Real-World First-Line Maintenance Niraparib Monotherapy Use Following Chemotherapy Plus Bevacizumab: The SW1TCH Study.

INTRODUCTION: Clinical trials have demonstrated prolonged survival associated with niraparib first-line maintenance (1LM) therapy, compared with placebo, for patients with ovarian cancer (OC). However, data are limited on real-world 1LM niraparib monotherapy use, particularly as switch 1LM, following first-line (1L) combination chemotherapy plus bevacizumab. This real-world study aimed to describe patient demographics, clinical characteristics, and clinical outcomes of patients with OC receiving 1LM niraparib monotherapy following 1L combination chemotherapy plus bevacizumab. METHODS: This retrospective observational study used data from a US-based nationwide database of deidentified, electronic health record-derived data. Patients diagnosed with OC during the study period (1 January 2011-30 November 2022, inclusive) were eligible if they received 1L chemotherapy plus bevacizumab treatment followed by 1LM niraparib monotherapy, initiated between 1 January 2017 (inclusive) and 2 September 2022. Patients were followed from index date (initiation of niraparib 1LM) until the first occurrence of death, end of follow-up, or end of study. Clinical outcomes were time to treatment discontinuation (TTD) and time to next treatment (TTNT). Kaplan-Meier curves were used to estimate TTD, TTNT, and 95% confidence intervals (CIs). RESULTS: Among 93 patients selected, median age at index was 67 years (interquartile range [IQR] 60-72 years). Most patients had BRCA wild-type/homologous recombination (HR)-proficient or BRCA wild-type/HR unknown disease (75.3%). In all, 18 (19.4%) patients had HR-deficient disease. Five (5.4%) patients had unknown test results for both BRCA and HR deficiency status. Median follow-up time was 16.3 months (IQR 8.7-25.4 months), and median time from end of 1L therapy to 1LM initiation was 35.0 days (IQR 25.0-53.9 days). Median TTD was 9.3 months (95% CI 6.1-11.3 months). Median TTNT was 12.9 months (95% CI 11.5-19.0 months). CONCLUSIONS: This real-world study provided insights into switch maintenance with 1LM niraparib monotherapy, which may be a viable treatment option for patients with advanced OC.

The impact of varying levels of residual disease following cytoreductive surgery on survival outcomes in patients with ovarian cancer: a meta-analysis.

BACKGROUND: Residual disease following cytoreductive surgery in patients with ovarian cancer has been associated with poorer survival outcomes compared with no residual disease. We performed a meta-analysis to assess the impact of varying levels of residual disease status on survival outcomes in patients with ovarian cancer who have undergone primary cytoreductive surgery or interval cytoreductive surgery in the setting of new therapies for this disease. METHODS: Medline, Embase, and Cochrane databases (January 2011 - July 2020) and grey literature, bibliographic and key conference proceedings, were searched for eligible studies. Fixed and random-effects meta-analyses compared progression and survival by residual disease level across studies. Heterogeneity between comparisons was explored via type of surgery, disease stage, and type of adjuvant chemotherapy. RESULTS: Of 2832 database and 16 supplementary search articles screened, 50 studies were selected; most were observational studies. The meta-analysis showed that median progression-free survival and overall survival decreased progressively with increasing residual disease (residual disease categories of 0 cm, > 0-1 cm and > 1 cm). Compared with no residual disease, hazard ratios (HR) for disease progression increased with increasing residual disease category (1.75 [95% confidence interval: 1.42, 2.16] for residual disease > 0-1 cm and 2.14 [1.34, 3.39] for residual disease > 1 cm), and also for reduced survival (HR versus no residual disease, 1.75 [ 1.62, 1.90] for residual disease > 0-1 cm and 2.32 [1.97, 2.72] for residual disease > 1 cm). All comparisons were significant (p < 0.05). Subgroup analyses showed an association between residual disease and disease progression/reduced survival irrespective of type of surgery, disease stage, or type of adjuvant chemotherapy. CONCLUSIONS: This meta-analysis provided an update on the impact of residual disease following primary or interval cytoreductive surgery, and demonstrated that residual disease was still highly predictive of progression-free survival and overall survival in adults with ovarian cancer despite changes in ovarian cancer therapy over the last decade. Higher numerical categories of residual disease were associated with reduced survival than lower categories.

Cytochrome P450 inhibitor/inducer treatment patterns among patients in the United States with advanced ovarian cancer who were prescribed or were eligible for poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors in the first-line maintenance setting.

Poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) are metabolized either via carboxylesterase (niraparib) or cytochrome P450 (CYP) enzymes (olaparib and rucaparib). Patients with advanced epithelial ovarian cancer (aOC) who receive concomitant medication metabolized by the CYP system may be at risk of drug-drug interactions impacting PARPi efficacy and tolerability. This study investigated CYP inhibitor/inducer treatment patterns in the first-line maintenance (1Lm) setting for patients with aOC. This retrospective cohort study used de-identified databases of US patients with aOC. Eligible patients were aged ≥18 years, diagnosed with aOC between January 2015-March 2021, and received CYP inhibitors/inducers during 1Lm PARPi initiation or the eligibility window (90 days before to 120 days after first-line platinum-based therapy ended [index]). Patients were either prescribed 1Lm PARPi monotherapy (PARPi cohort) or were not prescribed any 1Lm therapy within 120 days post-index (PARPi-eligible cohort). Strong/moderate CYP inhibitors/inducers were defined as area under the plasma concentration-time curve ratio (AUCR) ≥2 or clearance ratio (CL) ≤0.5 (inhibitors), and AUCR ≤0.5 or CL ratio ≥2 (inducers). Of 1411 patients (median age 63), 158 were prescribed PARPis and 1253 were PARPi-eligible. Among the PARPi cohort, 46.2%, 48.7%, and 5.1% were prescribed niraparib, olaparib, and rucaparib, respectively. For patients prescribed olaparib or rucaparib, 42.4% also received strong and/or moderate CYP inhibitors/inducers. This real-world study indicated a considerable proportion of patients received strong and/or moderate CYP inhibitors/inducers and were prescribed PARPis metabolized by the CYP system. Understanding potential impacts of concomitant CYP inhibitors/inducers on PARPi efficacy and safety is warranted.

Correlation between progression-free survival and overall survival in patients with ovarian cancer after cytoreductive surgery: a systematic literature review.

OBJECTIVES: This analysis aimed to better define the relationship between progression-free survival and overall survival in adult patients with ovarian cancer (including fallopian tube or primary peritoneal cancer) following primary cytoreductive surgery or interval cytoreductive surgery. METHODS: A systematic literature review was carried out across the Medline, Embase, and Cochrane Central databases on 7 July 2020 (date limits 1 January 2011 to 7 July 2020) to identify studies with the following eligibility criteria: clinical trials/observational studies including >200 patients with ovarian cancer aged ≥18 years, evaluating overall survival/progression-free survival following cytoreductive surgery by residual disease status in the United States, Europe, Japan, or China. Weighted linear regression models were used to assess any correlation between median progression-free survival and overall survival, and between logHR for progression-free survival and logHR for overall survival. Risk of bias was assessed for all included studies. RESULTS: Of the 50 studies reported, 43 were observational studies (41 retrospective and two prospective cohort studies), and seven were reporting for randomized clinical trials-of which four were retrospective data analyses. For analyses of the relationship between overall survival and progression-free survival, 21 studies were eligible. The weighted linear regression model showed a strong positive association between the two survival endpoints. Goodness-of-fit analysis measured the adjusted R2 as 0.84 (p<0.001); a positive association was also observed between logHRs for overall survival and progression-free survival in the included studies. CONCLUSIONS: Median progression-free survival was predictive of median overall survival. This correlation between progression-free survival and overall survival after primary treatment for ovarian cancer highlights the validity of progression-free survival as a primary endpoint. Observational studies contributed most data, with limited information on disease stage and histology.

The Utility of ctDNA in Lung Cancer Clinical Research and Practice: A Systematic Review and Meta-Analysis of Clinical Studies.

This systematic review with embedded meta-analysis aimed to evaluate the clinical utility of circulating tumor DNA (ctDNA) in lung cancer. After screening and review of the Embase database search, 111 studies from 2015 to 2020 demonstrated ctDNA's value in prognostication/monitoring disease progression, mainly in patients with advanced/metastatic disease and non-small cell lung cancer. ctDNA positivity/detection at any time point was associated with shorter progression-free survival and overall survival, whereas ctDNA clearance/decrease during treatment was associated with a lower risk of progression and death. Validating these findings and addressing challenges regarding ctDNA testing integration into clinical practice will require further research.

Association of Multiple High-Risk Factors on Observed Outcomes in Real-World Patients With Advanced Ovarian Cancer Treated With First-Line Therapy.

