baseline and at a time point between study days 240 and 300. RESULTS: A total of 413 subjects were included in the analyses. The incidence of SAEs reported was 8.5% with liquid palivizumab and 5.9% with lyophilized palivizumab; none were deemed drug-related. The reported SAEs were consistent with expected conditions in this pediatric age group; there was no increase in respiratory syncytial virus (RSV) disease with liquid palivizumab. At study days 240-300, antipalivizumab antibodies were detected in none of the subjects in the liquid palivizumab group and in 1 subject in the lyophilized group. The true ADA percent positive, based on the upper limit of the 95% confidence interval (CI), was <1.5% for both treatments combined. CONCLUSION: The frequency of detection of ADAs was low. The true ADA percent positive for both treatment groups combined based on the upper limit of the 95% CI was <1.5%. The type and frequency of SAEs reported were as expected, and there was no evidence of an increase in RSV disease with liquid palivizumab.

Randomized, Double-Blind Study of the Pharmacokinetics and Safety of Palivizumab Liquid Formulation Compared with Lyophilized Formulation.

OBJECTIVE: To assess the pharmacokinetics and safety of liquid palivizumab compared with lyophilized palivizumab. METHODS: This phase 2, randomized, double-blind crossover study included premature infants aged ≤6 months born ≤35 weeks gestational age. Patients were randomized in a 1:1 ratio to receive a single 15 mg/kg intramuscular dose of liquid (sequence A group) or lyophilized (sequence B group) palivizumab on Day 0. Patients crossed over to receive the alternate formulation on Day 30. Serum palivizumab and antidrug antibody (ADA) levels were measured on Day 0 (predose), Day 30 (before the dose of alternate formulation), and Day 60 (30 days after the dose of alternate formulation). Patients were followed for safety through Day 60 (30 days after the dose of alternate formulation). RESULTS: A total of 153 infants were randomized into the study (sequence A 75; sequence B 78). Sequence A and sequence B trough serum palivizumab levels were similar on Day 30 (51.7 and 49.1 µg/mL, respectively) and Day 60 (84.8 and 87.2 µg/mL, respectively). The ratio of the geometric means using both Day 30 and Day 60 serum concentrations was 1.040 (90% CI 0.998-1.083), which was within the prespecified bioequivalence range of 0.8-1.25. Adverse events (AEs) were similar between the palivizumab liquid and lyophilized groups and within each treatment sequence. Serious AEs (SAEs) were experienced by 3% of infants in both liquid palivizumab and lyophilized palivizumab groups. None of the SAEs were determined to be related to study drug. Among the 124 infants (81% of total) evaluated for ADA, 2 (1.6%) tested positive for ADA at Day 60 (1 in each of sequence A and B). CONCLUSION: Liquid and lyophilized formulations of palivizumab were bioequivalent with similar safety profiles in infants.

Safety and Effectiveness of Palivizumab in Children at High Risk of Serious Disease Due to Respiratory Syncytial Virus Infection: A Systematic Review.

INTRODUCTION: Lower respiratory tract infection (LRTI) is the leading cause of infant mortality globally in post-neonatal infants (i.e., 28-364 days of age). Respiratory syncytial virus (RSV) is the most commonly identified pathogen for infant LRTI and is the second most important cause of death in post-neonatal infants. Despite 50 years of RSV vaccine research, there is still no approved vaccine. Therefore, passive immunity with the monoclonal antibody palivizumab is the sole regulatory-approved option for the prevention of serious LRTI caused by RSV in pediatric patients at high risk of RSV disease. METHODS: We conducted a comprehensive systematic literature review of randomized controlled trials (RCTs), open-label non-comparative clinical trials, and prospective observational studies/registries, and summarized the evidence related to the safety, efficacy, and effectiveness of palivizumab. RESULTS: The efficacy of palivizumab, as measured by the relative reduction in RSV-related hospitalization rate compared with placebo ranged from 39% to 78% (P < 0.05) in the 2 pivotal RCTs. A meta-analysis of the RSV-related hospitalization rate from 5 randomized placebo-controlled trials yielded an overall odds ratio of 0.41 (95% CI, 0.31-0.55) in favor of palivizumab prophylaxis over placebo (P < 0.00001). Low rates of RSV-related hospitalizations were observed in palivizumab recipients consistently over time in more than 42,000 pediatric subjects across 7 RCTs, 4 open-label non-comparative trials, and 8 observational studies/registries conducted in 34 countries. In addition, among palivizumab-prophylaxed subjects with breakthrough RSV LRTI, rates of intensive care unit admission and mechanical ventilation from RSV hospitalization also were low and consistent across studies. With respect to safety, no differences were observed between palivizumab and placebo in the blinded RCTs. CONCLUSION: Rates of RSV hospitalizations and RSV hospitalization-related endpoints in pediatric subjects who received prophylaxis with palivizumab were low and constant over time and across RCTs, open-label non-comparative trials, and observational studies/registries.

