Management of infection among Medicare beneficiaries with HIV/AIDS: risk of diabetes with protease inhibitors and associated racial disparities using big data approach.

Association between protease inhibitors (PI) and Type II diabetes mellitus (T2DM) in human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) patients is largely debated. This study examined the odds of developing T2DM among HIV/AIDS Medicare beneficiaries treated with PI and possible racial disparities in the odds. We performed a nested casecontrol study of Medicare database 2013-2017. We included HIV/AIDS positive beneficiaries who were enrolled continuously in Medicare Part A/B with no previous history of T2DM. PI-users were matched to non-PI users and non-anti-retroviral therapies (ART) users using a1:1 greedy propensity score (PS) matching . Multivariablee logistic regressions were performed to assess the odds of developing T2DM. The analysis included 2,353 HIV/AIDS beneficiaries. Matched samples were generated for PI vs. non-PI groups (n = 484) and PI vs. non-ART groups (n = 490). Compared to the non-PI group, the odds of developing T2DM were higher in PI-users (AOR: 1.76; 95% CI: 1.17-2.64), in Caucasian PI-users (AOR: 1.81; 95% CI: 1.02-3.22) and in African-American PI-users (AOR: 1.86; 95% CI: 1.03-3.36). Compared to the non-ART group, the odds of developing T2DM were higher in PI-users (AOR: 1.87; 95% CI: 1.25-2.81), in Caucasian PI-users (AOR: 1.96; 95% CI: 1.14-3.39) and in African-American PI-users (AOR: 2.05; 95% CI: 1.03-4.09). The use of PI is associated with higher odds of T2DM; odds were higher among African-Americans than Caucasians.

Economic impact of comorbid diabetes and associated racial disparities in managing Medicare beneficiaries with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS).

Clinical management of human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) is progressing to include chronic/metabolic complications, which may impose a significant economic burden on beneficiaries and Medicare. We assessed the national economic impact of comorbid Type-II Diabetes Mellitus (T2DM) on HIV/AIDS patients and potential raical disparities. This study was a cross-sectional study of Medicare database 2013-2017. Analytical sample included HIV/AIDS positive beneficiaries continuously enrolled in Part A/B. Total medical costs, prescription costs, inpatient costs, outpatient costs, out-of-pocket (OOP) costs, and Medicare costs were assessed from Medicare claims. Generalized linear models with log-link and gamma distribution were used to examine the impact of T2DM on different costs. A total of 2,509 eligible HIV/AIDS positive beneficiaries were identified of which 19.9% (n=498) had T2DM. After adjusting for covariates, T2DM beneficiaries had higher inpatient costs: 63.34% (95% CI: 42.73%-86.94%), outpatient costs: 50.26% (95% CI: 30.70%-72.75%), Medicare costs: 27.95% (95% CI: 13.81%-43.84%), OOP costs: 59.15% (95% CI: 40.02%-80.92%), and total medical costs: 27.83% (95% CI: 14.27%-43.00%) than non-T2DM beneficiaries. Incremental costs were higher among African Americans than Caucasians. Comorbid T2DM mposes a significant economic burden on HIV/AIDS patients and Medicare, which is higheramong African Americans.

Relationship of Nonsteroidal Anti-Inflammatory Drug Use During Pregnancy with Autism Spectrum Disorder and Intellectual Disability Among Offspring.

Objective: This study aimed to examine the association of nonsteroidal anti-inflammatory drug (NSAID) use by pregnant women during pregnancy with autism spectrum disorder (ASD) and intellectual disability (ID) in their children among Medicaid-insured mother-child dyads. Materials and Methods: We conducted a retrospective cohort study linking multiple datasets of South Carolina for the years between 2010 and 2017, in which the main exposure variable was NSAID use during pregnancy and outcome variables were ASD only, ID only, and ASD with ID. We conducted a multinomial logistic regression analysis, controlling for identified risk factors for ASD (mother's age, race, body-mass index, preeclampsia, and gestational diabetes). Results: NSAID use during pregnancy was found to be associated with ID only in both unadjusted and adjusted analyses. Children with mothers who had NSAID prescriptions were 26% more likely to have ID in comparison with children whose mothers did not have NSAID prescriptions (odds ratio: 1.26 [1.10-1.46]). The other risk factors identified for ASD were maternal age, race, preeclampsia, smoking, low birth weight, and obesity. For ID, the risk factors were maternal age, race, smoking, birth weight, overweight, and obesity, all of which were also associated with ASD with ID, except for overweight. Conclusions: NSAID usage during pregnancy was found to be associated with ID only and not with ASD. However, more research is needed to validate the effect of NSAIDs during pregnancy on ASD and ID among children.