PURPOSE: To identify risk factors for disease progression or death and assess outcomes by risk categories in real-world patients with advanced ovarian cancer. METHODS: This retrospective study included adult patients from a nationwide electronic health record-derived deidentified database with stage III/IV ovarian cancer who received first-line therapy and had ≥12 weeks of follow-up after index date (end of first-line therapy). Factors predictive of time to next treatment and overall survival (OS) were assessed. Patients were grouped according to the cumulative number of high-risk factors present (stage IV disease, no debulking surgery or neoadjuvant therapy and interval debulking surgery, visible residual disease after surgery, and breast cancer gene [BRCA] wild-type disease/unknown BRCA status), and time to next treatment and OS were assessed. RESULTS: Region of residence, disease stage, histology, BRCA status, surgery modality, and visible residual disease were significant predictors of time to next treatment; age, Eastern Cooperative Oncology Group performance status, disease stage, BRCA status, surgery modality, visible residual disease, and platelet levels were significant predictors of OS (N = 1,920). Overall, 96.4%, 74.1%, and 40.3% of patients had at least 1, 2, or 3 high-risk factors, respectively; 15.7% of patients had all four high-risk factors. Observed median time to next treatment was 26.4 months (95% CI, 17.1 to 49.2) in patients with no high-risk factors and 4.6 months (95% CI, 4.1 to 5.7) in patients with four high-risk factors. Observed median OS was shorter among patients with more high-risk factors. CONCLUSION: These results underscore the complexity of risk assessment and demonstrate the importance of assessing a patient's cumulative risk profile rather than the impact of individual high-risk factors. They also highlight the potential for bias in cross-trial comparisons of median progression-free survival because of differences in risk-factor distribution among patient populations.

Real-world Outcomes Associated With Poly(ADP-ribose) Polymerase Inhibitor Monotherapy Maintenance in Patients With Primary Advanced Ovarian Cancer.

OBJECTIVE: This study used real-world population data to assess the trends of first-line (1L) poly(ADP-ribose) polymerase inhibitor (PARPi) maintenance treatment uptake and outcomes in patients with primary advanced ovarian cancer (AOC). METHODS: Patients diagnosed with AOC between January 1, 2017, and June 30, 2021, who completed 1L chemotherapy were selected from a real-world database. Descriptive analyses were performed to evaluate patient demographics, clinicopathological characteristics, and 1L treatment patterns. Time to next treatment or death was used as a proxy for real-world progression-free survival (rwPFS). Kaplan-Meier methods and Cox models were used for statistical analyses. RESULTS: Of 705 patients who completed 1L chemotherapy, 166 received PARPi monotherapy and 539 underwent active surveillance (AS). Median follow-up was 10.9 months for PARPi monotherapy and 20.6 months for AS. PARPi monotherapy use increased from 6% in 2017 to 53% in 2021. Overall, patients receiving PARPi monotherapy had longer rwPFS than those who underwent AS (not reached vs 9.53 mo) respectively. rwPFS was also longer in patients who received PARPi monotherapy compared with AS in patients with BRCA- mutated disease (not reached vs 11.4 mo), BRCA- wild-type disease (13.5 vs 9.1 mo), homologous recombination-deficient tumors (not reached vs 10.2 mo), and homologous recombination-proficient or unknown status tumors (13.5 vs 9.3 mo). CONCLUSIONS: Our real-world analysis suggested that 47% of patients with primary AOC did not receive PARPi maintenance in the year 2021. PARPi use was associated with significantly improved outcomes compared with AS.

Real-World Outcomes Following First-Line Treatment in Patients with Advanced Ovarian Cancer with Multiple Risk Factors for Disease Progression who Received Maintenance Therapy or Active Surveillance.

INTRODUCTION: We evaluated real-world outcomes in patients with advanced ovarian cancer (AOC) based on their cumulative risk profile and maintenance therapy (MT) status following first-line (1L) treatment. METHODS: This retrospective observational study of a nationwide electronic health record-derived de-identified database included adult patients diagnosed with stage III/IV OC from January 1, 2011 to February 28, 2021, who received 1L therapy and had ≥ 12 weeks of follow-up after the index date (end of 1L therapy). Patients were grouped according to whether they received MT or active surveillance (AS) following 1L treatment and by the cumulative number of risk factors (RF) present (stage IV disease; no surgery/treated with neoadjuvant therapy and interval debulking surgery; had postoperative visible residual disease; and had BRCA wild-type disease/unknown BRCA status). Time to next treatment (TTNT) and overall survival (OS) were assessed with a cloning and inverse probability of censoring (IPC)-weighted Kaplan-Meier method. RESULTS: Among 1920 patients, 22.2% received MT and 77.8% received AS. Median IPC-weighted TTNT and OS were 13.3 months (95% CI 11.7-15.8) and 39.1 months (95% CI 32.5-48.6) in the MT cohort, respectively, and 8.6 months (95% CI 8.0-9.5) and 38.4 months (95% CI 36.4-41.0) in the AS cohort, respectively. Almost all patients had ≥ 1 RF (MT 95.3%; AS 96.7%). Median IPC-weighted TTNT was shorter among patients with more RF in both cohorts (MT: 1 RF, 19.3 months, 95% CI 13.5-37.8; 2 RF, 17.2 months, 95% CI 12.8-20.2; 3 RF, 11.0 months, 95% CI 8.2-13.8; 4 RF, 7.0 months, 95% CI 6.2-8.8; AS: 1 RF, 17.7 months, 95% CI 13.5-22.3; 2 RF, 10.2 months, 95% CI 9.1-11.5; 3 RF, 6.5 months, 95% CI 5.8-7.4; 4 RF, 4.1 months, 95% CI 3.5-4.5). CONCLUSION: Regardless of RF number, MT was associated with longer TTNT in real-world patients with AOC.

