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BACKGROUND: There are limited data on outcomes for patients with peripheral artery disease undergoing endovascular revascularization by multi-disciplinary teams in a community hospital setting. METHODS: From January 2015 through December 2015, we assembled a multi-disciplinary program comprised of cardiologists, surgeons, radiologists, nurses, and administrative staff for managing patients with peripheral artery disease undergoing endovascular revascularization. Demographic, procedural, and outcomes data were collected with use of a template from the Society for Vascular Surgery Vascular Quality Initiative database. We compared characteristics and outcomes of patients with intermittent claudication and critical limb ischemia. We used Kaplan-Meier methods to estimate the rate of overall survival and freedom from rehospitalization between groups. RESULTS: After excluding patients with acute limb ischemia (n = 5), peripheral intervention to the upper extremity (n = 6), or abdominal aorta (n = 11), there were 82 patients in the study cohort; 45 had intermittent claudication and 37 had critical limb ischemia. Baseline and procedural characteristics were similar between groups, although critical limb ischemia patients were more likely to have hyperlipidemia (75.7% vs. 53.3%, P = .42). Procedural success was achieved in 91.3% of cases. Actionable access site bleeding occurred in 2.4% of patients. High rates of aspirin (91.5%) and statin (87.8%) were noted at discharge. After two years of post endovascular revascularization, survival was 57.5% for critical limb ischemia patients and 94.4% for intermittent claudication patients (P < .001). Freedom from rehospitalization was 32.7% for critical limb ischemia patients and 83.5% for intermittent claudication patients (P < .001). CONCLUSIONS: We found that favorable outcomes may be achieved with a multi-disciplinary peripheral artery disease program at community hospitals. The incorporation of quality improvement practices may further help to develop standardized and regionalized approaches to care delivery for patients with peripheral artery disease.
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Procedimentos Endovasculares , Hospitais Comunitários , Claudicação Intermitente/terapia , Isquemia/terapia , Doença Arterial Periférica/terapia , Idoso , Idoso de 80 Anos ou mais , Estado Terminal , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/mortalidade , Feminino , Humanos , Claudicação Intermitente/diagnóstico por imagem , Claudicação Intermitente/mortalidade , Claudicação Intermitente/fisiopatologia , Isquemia/diagnóstico por imagem , Isquemia/mortalidade , Isquemia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Equipe de Assistência ao Paciente , Readmissão do Paciente , Doença Arterial Periférica/diagnóstico por imagem , Doença Arterial Periférica/mortalidade , Doença Arterial Periférica/fisiopatologia , Avaliação de Programas e Projetos de Saúde , Melhoria de Qualidade , Indicadores de Qualidade em Assistência à Saúde , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
PURPOSE: We examined the therapeutic effects of avanafil 15 minutes after dosing in men with mild to severe erectile dysfunction. MATERIALS AND METHODS: This randomized, double-blind, placebo controlled, 12-week study (4-week run-in and 8-week treatment) randomized 145 men to placebo, 147 to avanafil 100 mg and 148 to avanafil 200 mg on demand. The primary efficacy variable was the per subject proportion of sexual attempts during the treatment period in which subjects achieved erection sufficient for vaginal penetration within approximately 15 minutes after dosing as measured by a stopwatch. The attempt had to enable successful completion of sexual intercourse according to SEP question 3. RESULTS: Significantly greater mean per subject percentages of successful intercourse attempts within approximately 15 minutes after dosing were observed for avanafil 100 mg (mean 25.9%, LS mean ± SE 24.7% ± 2.9%) and 200 mg (mean 29.1%, LS mean 28.2% ± 2.9%) vs placebo (mean 14.9%, LS mean 13.8% ± 2.9%, p = 0.001 and <0.001, respectively). After treatment we noted a statistically significant difference between avanafil and placebo in the average per subject proportion of successful intercourse attempts according to SEP question 3 as early as 10 minutes in the 200 mg group and 12 minutes in the 100 mg group. Treatment emergent adverse events included headache, upper respiratory tract infection and nasal congestion, and most such events were mild or moderate in severity. CONCLUSIONS: Avanafil was efficacious within approximately 15 minutes of dosing compared to placebo. A statistically significant treatment difference in the percentage of successful sexual attempts was demonstrated as early as 10 minutes after treatment.
