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1.
J Pharm Biomed Anal ; 207: 114417, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34678556

RESUMO

Analytical procedure development for quantifying 10 impurities in Tenofovir Alafenamide Fumarate (TAF) tablets was a challenge for analytical and formulation researchers. The aim of this paper was to develop a robust, regulatory-flexible, application-specific Ultra Performance Liquid Chromatography (UPLC) analytical procedure using the Analytical Lifecycle Management (ALM) and the Analytical Quality by Design (AQbD) for the estimation of the TAF tablets. In this work, the Analytical Target Profile (ATP) for the analytical procedure and the Critical Analytical Attributes (CAAs) were identified. Through the risk assessment studies, the high-risk analytical conditions were found, and they were screened and optimized by the Design of Experiment (DoE) to obtain the Design Space (DS) and identify the working point. The prediction intervals were used to examine the robustness of the analytical procedure. And the procedure performance qualification and the continued procedure performance verification were used to ensure routine application of analytical procedure. Finally, the 10 impurities were separated within 20 min by UPLC. The success of this study demonstrates the usefulness of using ALM and AQbD for analytical procedure development and provides a reference for the analytical procedure development for other drugs.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Adenina/uso terapêutico , Alanina , Fármacos Anti-HIV/uso terapêutico , Cromatografia Líquida , Fumaratos , Infecções por HIV/tratamento farmacológico , Humanos , Comprimidos , Tenofovir/análogos & derivados
2.
Trials ; 22(1): 831, 2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34814933

RESUMO

BACKGROUND: Remdesivir is a novel broad-spectrum antiviral therapeutic with activity against several viruses that cause emerging infectious diseases. The purpose of this study is to explore how commonly utilized antiretroviral therapy (tenofovir disoproxil fumarate/lamivudine [TDF/3TC] and atazanavir/ritonavir [ATV/r]) influence plasma and intracellular concentrations of remdesivir. METHODS: This is an open-label, randomized, fixed sequence single intravenous dosing study to assess pharmacokinetic interactions between remdesivir and TDF/3TC (Study A, crossover design) or TDF/3TC plus ATV/r (Study B). Healthy volunteers satisfying study entry criteria will be enrolled in the study and randomized to either Study A; N=16 (Sequence 1 or Sequence 2) or Study B; N=8. Participants will receive standard adult doses of antiretroviral therapy for 7 days and a single 200mg remdesivir infusion administered over 60 min. Pharmacokinetic blood sampling will be performed relative to the start of remdesivir infusion; predose (before the start of remdesivir infusion) and 30 min after the start of remdesivir infusion. Additional blood samples will be taken at 2, 4, 6, 12, and 24 h after the end of remdesivir infusion. DISCUSSION: This study will characterize the pharmacokinetics of remdesivir from a typical African population in whom clinical use is anticipated. Furthermore, this study will deliver pharmacokinetic datasets for remdesivir drug concentrations and demographic characteristics which could support pharmacometric approaches for simulation of remdesivir treatment regimens in patients concurrently using tenofovir/lamivudine and/or atazanavir/ritonavir. TRIAL REGISTRATION: ClinicalTrials.gov NCT04385719 . Registered 13 May 2020.


Assuntos
Fármacos Anti-HIV , Lamivudina , Monofosfato de Adenosina/análogos & derivados , Adulto , Alanina/análogos & derivados , Fármacos Anti-HIV/efeitos adversos , Sulfato de Atazanavir/efeitos adversos , Voluntários Saudáveis , Humanos , Lamivudina/efeitos adversos , Oligopeptídeos , Piridinas/efeitos adversos , Ritonavir/efeitos adversos , Tenofovir/efeitos adversos , Uganda
3.
Front Public Health ; 9: 718013, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34760861