Publisher Correction: Early-onset colorectal cancer: initial clues and current views.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Changes in Cost-Effectiveness for Chronic Hepatitis C Virus Pharmacotherapy: The Case for Continuous Cost-Effectiveness Analyses.

BACKGROUND: Cost-effectiveness evaluations for hepatitis C virus (HCV) treatments have been published frequently, but new products with significant cost and effectiveness differences make these analyses obsolete. How valuable are economic models for a fixed time period in a dynamic market? OBJECTIVE: To estimate the cost-effectiveness of the best available HCV treatment at different points in time, using the same comparator to demonstrate how rapid innovation in a disease area influences economic outcomes. METHODS: A Markov model was used to calculate the cost-effectiveness of treatment in 2010, 2012, 2014, 2016, and 2018 compared with a standard comparator (no treatment) from the payer perspective. Expected drug costs and treatment effectiveness estimates for sustained virologic response (SVR) were calculated using recommended regimens for each of the 6 HCV genotypes at each time point and distribution of genotypes in the United States. Patients entered the model with different stages of fibrosis. Utility estimates for each health state were used to calculate quality-adjusted life-years (QALYs) earned at each cycle. Incremental cost-effectiveness ratios were reported for each year to compare the "treatment versus no treatment" decision at that time. RESULTS: No HCV treatment resulted in a gain of 11.54 QALYs over a 20-year time horizon at a cost of $42,938. Costs for treated groups were $69,075, $123,267, $125,431, $86,782, and $56,470 for the 2010, 2012, 2014, 2016, and 2018 scenarios, respectively. QALYs gained for treated groups were 12.90, 12.97, 13.34, 13.39, and 13.46 for the 2010, 2012, 2014, 2016, and 2018 scenarios, respectively. The incremental cost-effectiveness ratios in each year compared with no treatment were $19,218 per QALY, $56,104 per QALY, $45,829 per QALY, $23,699 per QALY, and $7,048 per QALY. CONCLUSIONS: Treatment effectiveness for HCV has increased steadily, while treatment costs increased substantially from 2010-2014 before decreasing to its lowest point in 2018. Thus, the dynamic nature of innovation creates the need for iterative cost-effectiveness analyses. DISCLOSURES: No outside funding supported this study. Mattingly reports unrelated consulting from the National Health Council, Bristol Myers Squibb, G&W Laboratories, Allergy and Asthma Foundation of American, and the Massachusetts Health Policy Commission. Love reports an unrelated research grant from the American Cancer Society.

Early-onset colorectal cancer: initial clues and current views.

Over the past several decades, the incidence of early-onset colorectal cancer (EOCRC; in patients <50 years old) has increased at an alarming rate. Although robust and scientifically rigorous epidemiological studies have sifted out environmental elements linked to EOCRC, our knowledge of the causes and mechanisms of this disease is far from complete. Here, we highlight potential risk factors and putative mechanisms that drive EOCRC and suggest likely areas for fruitful research. In addition, we identify inconsistencies in the evidence implicating a strong effect of increased adiposity and suggest that certain behaviours (such as diet and stress) might place nonobese and otherwise healthy people at risk of this disease. Key risk factors are reviewed, including the global westernization of diets (usually involving a high intake of red and processed meats, high-fructose corn syrup and unhealthy cooking methods), stress, antibiotics, synthetic food dyes, monosodium glutamate, titanium dioxide, and physical inactivity and/or sedentary behaviour. The gut microbiota is probably at the crossroads of these risk factors and EOCRC. The time course of the disease and the fact that relevant exposures probably occur in childhood raise important methodological issues that are also discussed.