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Disfunção Erétil/tratamento farmacológico , Satisfação do Paciente , Ereção Peniana/efeitos dos fármacos , Pirimidinas/administração & dosagem , Comportamento Sexual/efeitos dos fármacos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Disfunção Erétil/fisiopatologia , Disfunção Erétil/psicologia , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVES: This is the first study to compare the incidence and health care costs of medically attended adverse effects in atazanavir- and darunavir-based antiretroviral therapy (ART) among U.S. Medicaid patients receiving routine HIV care. METHODS: This was a retrospective study using Medicaid administrative health care claims from 15 states. Subjects were HIV patients aged 18 to 64 years initiating atazanavir- or darunavir-based ART from January 1, 2003, to July 1, 2010, with continuous enrollment for 6 months before (baseline) and 6 months after (evaluation period) ART initiation and 1 or more evaluation period medical claim. Outcomes were incidence and health care costs of the following medically attended (International Classification of Diseases, Ninth Revision, Clinical Modification-coded or treated) adverse effects during the evaluation period: gastrointestinal, lipid abnormalities, diabetes/hyperglycemia, rash, and jaundice. All-cause health care costs were also determined. Patients treated with atazanavir and darunavir were propensity score matched (ratio = 3:1) by using demographic and clinical covariates. Multivariable models adjusted for covariates lacking postmatch statistical balance. RESULTS: Propensity-matched study sample included 1848 atazanavir- and 616 darunavir-treated patients (mean age 41 years, 50% women, 69% black). Multivariable-adjusted hazard ratios (HRs) (for darunavir, reference = atazanavir) and per-patient-per-month health care cost differences (darunavir minus atazanavir) were as follows: gastrointestinal, HR = 1.25 (P = 0.04), $43 (P = 0.13); lipid abnormalities, HR = 1.38 (P = 0.07), $3 (P = 0.88); diabetes/hyperglycemia, HR = 0.84 (P = 0.55), $13 (P = 0.69); and rash, HR = 1.11 (P = 0.23), $0 (P = 0.76); all-cause health care costs were $1086 (P<0.001). Too few instances of jaundice (11 in atazanavir and 1 in darunavir) occurred to support multivariable modeling. CONCLUSIONS: Medication tolerability can be critical to the success or failure of ART. Compared with darunavir-treated patients, atazanavir-treated patients had significantly fewer instances of medically attended gastrointestinal issues and more instances of jaundice and incurred significantly lower health care costs.
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Infecções por HIV/tratamento farmacológico , Custos de Cuidados de Saúde , Oligopeptídeos/efeitos adversos , Oligopeptídeos/economia , Piridinas/efeitos adversos , Piridinas/economia , Sulfonamidas/efeitos adversos , Sulfonamidas/economia , Adolescente , Adulto , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/economia , Fármacos Anti-HIV/uso terapêutico , Sulfato de Atazanavir , Darunavir , Exantema/induzido quimicamente , Exantema/economia , Feminino , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/economia , Transtornos do Metabolismo de Glucose/induzido quimicamente , Transtornos do Metabolismo de Glucose/economia , Infecções por HIV/economia , Humanos , Revisão da Utilização de Seguros , Icterícia/induzido quimicamente , Icterícia/economia , Transtornos do Metabolismo dos Lipídeos/induzido quimicamente , Transtornos do Metabolismo dos Lipídeos/economia , Masculino , Medicaid/economia , Pessoa de Meia-Idade , Oligopeptídeos/uso terapêutico , Piridinas/uso terapêutico , Estudos Retrospectivos , Sulfonamidas/uso terapêutico , Estados Unidos , Adulto JovemRESUMO
INTRODUCTION: Guselkumab, an anti-interleukin-23 biologic therapy, has been shown to significantly reduce disease activity and improve patient-reported outcome measures (PROMs) among patients with moderate-to-severe plaque psoriasis in clinical trials. However, characterization of the real-world effectiveness of guselkumab among patients living in the USA and Canada is warranted. METHODS: Patients who participated in the CorEvitas Psoriasis Registry between 18 July 2017 and 10 March 2020 were included if they met the following criteria: Investigator's Global Assessment (IGA) score ≥ 3 and body surface area (BSA) ≥ 10% (moderate-to-severe psoriasis), initiated guselkumab at a registry (index) visit, and had a registry follow-up visit after 9-12 months of persistent guselkumab therapy. Data were retrieved for baseline patient demographics and disease characteristics, treatment history, disease activity, and PROMs. Outcomes were assessed at index and follow-up visits; response rates and mean changes were calculated. RESULTS: Among 113 patients, mean age was 49.7 years, mean psoriasis duration was 17.5 years, and 65.5% of patients were biologic experienced. At baseline, mean IGA score was 3.3, Psoriasis Area Severity Index (PASI) score was 13.6, and Dermatology Life Quality Index (DLQI) score was 9.6. At follow-up, IGA 0/1, PASI 90, and DLQI 0/1 were achieved by 62.2%, 56.8%, and 54.7% of patients, respectively. Statistically significant improvements were observed in all disease activity scores and PROMs, including the EuroQoL Visual Analogue Scale, Work Productivity and Activity Impairment, Patient Global Assessment, fatigue, skin pain, and itch (p < 0.05). CONCLUSIONS: This real-world study showed that patients with moderate-to-severe psoriasis who received 9-12 months of persistent guselkumab therapy experienced improvements in disease severity and PROMs.