Incidence of Acute Renal Failure in Patients Using Levetiracetam Versus Other Antiseizure Medications: A Voluntary Post-Authorization Safety Study.

INTRODUCTION: Acute kidney injury is an expected adverse drug reaction listed in the European Union (EU) Summary of Product Characteristics (SmPC) for levetiracetam, one of the most widely used modern antiseizure medications (ASMs). OBJECTIVE: We conducted a voluntary post-authorization safety study to characterize the rate of acute renal failure (ARF) in patients exposed to levetiracetam versus other ASMs. METHODS: New users of ASMs without prior renal dysfunction were identified and followed for 30 days in the IBM® MarketScan® database (USA, January 2008-December 2017). ARF was defined as a diagnosis on inpatient or emergency department claims. We estimated adjusted incidence rates, incidence rate ratios (IRRs), and incidence rate differences (IRDs) of ARF in patients initiating levetiracetam versus other ASMs. RESULTS: Overall, 110,336 patients were eligible for the monotherapy cohort and 96,215 were eligible for the polytherapy cohort. The overall crude rate of ARF following a new ASM was 6.0 and 6.5 per 10,000 patients for the 'monotherapy' and 'polytherapy' cohorts, respectively, in the first 30 days after the index date. In the monotherapy cohort, the IRR for ARF was 1.37 (95% confidence interval [CI] 0.80-2.34) and the corresponding IRD was 2.0 (95% CI - 1.12 to 5.12) additional ARFs per 10,000 patient-months. In the polytherapy cohort, the adjusted IRR for ARF was 0.94 (95% CI 0.51-1.74) and the corresponding IRD was - 0.42 cases per 10,000 patient-months (95% CI - 4.01 to 3.17). CONCLUSIONS: The rate of ARFs in ASM new users was very low. In patients without prior ASMs, the estimated difference in risk of ARF associated with initiation of levetiracetam versus initiation of other ASMs was small, with 95% CIs compatible with small protective or harmful effects. In patients receiving polytherapy, the difference was compatible with the null and the 95% CI with small protective or harmful effects.

Synthetic Negative Controls: Using Simulation to Screen Large-scale Propensity Score Analyses.

The propensity score has become a standard tool to control for large numbers of variables in healthcare database studies. However, little has been written on the challenge of comparing large-scale propensity score analyses that use different methods for confounder selection and adjustment. In these settings, balance diagnostics are useful but do not inform researchers on which variables balance should be assessed or quantify the impact of residual covariate imbalance on bias. Here, we propose a framework to supplement balance diagnostics when comparing large-scale propensity score analyses. Instead of focusing on results from any single analysis, we suggest conducting and reporting results for many analytic choices and using both balance diagnostics and synthetically generated control studies to screen analyses that show signals of bias caused by measured confounding. To generate synthetic datasets, the framework does not require simulating the outcome-generating process. In healthcare database studies, outcome events are often rare, making it difficult to identify and model all predictors of the outcome to simulate a confounding structure closely resembling the given study. Therefore, the framework uses a model for treatment assignment to divide the comparator population into pseudo-treatment groups where covariate differences resemble those in the study cohort. The partially simulated datasets have a confounding structure approximating the study population under the null (synthetic negative control studies). The framework is used to screen analyses that likely violate partial exchangeability due to lack of control for measured confounding. We illustrate the framework using simulations and an empirical example.

Intermittent screening and treatment with artemisinin-combination therapy versus intermittent preventive treatment with sulphadoxine-pyrimethamine for malaria in pregnancy: a systematic review and individual participant data meta-analysis of randomised clinical trials.