Hepatitis B Virus Reactivation: Risk Factors and Current Management Strategies.

Hepatitis B virus (HBV) is a global disease with significant morbidity and mortality. Worldwide, ~257 million people are chronically infected with HBV, defined as having a positive hepatitis B surface antigen, but millions more have prior HBV exposure indicated by positive hepatitis B core antibody. Reactivation of hepatitis B implies a sudden increase in viral replication in a patient with chronic HBV infection or prior HBV exposure. Hepatitis B virus reactivation (HBVr) can occur spontaneously, but it is more commonly triggered by immunosuppressive therapies for cancer, immunologic diseases, or transplantation. Elimination of hepatitis C virus (HCV) in HBV-HCV coinfected individuals treated with direct-acting antivirals (DAAs) has also been identified as an important cause of HBVr. Hepatitis B virus reactivation is an underappreciated but important complication of common medical therapies that can delay treatment or result in clinical episodes of hepatitis, hepatic failure, or death. In this review, factors associated with HBVr, particularly medication-related risks, are explored. We review data involving rituximab and ofatumumab, doxorubicin, corticosteroids, tumor necrosis factor antagonists, tyrosine kinases, bortezomib, hematologic stem cell transplantation, and DAAs for HCV treatment. In addition, we discuss screening strategies, choice of antiviral prophylaxis, and the optimal duration of therapy for HBVr. With additional awareness, screening, and appropriate antiviral therapy, it is expected that most cases of HBVr can be prevented.

Regulatory and Clinical Experiences with Biosimilar Filgrastim in the U.S., the European Union, Japan, and Canada.

Biosimilar filgrastims are primarily indicated for chemotherapy-induced neutropenia prevention. They are less expensive formulations of branded filgrastim, and biosimilar filgrastim was the first biosimilar oncology drug administered in European Union (EU) countries, Japan, and the U.S. Fourteen biosimilar filgrastims have been marketed in EU countries, Japan, the U.S., and Canada since 2008, 2012, 2015, and 2016, respectively. We reviewed experiences and policies for biosimilar filgrastim markets in EU countries and Japan, where uptake has been rapid, and in the U.S. and Canada, where experience is rapidly emerging. U.S. regulations for designating biosimilar interchangeability are under development, and such regulations have not been developed in most other countries. Pharmaceutical substitution is allowed for new filgrastim starts in some EU countries and in Canada, but not Japan and the U.S. In EU countries, biosimilar adoption is facilitated with favorable hospital tender offers. U.S. adoption is reportedly 24%, while the second filgrastim biosimilar is priced 30% lower than branded filgrastim and 20% lower than the first biosimilar filgrastim approved by the U.S. Food and Drug Administration. Utilization is about 60% in EU countries, where biosimilar filgrastim is marketed at a 30%-40% discount. In Japan, biosimilar filgrastim utilization is 45%, primarily because of 35% discounts negotiated by Central Insurance and hospital-only markets. Overall, biosimilar filgrastim adoption barriers are small in many EU countries and Japan and are diminishing in Canada in the U.S. Policies facilitating improved U.S. adoption of biosimilar filgrastim, based on positive experiences in EU countries and Japan, including favorable insurance coverage; larger price discount relative to reference filgrastim pricing; closing of the "rebate trap" with transparent pricing information; formal educational efforts of patients, physicians, caregivers, and providers; and allowance of pharmaceutical substitution of biosimilar versus reference filgrastim, should be considered. IMPLICATIONS FOR PRACTICE: We reviewed experiences and policies for biosimilar filgrastims in Europe, Japan, Canada, and the U.S. Postmarketing harmonization of regulatory policies for biosimilar filgrastims has not occurred. Acceptance of biosimilar filgrastims for branded filgrastim, increasing in the U.S. and in Canada, is commonplace in Japan and Europe. In the U.S., some factors, accepted in Europe or Japan, could improve uptake, including acceptance of biosimilars as safe and effective; larger cost savings, decreasing "rebate traps" where pharmaceutical benefit managers support branded filgrastim, decreased use of patent litigation/challenges, and allowing pharmacists to routinely substitute biosimilar for branded filgrastim.