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INTRODUCTION: In clinical trials, treatment with the interleukin-23 inhibitor guselkumab was associated with significantly improved disease severity and patient-reported outcome measures (PROMs) among patients with moderate-to-severe plaque psoriasis. However, limited information is available regarding the real-world effectiveness of guselkumab among patients with psoriasis of mild, moderate, and severe Investigator's Global Assessment (IGA) severities living in the USA and Canada. METHODS: Patients participating in the CorEvitas Psoriasis Registry between 18 July 2017 and 10 July 2019 who met the following criteria were included: IGA ≥ 2 (mild or greater disease severity), initiated guselkumab at a registry (index) visit, and had a registry follow-up visit after persistent guselkumab treatment for 9 to 12 months. Data were collected for patient demographics, disease characteristics, treatment history, disease activity, and PROMs. At follow-up, outcome measure response rates and mean changes from the index visit were calculated. RESULTS: Among 130 patients, the mean age was 50.2 years, 39.2% were female, and 56.9% had a body mass index ≥ 30 kg/m2. Mean psoriasis duration was 17.5 years and 79.2% of patients had previously received one or more biologic therapy. At the index visit, mean IGA, Psoriasis Area Severity Index (PASI), and Dermatology Life Quality Index (DLQI) scores were 3.0, 9.9, and 8.0, respectively. At follow-up, IGA 0/1 and IGA 0 were achieved by 64.6% and 36.2% of patients, respectively. PASI 75, 90, and 100 were achieved by 61.5%, 46.9%, and 36.9% of patients; 55.4% had maintained or achieved DLQI 0/1. Mean improvements were observed in all evaluated disease activity outcomes and PROMs, with all differing significantly from zero except for the percent of work hours missed due to psoriasis. CONCLUSION: In this real-world study, patients with a baseline IGA score ≥ 2 experienced improvements in disease activity and PROMs after 9-12 months of persistent guselkumab treatment.
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INTRODUCTION: Prior studies have demonstrated guselkumab improves disease activity and patient-reported outcomes (PROs) among patients with moderate-to-severe plaque psoriasis. However, the real-world effectiveness of guselkumab across different subgroups [e.g., body mass index (BMI) categories] remains an area of active research. METHODS: This study included patients enrolled in the CorEvitas Psoriasis Registry between July 18, 2017 and March 10, 2020 who had moderate-to-severe psoriasis [Investigator's Global Assessment (IGA) score ≥ 3], initiated guselkumab at a registry visit (index date), and had a follow-up registry visit after persistent guselkumab therapy for 9-12 months. Patients were stratified into three BMI categories: obese (≥ 30 kg/m2), overweight (25- < 30 kg/m2), and underweight/normal weight (< 25 kg/m2). Response rates and mean changes for disease activity outcomes and PROs at follow-up were assessed within each BMI category. RESULTS: Of the 180 patients included in the study, 101 (56%) were obese, 52 (29%) were overweight, and 27 (15%) were underweight/normal weight. Among the obese, overweight, and underweight/normal weight patients, 57%, 58%, and 72%, respectively, achieved an IGA score of 0/1 after 9-12 months of persistent guselkumab treatment. An IGA score of 0 was achieved by 33%, 35%, and 48% of obese, overweight, and underweight/normal weight patients, respectively. A 90% improvement in the Psoriasis Area and Severity Index was achieved by 46%, 46%, and 56% in these respective subgroups. Mean improvements in disease activity and PRO scores were similar among BMI subgroups. CONCLUSION: The results of this real-world study showed improvements in disease severity and several PRO scores within all BMI categories among patients with moderate-to-severe psoriasis treated with guselkumab. These unadjusted findings suggest that obese and overweight patients have comparable absolute improvements to those with lower BMI; however, they may be less likely to achieve relative endpoints. Additional analyses are needed to fully characterize this relationship.
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Anticorpos Monoclonais , Psoríase , Humanos , Anticorpos Monoclonais/uso terapêutico , Índice de Massa Corporal , Sobrepeso/complicações , Magreza/induzido quimicamente , Resultado do Tratamento , Índice de Gravidade de Doença , Psoríase/complicações , Psoríase/tratamento farmacológico , Obesidade/complicações , Imunoglobulina ARESUMO
BACKGROUND: Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world. METHODS AND FINDINGS: 1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure. An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72-1.27; pâ=â0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54-0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39-0.64 for women; HR 0.79, CI 0.62-1.00 for men; pâ=â0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12-2.04; pâ=â0.007). CONCLUSION: EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are advantageous for use of this regimen for initial treatment of HIV-1 infection in resource-limited countries. ATV+DDI+FTC had inferior efficacy and is not recommended as an initial antiretroviral regimen. TRIAL REGISTRATION: www.ClinicalTrials.gov NCT00084136. Please see later in the article for the Editors' Summary.
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Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Internacionalidade , Fármacos Anti-HIV/farmacologia , Coinfecção , Quimioterapia Combinada , Feminino , Seguimentos , Infecções por HIV/microbiologia , Humanos , Masculino , Mycobacterium tuberculosis/fisiologia , Gravidez , Fatores de Tempo , Resultado do Tratamento , Suspensão de TratamentoRESUMO
INTRODUCTION: Guselkumab is approved for the treatment of both moderate-to-severe plaque psoriasis and active psoriatic arthritis (PsA) in the USA. However, little is known about patients initiating guselkumab in a real-world setting. The objective of this study was to describe baseline characteristics among patients with plaque psoriasis who initiated guselkumab at or after enrollment in CorEvitas' Psoriasis Registry. METHODS: Adult patients who initiated guselkumab in the Psoriasis Registry between July 18, 2017 and November 6, 2018 were included. Demographics, disease characteristics, and patient-reported outcome measures (PROMs) were assessed at the time of guselkumab initiation (baseline). Patients with psoriasis were stratified according to the number of previously received biologics (0 to 4+) for comparison. A subset of patients with psoriasis and concomitant dermatologist-diagnosed PsA were stratified into biologic-naïve and biologic-experienced groups. RESULTS: Among 687 patients with psoriasis who initiated guselkumab, biologic-naïve patients and those with four or more prior biologics had the most severe disease and the worst PROM scores at baseline. Among 251 patients with concomitant dermatologist-diagnosed PsA, biologic-naïve patients had more severe disease and worse PROM scores than biologic-experienced patients. CONCLUSIONS: These findings highlight important differences in baseline characteristics according to biologic experience among patients with plaque psoriasis with or without concomitant PsA initiating guselkumab in a real-world setting.