BACKGROUND: In sub-Saharan Africa, the efficacy of intermittent preventive therapy in pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) for malaria in pregnancy is threatened by parasite resistance. We conducted an individual-participant data (IPD) meta-analysis to assess the efficacy of intermittent screening with malaria rapid diagnostic tests (RDTs) and treatment of RDT-positive women with artemisinin-based combination therapy (ISTp-ACT) compared to IPTp-SP, and understand the importance of subpatent infections. METHODS: We searched MEDLINE and the Malaria-in-Pregnancy Library on May 6, 2021 for trials comparing ISTp-ACT and IPTp-SP. Generalised linear regression was used to compare adverse pregnancy outcomes (composite of small-for-gestational-age, low birthweight (LBW), or preterm delivery) and peripheral or placental Plasmodium falciparum at delivery. The effects of subpatent (PCR-positive, RDT/microscopy-negative) infections were assessed in both arms pooled using multi-variable fixed-effect models adjusting for the number of patent infections. PROSPERO registration: CRD42016043789. FINDINGS: Five trials conducted between 2007 and 2014 contributed (10,821 pregnancies), two from high SP-resistance areas where dhfr/dhps quintuple mutant parasites are saturated, but sextuple mutants are still rare (Kenya and Malawi), and three from low-resistance areas (West-Africa). Four trials contributed IPD data (N=10,362). At delivery, the prevalence of any malaria infection (relative risk [RR]=1.08, 95% CI 1.00-1.16, I2=67.0 %) and patent infection (RR=1.02, 0.61-1.16, I2=0.0%) were similar. Subpatent infections were more common in ISTp recipients (RR=1.31, 1.05-1.62, I2=0.0%). There was no difference in adverse pregnancy outcome (RR=1.00, 0.96-1.05; studies=4, N=9,191, I2=54.5%). Subpatent infections were associated with LBW (adjusted RR=1.13, 1.07-1.19), lower mean birthweight (adjusted mean difference=32g, 15-49), and preterm delivery (aRR=1.35, 1.15-1.57). INTERPRETATION: ISTp-ACT was not superior to IPTp-SP and may result in more subpatent infections than the existing IPTp-SP policy. Subpatent infections were associated with increased LBW and preterm delivery. More sensitive diagnostic tests are needed to detect and treat low-grade infections. FUNDING: Centers for Disease Control and Prevention and Worldwide Antimalarial Resistance Network.

Cost of epilepsy-related health care encounters in the United States.

BACKGROUND: The cost of epilepsy is usually reported as total expenditure over a certain period. However, with the increased availability of acute treatments for use in the community setting, intermittent, single-seizure treatment is now possible in addition to the chronic epilepsy drug treatment paradigm. Data on the cost of discrete health care encounters are needed to substantiate the cost-benefit of these new treatments. OBJECTIVE: To estimate the health plan-paid costs of discrete epilepsy-related health care encounters in patients with epilepsy. METHODS: This retrospective cohort study utilized IBM MarketScan Commercial Claims, Medicare Supplemental and Coordination of Benefits (Medicare patients with supplemental insurance), and Multi-State Medicaid research databases. The primary analysis determined health plan-paid cost (adjudicated claims) of discrete epilepsy-related health care encounters, defined as having a primary diagnosis code of epilepsy or convulsion, from 2013 to 2018, in patients with epilepsy aged ≥ 12 years. Costs were adjusted to 2018 prices. Epilepsy cases were defined using ICD-CM codes. We excluded patients on capitated insurance plans as their cost per health care encounter is unknown. RESULTS: In total, 353,530 commercially insured, 378,051 Medicaid, and 69,176 Medicare plus supplemental insurance patients with epilepsy were included. More than 160,000 epilepsy-related emergency transportations, 225,000 emergency department (ED) visits, 49,000 hospitalizations, 700 urgent care visits, and ~2.5 million office visits were analyzed. 37.4% of epilepsy-related hospitalizations included care in the intensive care unit (ICU). In commercially insured patients, epilepsy-related health care encounters had median health plan-paid costs of $22,305 (Q1-Q3 = $14,336-$36,096, hospitalization); $3,375 ($565-$9,095, ICU visit); $1,913 ($417-$4,163, ED visit); $687 ($415-$1,083, emergency transportation); $95 ($23-$232, office visit); and $57 ($0-$171, urgent care visit). The median length of stay for epilepsy-related hospitalizations in working age, commercially insured patients was 4 (Q1-Q3 = 2-5) days. CONCLUSIONS: This is the first study to report health plan-paid cost per epilepsy-related health care encounter. These data can serve as a basis for more granular cost-benefit analyses of not only chronic but also acute treatments of epilepsy. DISCLOSURES: This analysis was funded by UCB Pharma. The sponsor had a role in the identification, design, conduct, and reporting of the analysis. Borghs, Beaty, Boudiaf, and Loewendorf are employees of UCB Pharma. Kalilani and Parekh were employees of UCB Pharma at the time of the analysis. Borghs, Beaty, and Loewendorf have received UCB Pharma stock from their employment. Kalilani and Parekh had received UCB Pharma stock at the time of employment, but no longer hold any. This work was presented in part as a poster at the 73rd Annual Meeting of the American Epilepsy Society; December 7, 2019; Baltimore, MD.

Treatment initiation decisions in newly diagnosed epilepsy-A longitudinal cohort study.