Opioid Prescription Patterns for Adults With Longstanding Disability and Inflammatory Conditions Compared to Other Users, Using a Nationally Representative Sample.

OBJECTIVES: To investigate the opioid prescription patterns for adults with longstanding physical disability and inflammatory conditions, compared to a mixed group of other opioid users, after excluding cancer patients. DESIGN: Nationally representative cross-sectional study, 2010-2014. SETTING: Medical Expenditure Panel Survey (MEPS). PARTICIPANTS: The participants (N=7134) were adults who participated in MEPS and had at least 1 opioid prescription, did not have cancer, and were between 18 years and 64 years of age. The participants were grouped as longstanding physical disability (group 1), inflammatory conditions (group 2), and a mixed group with at least 1 opioid prescription during the 2-year study period (comparison group). Participants with both groups of conditions were excluded. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Morphine milligram equivalent (MME) doses for each participant were cumulated over a 2-year panel period. RESULTS: By using quantile regression, cumulative MME in groups 1 and 2 was higher than the comparison group across all the percentiles, and differences between condition groups and comparison group became larger in higher percentiles. Participants in group 1 had the highest cumulative MME in 75th and 90th percentiles after controlling for other covariates. CONCLUSIONS: This study documented the opioid prescription patterns for patients with longstanding physical disability or inflammatory conditions. All indexed groups (groups 1 and 2) had higher MME use compared to the comparison group.

Long-term pharmacotherapy considerations in the bariatric surgery patient.

PURPOSE: Pharmacists' role in optimizing long-term pharmacotherapy for bariatric surgery patients is detailed. SUMMARY: Bariatric surgery patients provide a difficult challenge in terms of many pharmacotherapy issues, especially in the chronic care setting, where data on long-term effects of bariatric surgery are limited. The most common procedures are Roux-en-Y gastric bypass (RYGB), adjustable gastric banding, and sleeve gastrectomy. Sleeve gastrectomy has become the most common procedure in the United States, primarily because it has less overall chronic malabsorption effects than RYGB. Pharmacotherapy management is complicated by rapid weight loss combined with a number of pharmacokinetic changes, such as decreased absorption of some medications due to altered gastrointestinal tract anatomy and potentially increased concentrations of some medications due to a decreased volume of distribution resulting from weight loss. Nutritional and metabolic supplementation are of the utmost importance in order to limit deficiencies that can lead to a number of conditions. Many chronic diseases, including hypertension, diabetes, gastroesophageal reflux disease, and urinary incontinence, are improved by bariatric surgery but require close monitoring to ensure the effectiveness of maintenance pharmacotherapy and avoidance of adverse effects. Psychotropic medication management is also an important pharmacotherapy concern, as evidenced by antidepressants being the most commonly used medication class among preoperative bariatric surgery patients. CONCLUSION: Pharmacists have an increasing role in the chronic management of the bariatric surgery patient due to their knowledge of medication dosage forms and expertise in disease states affected by bariatric surgery.

Report: pharmacotherapy for moderate to severe inflammatory bowel disease: evolving strategies.

Moderate to severe disease causes substantial morbidity in inflammatory bowel disease (IBD). The approach to pharmacotherapy for patients with moderate to severe ulcerative colitis and Crohn's disease is undergoing a fundamental transformation to change the course of disease in these patients. Disease severity is being redefined to consider the impact on the patient, its inflammatory burden, and the disease course. Prevention of disease progression and complications are replacing symptomatic remission as the goal of therapy. To achieve these goals, the treatment approach is evolving from a stepwise to a treat-to-target approach, with patients stratified to treatment according to their risk of disease progression or complications. The primary drug classes for induction and maintenance of remission in moderate to severe IBD are corticosteroids, thiopurines, tumor necrosis factor antagonists, and vedolizumab. Use of these drug classes is changing as IBD management evolves. This article reviews the efficacy, adverse effects, drug interactions, and special issues for each class. The role for each class is formulated based on results of key clinical trials and meta-analyses, as well as clinical practice guideline recommendations.