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OBJECTIVES: To examine whether the overall results of the CASTLE study pertain to both genders, we analysed the efficacy and safety of atazanavir/ritonavir and lopinavir/ritonavir in 277 female and 606 male patients in the open-label, multinational trial over 96 weeks. The trial is registered with ClinicalTrials.gov, number NCT00272779. METHODS: Treatment-naive patients aged ≥ 18 years with HIV-1 RNA ≥ 5000 copies/mL were randomized to receive either atazanavir/ritonavir 300/100 mg once daily or lopinavir/ritonavir 400/100 mg twice daily, with fixed-dose tenofovir/emtricitabine 300/200 mg once daily. RESULTS: At week 96, confirmed virological response rates (HIV RNA <50 copies/mL; intent-to-treat analysis) were higher in women and men receiving atazanavir/ritonavir than those receiving lopinavir/ritonavir and lower in women than men in both treatment arms (67% of women and 77% of men on atazanavir/ritonavir and 63% of women and 71% of men on lopinavir/ritonavir). These differences were not observed in the on-treatment analysis. Mean change in CD4 cell count from baseline to week 96 was 265 cells/mm(3) for women and 269 cells/mm(3) for men on atazanavir/ritonavir and 298 cells/mm(3) for women and 286 cells/mm(3) for men on lopinavir/ritonavir. Discontinuation rates were higher in women than men in each treatment arm (22% of women and 15% of men on atazanavir/ritonavir and 29% of women and 18% of men on lopinavir/ritonavir). In women and men, grade 2-4 nausea and diarrhoea were more frequent in the lopinavir/ritonavir group; jaundice and hyperbilirubinaemia occurred more frequently in the atazanavir/ritonavir group. CONCLUSIONS: Once-daily atazanavir/ritonavir is an effective and well-tolerated therapeutic option for women and men with HIV-1 infection. The sex-based differences in response may be due to higher discontinuation rates in women.
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Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Oligopeptídeos/uso terapêutico , Piridinas/uso terapêutico , Pirimidinonas/uso terapêutico , Ritonavir/uso terapêutico , Adulto , Idoso , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Sulfato de Atazanavir , Contagem de Linfócito CD4 , Quimioterapia Combinada , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Lopinavir , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/administração & dosagem , Oligopeptídeos/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Pirimidinonas/administração & dosagem , Pirimidinonas/efeitos adversos , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos , Fatores SexuaisRESUMO
Current guidelines for HIV therapy recommend initiating treatment at a CD4 cell count of 500 cells/mm(3). However, a large proportion of patients with HIV infection begin antiretroviral treatment at a more advanced stage. In the CASTLE study, patients with the most advanced HIV disease (CD4 cell count <50 cells/mm(3)) showed that 78% (45/58) vs. 58% (28/48) of the patients achieved HIV RNA <50 copies/mL in the intent-to-treat analysis at week 96 for atazanavir/ritonavir and lopinavir/ritonavir, respectively. This current sub-analysis of the CASTLE study describes demographics, virologic failure, discontinuations, safety, tolerability, immunologic response, and clinical outcomes for the following baseline strata: CD4 cell count (cells/mm(3)) <50, 50 to <100, 100 to <200, and ≥200 and HIV RNA (copies/mL) <100,000, 100,000 to <500,000, and ≥500,000. In the lowest CD4 cell count stratum (<50 cells/mm(3)), the proportion of discontinuations was 2-fold greater for the lopinavir/ritonavir arm (33%) than for the atazanavir/ritonavir arm (16%) with a similar rate of virologic failure between the two groups. Also in this CD4 cell count stratum, grades 2-4 treatment-related adverse events occurred in 25% in the atazanavir/ritonavir group and in 43% of lopinavir/ritonavir group, and the rate was also higher than in the higher CD4 cell count strata within the lopinavir/ritonavir treatment group (range: 29-34%). Grades 2-4 treatment-related diarrhea and nausea occurred in more patients receiving lopinavir/ritonavir than atazanavir/ritonavir in all strata. The atazanavir/ritonavir group had more grades 2-4 treatment-related jaundice than in the lopinavir/ritonavir group. These results highlight the importance of tolerability of antiretroviral therapy (ART) in the patients at greatest risk of morbidity and mortality when using regimens of similar potency.