RESUMO

Objectives: To assess the effects of the National Centralized Drug Purchasing Pilot Program on nucleos(t)ide analogs (NAs) in Shenzhen city. Methods: Drugs procurement records in medical institutions were analyzed covering the period from January 2018 to December 2019. An interrupted time series (ITS) analysis was used to evaluate the impact of the "4+7" pilot policy on NAs in Shenzhen city. The outcome measures were usage volume, expenditures, daily cost, and distribution structure of NAs. Findings: After the introduction of the "4+7" pilot policy, the defined daily doses (DDDs) of NA drugs increased by 76.48%, the expenditures and defined daily dose cost (DDDc) of NAs decreased by 45.43 and 69.08%, respectively. The proportion of winning products in Entecavir and Tenofovir Fumarate DDDs was increased by 64.21 and 19.20%, respectively. The post-intervention period witnessed a significant increase in the regression level for NAs DDDs (level coefficient: ß2 = 631.87, p < 0.05). The expenditures (trend coefficient: ß3 = 392.24, p < 0.05) and DDDc (level coefficient: ß2 = -6.17, p < 0.001; trend coefficient: ß3 = -0.21, p < 0.05) of NAs showed decreasing trend in the post-intervention period. The expenditures of original products and generic products both showed a decreasing trend in the post-intervention period (trend coefficient: ß3 = -372.78, p < 0.05, trend coefficient: ß3 = -130.78, p < 0.05, respectively). The DDDc of original products in the policy-related varieties was a significant decrease in the regression slope and level (level coefficient: ß2 = -2.18, p < 0.05; trend coefficient: ß3 = -0.32, p < 0.01). Conclusion: After the implementation of the"4+7" policy, the DDDc of NAs decreased, the accessibility of policy-related drugs was improved, and the usage of generic medicine was promoted.


Assuntos
Gastos em Saúde , Preparações Farmacêuticas , Análise de Séries Temporais Interrompida , Projetos Piloto , Tenofovir
4.
Medicine (Baltimore) ; 100(39): e27417, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34596169

RESUMO

ABSTRACT: This study evaluated the clinical implications of hepatitis B surface antigen quantification (qHBs Ag) in chronic hepatitis B (CHB) patients treated with entecavir (ETV) or tenofovir disoproxil fumarate (TDF) and identified the association between qHBs Ag and the risk of hepatocellular carcinoma (HCC) in these patients.Between January 2007 and December 2018, the qHBs Ag and clinical data of 183 CHB patients who initially received ETV (n = 45, 24.6%) or TDF (n = 138, 75.4%) were analyzed.The mean follow-up period of the 183 CHB patients was 45.3 months, of which 59 (32.2%) patients showed a reduction in qHBs Ag by >50% after 1 year of antiviral treatment (ETV or TDF). The HCC development (P = .179) or qHBs Ag reduction (P = .524) were similar in the ETV and TDF groups. Patients with a ≥50% decrease in qHBs Ag had a significantly lower incidence of HCC or decompensated cirrhosis complications (P = .005). Multivariate analysis showed that a >50% reduction of qHBs Ag (hazard ratio 0.085, P = .018) and the presence of cirrhosis (hazard ratio 3.32, P = .016) were independent factors predicting the development of HCC.Patients whose qHBs Ag value decreased >50% at 1 year after antiviral treatment for CHB showed a significant decrease in HCC or decompensated cirrhosis events. A reduction in qHBs Ag could be used as a predictive factor of HCC development or critical complications in CHB patients treated with TDF or ETV.


Assuntos
Antivirais/uso terapêutico , Guanina/análogos & derivados , Antígenos de Superfície da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Tenofovir/uso terapêutico , Adulto , Idoso , Carcinoma Hepatocelular/etiologia , Feminino , Guanina/uso terapêutico , Hepatite B Crônica/complicações , Humanos , Neoplasias Hepáticas/etiologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco
5.
Zhonghua Gan Zang Bing Za Zhi ; 29(9): 830-836, 2021 Sep 20.
Artigo em Chinês | MEDLINE | ID: mdl-34638200