Distribution of respiratory syncytial virus subtypes A and B among infants presenting to the emergency department with lower respiratory tract infection or apnea.

BACKGROUND: Respiratory syncytial virus (RSV), a leading viral respiratory pathogen worldwide, has 2 major subtypes, A and B. OBJECTIVE: To describe the temporal and geographic distribution and parameters of disease severity associated with RSV A and B in the United States. METHODS: A US multicenter active surveillance study was conducted in emergency departments (EDs) during 2 RSV seasons. Infants <1 year of age presenting to the ED with symptoms of lower respiratory tract infection or apnea were enrolled. RSV subtypes were detected in nasal swabs by reverse transcriptase polymerase chain reaction. RESULTS: Of 4248 patients enrolled, 4172 patients were evaluable; 32.4% of patients were positive for any RSV subtype in season 1 and 29.9% in season 2. RSV A and B were detected in each region studied. More patients presented to the ED with RSV A than with RSV B (853 [20.4%] versus 453 [10.9%], respectively); RSV A-positive patients were more likely to be admitted to the hospital or intensive care unit (47.7%, versus RSV B, 35.8%; P < 0.0001); hospitalized RSV A-positive patients were less likely to be prescribed antibiotics (32.4%, versus RSV B, 47.8%; P < 0.001). CONCLUSIONS: This is the largest epidemiologic study in EDs reporting trends in RSV subtypes. RSV subtypes A and B were documented in both seasons across all US regions studied and detected in September to May. The results of this study support suggestions from smaller studies that RSV A may be more virulent than RSV B; however, more quantitative assessments of disease severity are needed.

Prevalence of respiratory syncytial virus-associated lower respiratory infection and apnea in infants presenting to the emergency department.

The prevalence of respiratory syncytial virus in children presenting to US emergency departments with lower respiratory tract infection or apnea (N = 4172) was evaluated outside the traditional respiratory syncytial virus season (September to October and April to May) relative to January to February. The Mid-Atlantic and Southeast demonstrated positivity rates in September to October comparable with rates observed during January to February.

Definition and outpatient management of the very low-birth-weight infant with bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD), also known as chronic lung disease of prematurity, is the major cause of pulmonary disease in infants. The pathophysiology and management of BPD have evolved over the past four decades as improved neonatal intensive care unit (NICU) modalities have increased survival rates. The likelihood for developing BPD increases with the degree of prematurity and reaches 25-35% in very low-birth-weight and extremely low-birth-weight infants. BPD affects many organ systems, and infants with BPD are at increased risk for rehospitalization and numerous complications following NICU discharge. The management of BPD and medically related problems, particularly during the first 2 years of life, remains a continuing challenge for parents and healthcare providers. It is important that a multidisciplinary team consisting of the neonatologist/attending physician, primary care physician, and other specialized support staff work in concert and meet regularly to provide continuity of care and accurate patient assessments.

Respiratory syncytial virus hospitalization trends in infants with chronic lung disease of infancy, 1998-2008.

OBJECTIVE: Infants with chronic lung disease of infancy (CLDI) are at high risk for severe respiratory syncytial virus (RSV) illness requiring hospitalization. Palivizumab was first licensed in 1998 for the prevention of RSV disease in high-risk infants, including those with CLDI. We performed a retrospective cohort study of all hospitalized children with CLDI aged <2 years between 1998 and 2008 in the USA to determine trends in rates of hospitalizations due to RSV (RSVH) since the launch of palivizumab. MATERIALS AND METHODS: Data from the United States National Hospital Discharge Survey, a multistage systematic survey sample of US hospitals, were assembled. We defined RSVH using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes of 079.6 (RSV), 466.11 (acute bronchiolitis due to RSV), and 480.1 (pneumonia due to RSV). Quarterly rates of RSVH were assessed for children with CLDI (ICD-9-CM code 770.7) and calculated between 1998 and 2008. Because RSV may be miscoded, the analysis was repeated after expanding the definition of RSVH to include all acute bronchitis and acute bronchiolitis (ABH) (ICD-9-CM = 466). Trends were described using linear regression with seasonal indicators included in the model. RESULTS: On average, about 966 RSVH (range 98-1373 RSVH) per year were found for children <2 years with CLDI in the USA between 1998 and 2008. Over the 11-year period, the predicted rate of RSVH statistically significantly decreased by 48% (from 93.78 to 49.06 RSVH per 1 million children) (P = 0.013). Addition of ABH resulted in a nonstatisically significant decrease of 32% over the 10-year period (P = 0.102). CONCLUSION: These results suggest that there has been a decrease in the rate of RSVH in infants with CLDI between 1998 and 2008. The reasons for this decrease may include improved neonatal intensive care unit and outpatient management of CLDI, and possibly increased use of palivizumab in this high-risk population.