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Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/uso terapêutico , Adenina/administração & dosagem , Adenina/análogos & derivados , Adulto , Idoso , Antivirais/uso terapêutico , Sulfato de Atazanavir , Contagem de Linfócito CD4 , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Esquema de Medicação , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Emtricitabina , Feminino , Inibidores da Protease de HIV/administração & dosagem , Humanos , Lopinavir/administração & dosagem , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/administração & dosagem , Organofosfonatos/administração & dosagem , Estudos Prospectivos , Piridinas/administração & dosagem , RNA Viral/sangue , Inibidores da Transcriptase Reversa/administração & dosagem , Ritonavir/administração & dosagem , Tenofovir , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: Psoriasis Longitudinal Assessment and Registry (PSOLAR) was designed in 2007 as the first disease-based registry for patients with psoriasis. OBJECTIVE: The aim of this study was to discuss methodological limitations and post hoc analyses in long-term safety registries using learnings from analyses of a potential safety risk for major adverse cardiovascular events (MACE) in PSOLAR. METHODS: PSOLAR is an international observational study of over 12,000 psoriasis patients that was conducted to meet postmarketing safety commitments for infliximab and ustekinumab. A recent annual review of registry data indicated a potential MACE risk for ustekinumab vs. non-biologics based on prespecified COX model regression analyses, which yielded an adjusted hazard ratio (HR) of 1.533 (95% confidence interval [CI] 1.103-2.131). Therefore, we conducted a comprehensive review of key statistical methodology and implemented post hoc analytical methods to address specific limitations. RESULTS: The following limiting factors were identified: (1) inclusion of both prevalent and incident (new) users of biologics; (2) unanticipated imbalances in patient characteristics between treatment cohorts at baseline; (3) limited availability of relevant clinical data after enrollment; and (4) divergence of characteristics associated with outcomes among comparator groups over time. The analysis was modified to include only incident users, propensity scores were used to weight HRs, and adalimumab was deemed a more clinically appropriate comparator. The revised HR was 0.820 (95% CI 0.532-1.265), indicating no meaningful increase in MACE risk for ustekinumab. CONCLUSION: Our results, which do not support a causal association between ustekinumab exposure and MACE risk, underscore the need for ongoing assessment of analytical methods in long-term observational studies.
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Produtos Biológicos , Psoríase , Adalimumab , Produtos Biológicos/efeitos adversos , Humanos , Infliximab , Estudos Observacionais como Assunto , Psoríase/complicações , Psoríase/tratamento farmacológico , Sistema de Registros , Ustekinumab/uso terapêuticoRESUMO
BACKGROUND: Clinical utilization of genotype resistance testing is evolving. We examined the extent to which HIV care providers requesting genotype resistance tests used the information appropriately and the impact of inappropriate utilization. METHODS: Data from a prospective cohort of HIV-infected patients (the HIV Outpatient Study) were used in the analysis. We analysed the frequency with which patients were prescribed any non-nucleoside reverse transcriptase inhibitor after identification of the K103N mutation in reverse transcriptase and the frequency of prescription of nelfinavir after identification of the D30N mutation in HIV protease; the short-term impact of this action on HIV viral load and CD4+ T-cell count was assessed. RESULTS: Among 441 patients demonstrating either mutation, 18% who were taking the resistant antiretroviral at the time of the test were continued on the medication for >6 months after this finding. In 33% of these instances, prescribers reported these actions were erroneous oversights. For persons taking the resistant antiretroviral at the time of the genotype test, stopping this medication within 6 months of the test produced greater decreases in viral load (-1.35 versus -0.43 log copies/ml, P = 0.025) and a greater likelihood of achieving an undetectable viral load (25.3% versus 7.3%, P = 0.012) at 9 months. Changes in CD4+ T-cell count differed (+22.8 versus -23.0 cells/mm3), but not significantly (P = 0.167). CONCLUSIONS: Following evidence of definitive resistance by genotype testing, a substantial fraction of antiretroviral prescriptions were continued in error leading to an attenuated therapeutic response. These data highlight the need to consider better systems to manage genotype resistance testing data in the clinical setting.