RESUMO

Objective: To mine the signals of adverse drug reaction (ADR) of entecavir and tenofovir by using the US FDA Adverse Event Reporting System (FAERS) database, so as to provide reference for the safe clinical use of these two drugs. Methods: Reporting odds ratio (ROR) and proportion of report ratio (PRR) method were used to conduct data mining on the 26 quarterly reports of the US Food and Drug Administration Adverse Event Reporting System (FAERS) database between the fourth quarter of 2012 to the first quarter of 2019. The ADR descriptive terminology in the report were standardized by using the World Health Organization Adverse Reaction Terminology (System-Organ Class). ROR and PRR methods common signals were screened. Results: 104 and 187 signals of ADR of entecavir and tenofovir dipivoxil were obtained by ROR and PRR methods. The main screened system-organ classes affected by signals of ADR of entecavir were systemic damage, hepatobiliary system damage, and urinary system damage. The main screened system-organ classes affected by signals of ADR of tenofovir were urinary system damage, skeletal and musculoskeletal system damage, and metabolic and nutritional disorders. Conclusion: The mining signals of adverse drug reaction of entecavir and tenofovir dipivoxil indicate that these two drugs can cause female reproductive system damage, fetal abnormalities, neonatal and infant abnormalities, and male reproductive system damage. However, in addition to the above-mentioned ADR, the ADR instruction manual excludes entecavir and tenofovir dipivoxil primarily for respiratory and visual system damage, and the tenofovir disoproxil primarily for skin and appendage damage, and hearing and vestibular function damage. Therefore, in clinical medication management, it is suggested to pay close attention to the choice of drugs for special population infected with HBV, monitor possible ADR during medication course, and provide pharmacological monitoring to achieve personalized medication.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Guanina/análogos & derivados , Humanos , Recém-Nascido , Masculino , Tenofovir/efeitos adversos , Estados Unidos/epidemiologia , United States Food and Drug Administration
6.
BMJ Open ; 11(10): e050116, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34610939

RESUMO

INTRODUCTION: Substantial improvements in viral suppression among people living with HIV (PLHIV) are needed to end the HIV epidemic, requiring extensive scale-up of low-cost HIV monitoring services. Point-of-care (POC) tests for monitoring antiretroviral therapy (ART) adherence and viral load (VL) may be efficient and effective tools for real-time clinical decision making. We aim to evaluate the effects of a combined intervention of POC ART adherence and VL testing compared with standard-of-care on ART adherence, viral suppression and retention at 6 and 18 months post-ART initiation among PLHIV. METHODS AND ANALYSIS: Simplifying TREAtment and Monitoring for HIV (STREAM HIV) is a two-arm, open-label, randomised controlled superiority trial of POC urine tenofovir (POC TFV) and VL monitoring in PLHIV. We aim to enrol 540 PLHIV initiating a first-line ART regimen at a public HIV clinic in South Africa. Participants will be randomised 1:1 to the intervention or control arm. Intervention arm participants will receive monthly POC TFV testing for the first 5 months and POC VL testing at months 6 and 12. Intervention arm participants will also receive reflex POC TFV testing if viraemic and reflex HIV drug resistance testing for those with viraemia and detectable TFV. Control arm participants will receive standard-of-care, including laboratory-based VL testing at months 6 and 12. Primary outcomes include ART adherence (TFV-diphosphate concentration) at 6 months and viral suppression and retention at 18 months. Secondary outcomes include viral suppression and retention at 6 months, TFV-diphosphate concentration at 18 months, cost and cost-effectiveness of the intervention and acceptability of the intervention among PLHIV and healthcare workers. ETHICS AND DISSEMINATION: STREAM HIV has received ethical approval from the University of Washington Institutional Review Board (STUDY00007544), University of KwaZulu-Natal Biomedical Research Ethics Committee (BREC/00000833/2019) and Division of AIDS Regulatory Support Center (38509). Findings will be disseminated at international conferences and in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04341779.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Fármacos Anti-HIV/uso terapêutico , Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Humanos , Sistemas Automatizados de Assistência Junto ao Leito , Testes Imediatos , Ensaios Clínicos Controlados Aleatórios como Assunto , África do Sul , Tenofovir/uso terapêutico , Carga Viral
7.
BMJ Open ; 11(10): e049104, 2021 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-34697111