OBJECTIVE: To examine the factors and reasons influencing treatment initiation decisions in patients with newly diagnosed epilepsy. METHODS: We assessed antiseizure medication initiation decisions in adults with newly diagnosed epilepsy seen at first seizure clinics in Western Australia between 1999 and 2016 and followed to 2018. RESULTS: Of 610 patients (median age 40 years, 61.0% male), 426 (69.8%) were diagnosed after two or more seizures and 184 (30.2%) after a single seizure with risk factors for recurrence. Treatment was commenced in 427 patients (70.0%) at diagnosis, 112 (18.4%) during follow-up, mostly after further seizures, whereas 71 (11.6%) remained untreated at last follow-up. Elders (≥65 years, odds ratio [OR] = 3.06, 95% confidence interval [CI]: 1.62-5.80), more seizures (OR = 3.48, 95% CI: 2.03-5.96), and epileptogenic lesions on neuroimaging (OR = 2.15, 95% CI: 1.26-3.68) had a higher likelihood of treatment at diagnosis. Patients with less than one seizure per year within the preceding year (OR = 0.40, 95% CI: 0.21-0.73) and of higher socioeconomic status (OR = 0.985, 95% CI: 0.977-0.994) were less likely to be treated. For 93 patients (15.2%), treatment was not recommended at diagnosis, most commonly because only a single seizure had occurred. Ninety patients (14.8%) declined recommended treatment, mostly because they were unconvinced of the need for treatment or the diagnosis. SIGNIFICANCE: Thirty percent of adults with newly diagnosed epilepsy were not immediately treated. Treatment initiation in this real-world cohort was influenced by age, number of seizures prior to diagnosis, imaging findings, patient preferences, and socioeconomic status.

The characteristics and treatment patterns of patients with Parkinson's disease in the United States and United Kingdom: A retrospective cohort study.

OBJECTIVES: The objective of the study was to describe treatment patterns in patients newly diagnosed with Parkinson's disease (PD) in the United States (US) and the United Kingdom (UK). METHODS: This retrospective cohort study used the US IBM MarketScan database (2012-2017) and the UK Clinical Practice Research Datalink (CPRD) (2004-2015) database to describe treatment patterns in incident PD cases. Patients fulfilling the case definition of PD, ≥30 years, with a 2-year baseline period prior to the index date (date of PD diagnosis), and ≥90 days of follow-up were included in the study. Treatment was classified as monotherapy (one PD medication for ≥60 continuous days), polytherapy (at least two PD medications concurrently for ≥60 days), or untreated (no PD medication prescription). Treatment patterns described included type of medication, duration and outcome of treatment. RESULTS: There were 11,280 patients in IBM MarketScan and 7775 patients in CPRD who fulfilled the study criteria. The proportion of treated patients was 62.4% (US) and 78.6% (UK). The majority of patients were prescribed monotherapy as first-line treatment (US: 85.2%, UK: 68.5%). Levodopa was the most frequently prescribed first-line medication (US: 70.1%, UK: 29.0%). There were 57.9% in the US and 23.8% in the UK who remained on the first monotherapy treatment till the end of the study. CONCLUSION: The study has highlighted the current treatment practices in the US and UK, and underscored differences in the two regions impacted by treatment policies and guidelines.

New-onset lesional and nonlesional epilepsy in the US population: Patient characteristics and patterns of antiepileptic drug use.

PURPOSE: Describe treatment patterns in patients from the United States with new-onset epilepsy, comparing those with and without lesional epilepsy. METHODS: In this observational study we used Truven Health MarketScan databases derived from commercial health insurance, Medicare and Medicaid claims covering at least 5 years, commencing in 2008. We identified incident epilepsy cases based on International Classification of Diseases, Ninth Revision, Clinical Modification codes indicating epilepsy or recurrent seizures, taking into account antiepileptic drug (AED) claims, consistent with International League Against Epilepsy Commission on Epidemiology recommendations. We identified patients with lesional epilepsy when associated diagnoses indicated central nervous system infection, neoplasm, traumatic brain injury, stroke, senile dementia and static encephalopathy. Lesional and nonlesional cohorts were matched 1:1 on baseline characteristics of age, sex and insurance type for group comparisons. RESULTS: In unmatched cohorts lesional epilepsy patients (N = 15,302) were more commonly older (mean age 48.7 years) compared with nonlesional epilepsy patients (N = 15,970; mean age 18.5 years). Among lesional patients <20 years of age, the leading putative etiology was static encephalopathy, while among ages ≥20 years and older, the leading putative etiology was stroke or cerebrovascular disease. In matched cohorts (7063 patients each), those with lesional epilepsy were significantly less likely to be untreated at 1 year versus those with nonlesional epilepsy (37.2% vs 56.1%). In children and adults among matched cohorts, levetiracetam was the most common AED prescribed for initial AED therapy for the lesional (39.5%) and nonlesional (32.1%) groups. Lesional epilepsy patients on monotherapy were only slightly less likely than nonlesional epilepsy patients to be on the same AED 1 year after treatment initiation (55.6% vs 59.7%). SIGNIFICANCE: Compared with patients with lesional epilepsy, a higher proportion of patients with nonlesional epilepsy remain untreated 1 year after diagnosis. There were differences in AED selection by epilepsy etiology; levetiracetam is the most commonly prescribed drug for both cohorts.