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Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV/efeitos dos fármacos , Adulto , Algoritmos , Fármacos Anti-HIV/farmacologia , Contagem de Linfócito CD4 , Feminino , Genótipo , HIV/genética , Infecções por HIV/imunologia , Protease de HIV/genética , Inibidores da Protease de HIV/farmacologia , Inibidores da Protease de HIV/uso terapêutico , Transcriptase Reversa do HIV/genética , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Nelfinavir/farmacologia , Nelfinavir/uso terapêutico , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Carga ViralRESUMO
BACKGROUND: Treatment-naïve participants were randomized to three antiretroviral strategies (all with nucleoside reverse transcriptase inhibitor [NRTI] background): protease inhibitor (PI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or PI+NNRTI. The strategies were compared for drug resistance at first virologic failure (VF; HIV RNA >1000 copies/mL). The impact of resistance on AIDS or death was determined. METHOD: Drug resistance was determined by genotype. Cox models were used to compare the strategies for VF with resistance and to determine the impact of resistance on AIDS or death. RESULTS: Of 1,360 participants, 866 experienced VF; 226 experienced AIDS or death (median follow-up 5 years). Rates (per 100 personyears) for VF with resistance were 14.9 (PI), 10.8 (NNRTI), and 11.5 (PI+NNRTI); hazard ratio (HR) was 0.78 (95% CI 0.61-0.99) for NNRTI versus PI. Compared to those with no VF, there was a significantly increased risk of AIDS or death for participants with solitary NNRTI resistance (HR 2.31, 95% CI 1.46-3.66) and for those failing with no known resistance (HR 1.78, 95% CI 1.18-2.68). Participants failing with solitary NNRTI resistance and with no resistance had the lowest percent of time on antiretroviral treatment (ART) and the lowest cumulative mean adherence scores. CONCLUSION: For treatment-naïve participants, the risk of AIDS or death is increased for those who failed virologically with solitary NNRTI resistance and those who failed with no known drug resistance compared to those with no virologic failure. Both the lack of ART exposure in nonadherent participants and the development of NNRTI resistance among those who take and fail their ART regimen predict poor clinical outcomes.
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Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV/genética , Terapia Antirretroviral de Alta Atividade , Progressão da Doença , Infecções por HIV/mortalidade , Humanos , Incidência , Cooperação do Paciente , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
INTRODUCTION: The Biosimilars Forum conducted a survey through an independent organization from November 20, 2015 to January 4, 2016 in order to assess current levels of awareness, knowledge, and perceptions of biosimilars among US specialty physicians who already prescribe biologics. The survey was intended to provide a baseline level of knowledge about biosimilars and will be repeated in 2-3 years in order to monitor trends over time. METHODS: A 19-question survey was created by the Biosimilars Forum and was administered by an independent third party. RESULTS: Responses were obtained from 1201 US physicians across specialties that are high prescribers of biologics, including dermatologists, gastroenterologists, hematologist-oncologists, medical oncologists, nephrologists, and rheumatologists. CONCLUSIONS: The results of this survey highlight a significant need for evidence-based education about biosimilars for physicians across specialties. Five major knowledge gaps were identified: defining biologics, biosimilars, and biosimilarity; understanding the approval process and the use of "totality of evidence" to evaluate biosimilars; understanding that the safety and immunogenicity of a biosimilar are comparable to the originator biologic; understanding the rationale for extrapolation of indications; and defining interchangeability and the related rules regarding pharmacy-level substitution. FUNDING: Biosimilars Forum.
Assuntos
Medicamentos Biossimilares/farmacologia , Medicamentos Biossimilares/uso terapêutico , Conhecimentos, Atitudes e Prática em Saúde , Médicos/psicologia , Adulto , Atitude do Pessoal de Saúde , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Estados UnidosRESUMO
Voriconazole, a broad-spectrum triazole antifungal agent, is metabolized by cytochrome P450 (CYP) 2C19 and, to a lesser extent, by CYP3A. Genetic polymorphism of CYP2C19 not only plays a prominent role in its disposition but may also influence potential drug interactions with CYP450 modulators such as ritonavir. This study assessed 2-way drug interactions of voriconazole added on to ritonavir-boosted atazanavir in both CYP2C19 extensive-metabolizer (EM) and poor-metabolizer (PM) healthy subjects. Each subject received voriconazole alone on days 1-3, followed by a 7-day washout. Atazanavir/ritonavir 300/100 mg once daily was given on days 11-30 and voriconazole on days 21-30. Voriconazole doses were 200 mg (400 mg on days 1 and 21) twice daily and 50 mg (100 mg on days 1 and 21) twice daily for CYP2C19 EM and PM subjects, respectively. On coadministration, voriconazole AUC and Cmin decreased by 33% (90%CI, 22%-42%) and 39% (90%CI, 28%-49%), respectively, in CYP2C19 EMs, whereas voriconazole Cmax and AUC increased 4.4-fold (90%CI, 3.6-fold to 5.4-fold) and 5.6-fold (90%CI, 4.5-fold to 7.0-fold), respectively, in PMs. Adding voriconazole resulted in a 20%-30% decrease in atazanavir Cmin in both EMs and PMs. Ritonavir exposure was generally unchanged in either population. The safety and tolerability profiles of the combination were comparable with atazanavir/ritonavir and voriconazole administered alone. The most frequent adverse events with voriconazole were visual disturbance and headache. Coadministration of voriconazole and atazanavir/ritonavir is not recommended unless the benefit/risk to the patient justifies the use of the combination.