RESUMO

INTRODUCTION: Combination antiviral therapy of nucleos(t)ide analogue (NA) and pegylated interferon alpha (peg-IFN alpha) decrease hepatitis B virus (HBV) surface antigen (HBsAg) levels to achieve functional cure and improve long-term prognosis in chronic hepatitis B patients. However, for hepatitis B-related liver fibrosis, studies on combination of these two medicines are limited. This study was designed to compare the efficacy between peg-IFN alpha combined with tenofovir (TDF) and TDF monotherapy for the clearance of HBsAg in NA-experienced patients with HBV-related liver fibrosis. METHODS AND ANALYSIS: This study was designed to be a prospective, multicentre, open, randomised controlled study. A total of 272 patients with HBV-related liver fibrosis will be randomised into the combination therapy group or the monotherapy group at a 1:1 ratio. Participants in the combination group will receive subcutaneous injections of peg-IFN alpha 180 µg per week for 48 weeks combined with oral TDF 300 mg daily. Participants in the monotherapy group will receive 300 mg oral TDF daily alone. All participants will undergo long-term treatment with TDF and will be followed up at the outpatient department for 144 weeks after randomisation. Clinical symptoms, laboratory tests and examination indicators will be collected at each follow-up time point, and adverse events will be recorded. The primary endpoint is serological clearance rate of HBsAg at 48 weeks. ETHICS AND DISSEMINATION: The ethics committee of the Third Affiliated Hospital at Sun Yat-sen University approved this study (Approval Number: (2020)02-183-01). The results of the study will be presented at relevant meetings and published in an appropriate journal after the completion of the trial and the analysis of the data. TRIAL REGISTRATION NUMBER: NCT04640129.


Assuntos
Antígenos de Superfície da Hepatite B , Hepatite B Crônica , Antivirais/uso terapêutico , DNA Viral , Quimioterapia Combinada , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Humanos , Interferon-alfa/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Estudos Multicêntricos como Assunto , Polietilenoglicóis/uso terapêutico , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Tenofovir/uso terapêutico , Resultado do Tratamento
8.
PLoS One ; 16(10): e0258229, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34610052

RESUMO

BACKGROUND/AIMS: We measured the association between underlying chronic hepatitis B (CHB) and antiviral use with infection rates among patients who underwent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing. METHODS: In total, 204,418 patients who were tested for SARS-CoV-2 between January and June 2020 were included. For each case patient (n = 7,723) with a positive SARS-CoV-2 test, random controls (n = 46,231) were selected from the target population who had been exposed to someone with coronavirus disease 2019 (COVID-19) but had a negative SARS-CoV-2 test result. We merged claim-based data from the Korean National Health Insurance Service database collected. Primary endpoints were SARS-CoV-2 infection and severe clinical outcomes of COVID-19. RESULTS: The proportion of underlying CHB was lower in COVID-19 positive patients (n = 267, 3.5%) than in COVID-19 negative controls (n = 2482, 5.4%). Underlying CHB was associated with a lower SARS-CoV-2 positivity rate, after adjusting for comorbidities (adjusted odds ratio [aOR] 0.65; 95% confidence interval [CI], 0.57-0.74). Among patients with confirmed COVID-19, underlying CHB tended to confer a 66% greater risk of severe clinical outcomes of COVID-19, although this value was statistically insignificant. Antiviral treatment including tenofovir and entecavir was associated with a reduced SARS-CoV-2 positivity rate (aOR 0.49; 95% CI, 0.37-0.66), while treatment was not associated with severe clinical outcomes of COVID-19. CONCLUSIONS: Underlying CHB and antiviral agents including tenofovir decreased susceptibility to SARS-CoV-2 infection. HBV coinfection did not increase the risk of disease severity or lead to a worse prognosis in COVID-19.


Assuntos
COVID-19/patologia , Hepatite B Crônica/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/uso terapêutico , COVID-19/complicações , COVID-19/epidemiologia , COVID-19/virologia , Estudos de Casos e Controles , Estudos de Coortes , Bases de Dados Factuais , Feminino , Guanina/análogos & derivados , Guanina/uso terapêutico , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , República da Coreia/epidemiologia , Risco , Índice de Gravidade de Doença , Tenofovir/uso terapêutico , Adulto Jovem
9.
Nat Commun ; 12(1): 5458, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34531390