Fluoroquinolone-related neuropsychiatric and mitochondrial toxicity: a collaborative investigation by scientists and members of a social network.

BACKGROUND: The 3 fluoroquinolone (FQ) antibiotics - ciprofoxacin, levofoxacin, and moxifoxacin - are commonly administered to oncology patients. Although these oral antibiotics are approved by the US Food and Drug Administration (FDA) for treatment of urinary tract infections, acute bacterial sinusitis, or bacterial infection in patients with chronic obstructive pulmonary disease, they are commonly prescribed off-label to neutropenic cancer patients for the prevention and treatment of infections associated with febrile neutropenia. New serious FQ-associated safety concerns have been identified through novel collaborations between FQ-treated persons who have developed long-term neuropsychiatric (NP) toxicity, pharmacovigilance experts, and basic scientists. OBJECTIVE: To conduct basic science and clinical investigations of a newly identified adverse drug reaction, termed FQ-associated disability. METHODS: 5 groups of C57BL/6 mice receiving the antibiotic ciprofoxacin in 10-mg increments (10 mg/kg-50 mg/kg) and 1 group of control mice were evaluated. The Southern Network on Adverse Reactions (SONAR) and a social network of FQ-treated persons with long-term NP toxicity (the Floxed Network) conducted a web-based survey. The clinical toxicity manifestations reported by 94 respondents to the web-based survey of persons who had received 1 or more doses of an FQ prescribed for any indication (generally at FDA-approved dosages) and who subsequently experienced possible adverse drug reactions were compared with adverse event information included on the product label for levofoxacin and with FQ-associated adverse events reported to the FDA's MedWatch program. RESULTS: Mice treated with ciprofoxacin had lower grip strengths, reduced balance, and depressive behavior compared with the controls. For the survey, 93 of 94 respondents reported FQ-associated events including anxiety, depression, insomnia, panic attacks, clouded thinking, depersonalization, suicidal thoughts, psychosis, nightmares, and impaired memory beginning within days of FQ initiation or days to months of FQ discontinuation. The FDA Adverse Event Reporting System (FAERS) included 210,705 adverse events and 2,991 fatalities for FQs. Levofoxacin and ciprofoxacin toxicities were neurologic (30% and 26%, respectively), tendon damage (8% and 6%), and psychiatric (10% and 2%). In 2013, an FDA safety review reported that FQs affect mammalian topoisomerase II, especially in mitochondria. In 2013 and 2014, SONAR fled citizen petitions requesting black box revisions identifying neuropsychiatric toxicities and mitochrondrial toxicity as serious levofoxacin-associated adverse drug reactions. In 2015, FDA advisors recommended that FQ product labels be revised to include information about this newly identified disability syndrome termed "FQ-associated disability" (FQAD). LIMITATIONS: Basic science studies evaluated NP toxicity for only 1 FQ, ciprofoxacin. CONCLUSION: Pharmacovigilance investigators, a social network, and basic scientists can collaborate on pharmacovigilance investigations. Revised product labels describing a new serious adverse drug reaction, levofoxacin-associated long-term disability, as recommended by an FDA advisory committee, are advised.

Therapeutic Advances in HCV Genotype 1 Infection: Insights from the Society of Infectious Diseases Pharmacists.

Hepatitis C virus (HCV) is the most common blood-borne infection in the United States. The high morbidity and mortality due to untreated infection have prompted updated screening recommendations that now include one-time HCV screening for all patients born between 1945 and 1965, in addition to risk factor-based screening. Current guidelines recommend treatment for all patients with chronic HCV. Treatment for HCV genotype 1 has evolved dramatically since the approval of the direct-acting antivirals. The approval of ledipasvir-sofosbuvir, ombitasvir-paritaprevir-ritonavir and dasabuvir, and simeprevir with sofosbuvir has dramatically altered the treatment landscape. High sustained virologic response (SVR) rates favor treatment, yet access to care poses a challenge for patients and providers. Current and emerging data with new therapies indicate high SVR rates in treatment-naïve and treatment-experienced patients, including patients with cirrhosis and in other special populations. Additional data suggest the addition of ribavirin can decrease treatment duration without compromising SVR rates. Resistance is an increasing area of interest in HCV, with baseline mutations identified and the potential for the development of resistance-associate variants in patients undergoing treatment. Due to the rapid evolution of HCV treatment, pharmacists should address challenges and play an integral role in agent selection, dosing, drug interaction screening, adverse effect monitoring, and the coordination of treatment. Clinical application of the latest information will reduce patient risk and improve outcomes.