Assuntos
Antifúngicos/farmacocinética , Sulfato de Atazanavir/farmacocinética , Citocromo P-450 CYP2C19/genética , Inibidores da Protease de HIV/farmacocinética , Ritonavir/farmacocinética , Voriconazol/farmacocinética , Adolescente , Adulto , Antifúngicos/efeitos adversos , Área Sob a Curva , Sulfato de Atazanavir/efeitos adversos , Combinação de Medicamentos , Interações Medicamentosas , Feminino , Genótipo , Inibidores da Protease de HIV/efeitos adversos , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Ritonavir/efeitos adversos , Voriconazol/efeitos adversos , Adulto JovemRESUMO
BACKGROUND: The prevalence of drug resistance among persons with newly acquired human immunodeficiency virus (HIV) infection is well documented. However, it is unclear to what extent these mutations persist in chronically infected, treatment-naive patients. METHODS: Prevalence of and factors associated with genotypic drug resistance were analyzed retrospectively in a subset of 491 chronically HIV-infected, antiretroviral-naive patients enrolled at 25 cities in the Terry Beirn Community Programs for Clinical Research on Acquired Immune Deficiency Syndrome (AIDS) Flexible Initial Retrovirus Suppressive Therapies trial during 1999-2001. Resistance was defined on the basis of the International AIDS Society 2003 definition, as well as the presence of additional mutations at codons 215 (C/D/E/S) and 69 (A/N/S) in the pol gene. Prevalence of mutations was estimated by use of techniques for stratified random samples. Logistic regression models were used to determine factors associated with resistance. RESULTS: Among the 491 chronically HIV-infected patients (mean CD4 cell count, 269 cells/mm(3); 31% of patients had a prior AIDS diagnosis), 57 (11.6%) had >or=1 resistance mutation, resulting in an estimated prevalence for the cohort of 10.8% (95% confidence interval [CI], 9.5%-12.1%). The prevalence was 8.8% if the 118I mutation was excluded. By drug class, the estimated prevalence of mutations conferring resistance to nucleoside reverse-transcriptase inhibitors was 7.8%, and the prevalence was 3.0% for nonnucleoside reverse-transcriptase inhibitors and 0.7% for protease inhibitors. In a multiple logistic regression analysis, non-Hispanic white subjects were twice as likely than African American subjects to have resistance (odds ratio [OR], 2.1; 95% CI, 1.1-4.1; P=.03), and there was a 40% increase per year in prevalence of mutations by later year of enrollment (OR, 1.4; 95% CI, 1.0-2.1; P=.05). CONCLUSIONS: These results demonstrate the persistence of drug resistance mutations in chronically HIV-infected patients and an increasing prevalence of resistance over time, and they support genotyping of virus at baseline for chronically HIV-infected patients.
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Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Adulto , Feminino , HIV-1/genética , HIV-1/fisiologia , Humanos , Modelos Logísticos , Masculino , Análise Multivariada , Mutação , Razão de Chances , Fatores de TempoRESUMO
BACKGROUND: The impact of boosted protease inhibitor therapy on inflammatory and cardiovascular biomarker levels in treatment-naive HIV-infected patients remains unclear and may differ between agents. Unconjugated bilirubin elevation, which favourably affects vascular biomarkers and cardiovascular disease risk in Gilbert's syndrome, occurs with atazanavir. METHODS: CASTLE was a 96-week study comparing efficacy and safety in treatment-naive HIV-1-infected patients randomized to atazanavir/ritonavir (ATV/r) versus lopinavir/ritonavir (LPV/r), each in combination with tenofovir disoproxil fumarate/emtricitabine. In this substudy, fasting plasma tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), high sensitivity C-reactive protein (hs-CRP), plasminogen activator inhibitor-1 (PAI-1) and fibrinogen were assessed at baseline, week 12, 24, 48 and 96. Impact of grade 3-4 hyperbilirubinaemia on biomarkers was examined. RESULTS: CASTLE demonstrated similar efficacy in both treatment arms with higher rates of hyperbilirubinaemia on ATV/r and elevated lipids on LPV/r. In this substudy (n=224), patterns of biomarker expression were similar between the ATV/r and LPV/r groups and between-group differences in biomarker percentage change from baseline were not significant at 48 and/or 96 weeks. Hyperbilirubinaemia did not influence fasting biomarker expression. CONCLUSIONS: No significant differences were noted between ATV/r and LPV/r for biomarker percentage changes from baseline. Furthermore, no association was found between total bilirubin levels and biomarker expression.
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Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , HIV-1 , Adulto , Terapia Antirretroviral de Alta Atividade , Biomarcadores/sangue , Quimioterapia Combinada , Feminino , Infecções por HIV/diagnóstico , HIV-1/efeitos dos fármacos , Humanos , Masculino , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Data on the effectiveness of second-line combination antiretroviral therapy (cART) are limited. We evaluated virologic outcomes of second cART in a multicenter cohort collaboration. The study population initiated first and second modern cART between 1996 and 2010. The second cART required a switch in at least the anchor agent of first cART. We evaluated time to virologic failure of second cART and factors associated with greater risk of failure using multivariable Cox proportional hazards models. Of 488 patients who switched to second-line cART, 67% were black and 32% were women. The median HIV-1 RNA at second cART initiation was 9,565 copies/ml [interquartile range (IQR); 123, 94,108]. The time to virologic failure of second cART was longer if HIV-1 RNA was undetectable at switch (p=0.001), although 12% and 17% of patients with undetectable and detectable HIV-1 RNA experienced virologic failure within 6 months of second cART initiation, respectively. A lower CD4 cell count at second cART initiation was associated with a greater risk of virologic failure. Failure rates decreased in more recent calendar years [adjusted relative hazard of 0.40 comparing 2008 to 2010 with 1996 to 1998 (95% confidence interval; 0.15, 1.00)]; however, type of anchor agent was not associated with failure. In conclusion, virologic failure of second cART was less likely if patients switched with undetectable HIV-1 RNA, although risk of early failure was similar. The effectiveness of second cART regimens improved over calendar time and was independent of the anchor agent in the regimen.