Treatment patterns in patients with a new diagnosis of epilepsy and psychiatric comorbidities.

OBJECTIVE: The objective of this study was to describe antiepileptic drug (AED) treatment patterns in patients with epilepsy, with and without psychiatric comorbidities. METHODS: This was a retrospective claims-based cohort study using Truven Health MarketScan databases (Commercial and supplemental Medicare, calendar years 2012-2017; Medicaid, 2012-2016). Persons met epilepsy diagnostic criteria, had an index date (first epilepsy diagnosis) with a preceding 2-year baseline (<1 year for persons of 1 to <2 years of age; none for persons <1 year), and continuous medical and pharmacy enrolment without epilepsy/seizure diagnosis or AED prescription during baseline. Based on presence/absence of psychiatric diagnosis codes in the baseline period, persons were classified into two cohorts: with or without psychiatric comorbidities. Outcomes included percentage of treated persons (AED prescription), type, duration, and outcome of first-line AED treatment. RESULTS: There were 18,062 persons in each cohort with and without psychiatric comorbidities, matched by age, sex, and insurance type, who met selection (or inclusion) criteria. More patients with psychiatric comorbidities were prescribed an AED after diagnosis (57.6% vs. 52.8%), and had at least two AEDs prescribed during follow-up (16.7% vs. 11.4%) than patients without psychiatric comorbidities. Most patients with and without psychiatric comorbidities prescribed AED monotherapy as first-line treatment (73.0% vs. 78.7%). Levetiracetam was the most common AED prescribed less frequently in patients with than without psychiatric comorbidities (40.8% vs. 56.7%). More patients with psychiatric comorbidities changed first-line AED treatment than patients without psychiatric comorbidities. CONCLUSION: The presence of psychiatric comorbidities may impact treatment decisions in newly diagnosed persons with epilepsy to optimize patient outcomes.

Assessment and effect of a gap between new-onset epilepsy diagnosis and treatment in the US.

OBJECTIVE: To estimate the treatment gap between a new epilepsy diagnosis and antiepileptic drug (AED) initiation in the United States. METHODS: Retrospective claims-based cohort study using Truven Health MarketScan databases (commercial and supplemental Medicare, calendar years 2010-2015; Medicaid, 2010-2014) and a validation study using PharMetrics Plus Database linked to LRx claims database (2009-2014). Persons met epilepsy diagnostic criteria, had an index date (first epilepsy diagnosis) with a preceding 2-year baseline (1 year for persons aged 1 to <2 years; none for persons <1 year), and continuous medical and pharmacy enrollment without epilepsy/seizure diagnosis or AED prescription during baseline. Outcomes included percentage of untreated persons (no AED prescription) up to 3 years' follow-up and comparative outcomes (incidence rate ratio: untreated persons/treated persons), including medical events and health care resource utilization. RESULTS: In the primary study, 59,970 persons met selection (or inclusion) criteria; 36.7% of persons with newly diagnosed epilepsy remained untreated up to 3 years after diagnosis. In the validation study (N = 30,890), 31.8% of persons remained untreated up to 3 years after diagnosis. Lack of AED treatment was associated with an adjusted incidence rate ratio (95% confidence interval) of 1.2 (1.2-1.3) for medical events, 2.3 (2.2-2.3) for hospitalizations, and 2.8 (2.7-2.9) for emergency department visits. CONCLUSIONS: One-third of newly diagnosed persons remain untreated up to 3 years after epilepsy diagnosis. The increased risk of medical events and health care utilization highlights the consequences of delayed treatment after epilepsy diagnosis, which might be preventable.

Antiepileptic Drug Treatment Patterns in Women of Childbearing Age With Epilepsy.