Regulatory and clinical considerations for biosimilar oncology drugs.

Biological oncology products are integral to cancer treatment, but their high costs pose challenges to patients, families, providers, and insurers. The introduction of biosimilar agents-molecules that are similar in structure, function, activity, immunogenicity, and safety to the original biological drugs-provide opportunities both to improve health-care access and outcomes, and to reduce costs. Several international regulatory pathways have been developed to expedite entry of biosimilars into global marketplaces. The first wave of oncology biosimilar use was in Europe and India in 2007. Oncology biosimilars are now widely marketed in several countries in Europe, and in Australia, Japan, China, Russia, India, and South Korea. Their use is emerging worldwide, with the notable exception of the USA, where several regulatory and cost barriers to biosimilar approval exist. In this Review, we discuss oncology biosimilars and summarise their regulatory frameworks, clinical experiences, and safety concerns.

Linaclotide: a novel agent for chronic constipation and irritable bowel syndrome.

PURPOSE: The pharmacology, pharmaco-kinetics, and clinical efficacy and safety of linaclotide in the management of chronic constipation (CC) and constipation-predominant irritable bowel syndrome (IBS-C) are reviewed. SUMMARY: Linaclotide (Linzess, Forest Pharmaceuticals) is a 14-amino acid peptide indicated for the treatment of adults with CC and IBS-C. Linaclotide acts on guanylate cyclase-C receptors on the luminal membrane to increase chloride and bicarbonate secretions into the intestine and inhibit the absorption of sodium ions, thus increasing the secretion of water into the lumen and improving defecation; the drug is minimally absorbed into the systemic circulation. Linaclotide is approved by the Food and Drug Administration (FDA) for oral once-daily administration at doses of 145 µg for CC and 290 µg for IBS-C. In placebo-controlled Phase III clinical trials, linaclotide significantly increased weekly spontaneous bowel movements and complete spontaneous bowel movements (CSBMs) while reducing abdominal pain in patients with CC. In patients with IBS-C, linaclotide was demonstrated to be effective in meeting FDA-recommended endpoints such as reductions of at least 30% from baseline in abdominal pain scores and CSBM frequency. The most common adverse effect of linaclotide is diarrhea, which was reported in 16-20% of clinical trial participants. CONCLUSION: Linaclotide is an important advance in the treatment of CC and IBS-C, with a novel mechanism of action resulting in accelerated intestinal transit. In clinical trials, linaclotide demonstrated efficacy relative to placebo for treatment of both CC and IBS-C. Linaclotide's adverse effects are generally mild and confined to the gastrointestinal tract.

Hypertriglyceridaemia-induced acute pancreatitis due to patient non-compliance.

A 34-year-old woman presented with acute and progressive pain in the upper abdomen with worsening nausea, vomiting and diarrhoea. Her pain was described as severe, sharp and stabbing, with radiation to her chest and back. The patient's amylase and lipase levels were only mildly elevated. However, triglyceride levels (10,039 mg/dL) were markedly elevated upon presentation and no other causes of acute pancreatitis (e.g. obstruction, alcohol and medication) were identified. The patient was treated with opioids to control her pain and gemfibrozil was initiated to reduce her triglycerides. In addition, the patient received enoxaparin for deep vein thrombosis prevention and insulin for hyperglycaemia which also have been shown to decrease elevated triglycerides. The patient subsequently required antibiotic therapy with piperacillin-tazobactam after developing fever and an elevated white blood cell count. We review the role of adjunctive therapy with heparin and insulin in a patient with recurrent pancreatitis probably because of hypertriglyceridaemia and medication non-compliance.