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Fármacos Anti-HIV/administração & dosagem , Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , HIV-1/isolamento & purificação , Carga Viral , Adulto , População Negra , Contagem de Linfócito CD4 , Estudos de Coortes , Feminino , Humanos , Masculino , RNA Viral/sangue , Fatores de Tempo , Resultado do Tratamento , População BrancaRESUMO
BACKGROUND: It is unknown whether HIV-positive patients experiencing virologic failure (VF) on boosted-PI (PI/r) regimens without drug resistant mutations (DRM) by standard genotyping harbor low-level PI resistant variants. CASTLE compared the efficacy of atazanavir/ritonavir (ATV/r) with lopinavir/ritonavir (LPV/r), each in combination with TVD in ARV-naïve subjects. OBJECTIVE: To determine if VF on an initial PI/r-based regimen possess low-level resistant variants that may affect a subsequent PI-containing regimen. METHODS/RESULTS: Patients experiencing VF on a Tenofovir/Emtricitabine+PI/r regimen were evaluated by ultra deep sequencing (UDS) for mutations classified/weighted by Stanford HIVdb. Samples were evaluated for variants to 0.4% levels. 36 VF subjects were evaluated by UDS; 24 had UDS for PI and RT DRMs. Of these 24, 19 (79.2%) had any DRM by UDS. The most common UDS-detected DRM were NRTI in 18 subjects: M184V/I (11), TAMs(7) & K65R(4); PI DRMs were detected in 9 subjects: M46I/V(5), F53L(2), I50V(1), D30N(1), and N88S(1). The remaining 12 subjects, all with VLs<10,000, had protease gene UDS, and 4 had low-level PI DRMs: F53L(2), L76V(1), I54S(1), G73S(1). Overall, 3/36(8.3%) subjects had DRMs identified with Stanford-HIVdb weights >12 for ATV or LPV: N88S (at 0.43% level-mutational load 1,828) in 1 subject on ATV; I50V (0.44%-mutational load 110) and L76V (0.52%-mutational load 20) in 1 subject each, both on LPV. All VF samples remained phenotypically susceptible to the treatment PI/r. CONCLUSION: Among persons experiencing VF without PI DRMs with standard genotyping on an initial PI/r regimen, low-level variants possessing major PI DRMs were present in a minority of cases, occurred in isolation, and did not result in phenotypic resistance. NRTI DRMs were detected in a high proportion of subjects. These data suggest that PIs may remain effective in subjects experiencing VF on a PI/r-based regimen when PI DRMs are not detected by standard or UDS genotyping.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Infecções por HIV/genética , HIV-1/efeitos dos fármacos , Sequenciamento de Nucleotídeos em Larga Escala , Mutação/genética , Carga Viral/efeitos dos fármacos , Sulfato de Atazanavir , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Inibidores da Protease de HIV/uso terapêutico , Humanos , Lopinavir/uso terapêutico , Mutação/efeitos dos fármacos , Oligopeptídeos/uso terapêutico , Piridinas/uso terapêutico , Ritonavir/uso terapêutico , Carga Viral/genéticaRESUMO
CASTLE was a randomized 96-week study that demonstrated that atazanavir/ritonavir (ATV/r) was noninferior to lopinavir/ritonavir (LPV/r) in treatment-naïve HIV-infected patients. Analyses were carried out among patients who received ATV/r in the CASTLE study to better understand the clinical significance of unconjugated hyperbilirubinemia associated with administration of boosted ATV. Hyperbilirubinemia was defined as total bilirubin (conjugated and unconjugated) elevation greater than 2.5 times the upper limit of normal (grade 3-4). Patients in the ATV/r arm were assessed based on the presence or absence of hyperbilirubinemia through week 96. Analyses included number of confirmed virologic responders (CVR; HIV RNA<50 copies per milliliter), impact of hyperbilirubinemia on symptoms, elevations in liver enzymes, patient quality of life, and medication adherence. Through 96 weeks in the CASTLE study, 44% of patients who received ATV/r had hyperbilirubinemia at any time point, and between 12.5% and 21.6% had hyperbilirubinemia at any single study visit. At 96 weeks, 74% of patients overall and 84% and 69% of patients with and without hyperbilirubinemia, respectively, achieved CVR. Symptoms of jaundice or scleral icterus occurred in 5% of patients overall and in 11% with hyperbilirubinemia and 0% without hyperbilirubinemia. Four percent of patients with and 3% of patients without hyperbilirubinemia had grade 3-4 elevations in liver transaminases. Less than 1% of patients discontinued treatment due to hyperbilirubinemia. There were no differences in quality of life or adherence between patients with or without hyperbilirubinemia. In the CASTLE study, hyperbilirubinemia observed in the ATV/r group did not negatively impact clinical outcomes in HIV-infected patients.