Importance: Limited population-based data are available on antiepileptic drug (AED) treatment patterns in women of childbearing age with epilepsy; the current population risk is not clear. Objectives: To examine the AED treatment patterns and identify differences in use of valproate sodium and topiramate by comorbidities among women of childbearing age with epilepsy. Design, Setting, and Participants: A retrospective cohort study used a nationwide commercial database and supplemental Medicare as well as Medicaid insurance claims data to identify 46 767 women with epilepsy aged 15 to 44 years. The eligible study cohort was enrolled between January 1, 2009, and December 31, 2013. Data analysis was conducted from January 1, 2017, to February 22, 2018. Exposures: Cases required an International Classification of Diseases, Ninth Revision, Clinical Modification-coded epilepsy diagnosis with continuous medical and pharmacy enrollment. Incident cases required a baseline of 2 or more years without an epilepsy diagnosis or AED prescription before the index date. For both incident and prevalent cases, focal and generalized epilepsy cohorts were matched by age, payer type, and enrollment period and then compared. Main Outcomes and Measures: Antiepileptic drug treatment pattern according to seizure type and comorbidities. Results: Of the 46 767 patients identified, there were 8003 incident cases (mean [SD] age, 27.3 [9.4] years) and 38 764 prevalent cases (mean [SD] age, 29.7 [9.0] years). Among 3219 women in the incident epilepsy group who received AEDs for 90 days or more, 3173 (98.6%) received monotherapy as first-line treatment; among 28 239 treated prevalent cases, 18 987 (67.2%) received monotherapy. In 3544 (44.3%) incident cases and 9480 (24.5%) prevalent cases, AED treatment was not documented during 180 days or more of follow-up after diagnosis. Valproate (incident: 35 [5.81%]; prevalent: 514 [13.1%]) and phenytoin (incident: 33 [5.48%]; prevalent: 178 [4.53%]) were more commonly used for generalized epilepsy and oxcarbazepine (incident: 53 [8.03%]; prevalent: 386 [9.89%]) was more often used for focal epilepsy. Levetiracetam (incident: focal, 267 [40.5%]; generalized, 271 [45.0%]; prevalent: focal, 794 [20.3%]; generalized, 871 [22.2%]), lamotrigine (incident: focal, 123 [18.6%]; generalized, 106 [17.6%]; prevalent: focal, 968 [24.8%]; generalized, 871 [22.2%]), and topiramate (incident: focal, 102 [15.5%]; generalized, 64 [10.6%]; prevalent: focal, 499 [12.8%]; generalized, 470 [12.0%]) were leading AEDs prescribed for both focal and generalized epilepsy. Valproate was more commonly prescribed for women with comorbid headache or migraine (incident: 53 of 1251 [4.2%]; prevalent: 839 of 8046 [10.4%]), mood disorder (incident: 63 of 860 [7.3%]; prevalent: 1110 of 6995 [15.9%]), and anxiety and dissociative disorders (incident: 57 of 881 [6.5%]; prevalent: 798 of 5912 [13.5%]). Topiramate was more likely prescribed for those with comorbid headache or migraine (incident: 335 of 1251 [26.8%]; prevalent: 2322 of 8046 [28.9%]). Conclusions and Relevance: Many women appear to be treated with valproate and topiramate despite known teratogenicity risks. Comorbidities may affect selecting certain AEDs despite their teratogenicity risks.

Rare Detection of Antiviral Functions of Polyclonal IgA Isolated from Plasma and Breast Milk Compartments in Women Chronically Infected with HIV-1.

The humoral response to invading mucosal pathogens comprises multiple antibody isotypes derived from systemic and mucosal compartments. To understand the contribution of each antibody isotype/source to the mucosal humoral response, parallel investigation of the specificities and functions of antibodies within and across isotypes and compartments is required. The role of IgA against HIV-1 is complex, with studies supporting a protective role as well as a role for serum IgA in blocking effector functions. Thus, we explored the fine specificity and function of IgA in both plasma and mucosal secretions important to infant HIV-1 infection, i.e., breast milk. IgA and IgG were isolated from milk and plasma from 20 HIV-1-infected lactating Malawian women. HIV-1 binding specificities, neutralization potency, inhibition of virus-epithelial cell binding, and antibody-mediated phagocytosis were measured. Fine-specificity mapping showed IgA and IgG responses to multiple HIV-1 Env epitopes, including conformational V1/V2 and linear V2, V3, and constant region 5 (C5). Env IgA was heterogeneous between the milk and systemic compartments (Env IgA, τ = 0.00 to 0.63, P = 0.0046 to 1.00). Furthermore, IgA and IgG appeared compartmentalized as there was a lack of correlation between the specificities of Env-specific IgA and IgG (in milk, τ = -0.07 to 0.26, P = 0.35 to 0.83). IgA and IgG also differed in functions: while neutralization and phagocytosis were consistently mediated by milk and plasma IgG, they were rarely detected in IgA from both milk and plasma. Understanding the ontogeny of the divergent IgG and IgA antigen specificity repertoires and their effects on antibody function will inform vaccination approaches targeted toward mucosal pathogens.IMPORTANCE Antibodies within the mucosa are part of the first line of defense against mucosal pathogens. Evaluating mucosal antibody isotypes, specificities, and antiviral functions in relationship to the systemic antibody profile can provide insights into whether the antibody response is coordinated in response to mucosal pathogens. In a natural immunity cohort of HIV-infected lactating women, we mapped the fine specificity and function of IgA in breast milk and plasma and compared these with the autologous IgG responses. Antigen specificities and functions differed between IgG and IgA, with antiviral functions (neutralization and phagocytosis) predominantly mediated by the IgG fraction in both milk and plasma. Furthermore, the specificity of milk IgA differed from that of systemic IgA. Our data suggest that milk IgA and systemic IgA should be separately examined as potential correlates of risk. Preventive vaccines may need to employ different strategies to elicit functional antiviral immunity by both antibody isotypes in the mucosa.