RESUMO

Treatment and prevention of human immunodeficiency virus type one (HIV-1) infection was transformed through widespread use of antiretroviral therapy (ART). However, ART has limitations in requiring life-long daily adherence. Such limitations have led to the creation of long-acting (LA) ART. While nucleoside reverse transcriptase inhibitors (NRTI) remain the ART backbone, to the best of our knowledge, none have been converted into LA agents. To these ends, we transformed tenofovir (TFV) into LA surfactant stabilized aqueous prodrug nanocrystals (referred to as NM1TFV and NM2TFV), enhancing intracellular drug uptake and retention. A single intramuscular injection of NM1TFV, NM2TFV, or a nanoformulated tenofovir alafenamide (NTAF) at 75 mg/kg TFV equivalents to Sprague Dawley rats sustains active TFV-diphosphate (TFV-DP) levels ≥ four times the 90% effective dose for two months. NM1TFV, NM2TFV and NTAF elicit TFV-DP levels of 11,276, 1,651, and 397 fmol/g in rectal tissue, respectively. These results are a significant step towards a LA TFV ProTide.


Assuntos
Adenina/análogos & derivados , Alanina/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Organofosfatos/farmacologia , Pró-Fármacos/farmacologia , Tenofovir/análogos & derivados , Tenofovir/farmacologia , Adenina/química , Adenina/farmacocinética , Adenina/farmacologia , Alanina/química , Alanina/farmacocinética , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Estabilidade de Medicamentos , Feminino , Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/fisiologia , Humanos , Masculino , Nanopartículas/química , Organofosfatos/química , Organofosfatos/farmacocinética , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Ratos Sprague-Dawley , Tenofovir/química , Tenofovir/farmacocinética , Equivalência Terapêutica
10.
BMC Infect Dis ; 21(1): 910, 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488664

RESUMO

BACKGROUND: As cardiovascular diseases represent the main cause of non-AIDS related death in people living with HIV (PLWH) with undetectable viral load, we evaluated lipid profile, weight gain and calculated cardiovascular risk change after switching from tenofovir disoproxil fumarate (TDF)-based regimens to tenofovir alafenamide (TAF)-based regimens. METHODS: For this retrospective study, we selected HIV-infected patients with suppressed viral load who fitted in one of the two groups below: First group (TDF/TDF): Patients treated continuously with TDF-based regimens. Second group (TDF/TAF): Patients treated with TDF-regimens during at least 6 months then switched to TAF-regimens while maintaining other drugs unchanged. Available data included date of birth, gender, ethnicity, lymphocyte T CD4+ count, weight, height, blood pressure, current/ex/non-smoker, diabetes mellitus, familial cardiovascular event, lipid profile, duration and nature of antiretroviral therapy. Lipid parameters, weight and calculated cardiovascular risk using 5-year reduced DAD score algorithm [Friis-Møller et al. in Eur J Cardiovasc Prev Rehabil 17:491-501, 2010] were analyzed in each groups. RESULTS: Switching from TDF to TAF resulted in a significant increase in triglycerides levels, total cholesterol and HDL cholesterol. LDL cholesterol and total cholesterol/HDL ratio did not show significant changes. Calculated cardiovascular risk increased after switch from TDF- to TAF-based therapy. CONCLUSIONS: Together with favorable outcomes at the bone and kidney levels, potential negative impact of TAF on lipid profile should be included in the reflection to propose the most appropriate and tailored ARV treatment.


Assuntos
Fármacos Anti-HIV , Doenças Cardiovasculares , Infecções por HIV , Alanina , Fármacos Anti-HIV/efeitos adversos , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Fatores de Risco de Doenças Cardíacas , Humanos , Lipídeos , Estudos Retrospectivos , Fatores de Risco , Tenofovir/análogos & derivados , Tenofovir/uso terapêutico , Ganho de Peso
11.
Aliment Pharmacol Ther ; 54(9): 1134-1149, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34587302

RESUMO

BACKGROUND: Tenofovir amibufenamide (TMF) can provide more efficient delivery than tenofovir disoproxil fumarate (TDF). AIM: To compare the efficacy and safety of TMF and TDF for 48 weeks in patients with chronic hepatitis B (CHB). METHODS: We performed a randomised, double-blind, non-inferiority study at 49 sites in China. Patients with CHB were assigned (2:1) to receive either 25 mg TMF or 300 mg TDF with matching placebo. The primary efficacy endpoint was the proportion of patients with hepatitis B virus (HBV) DNA less than 20 IU/mL at week 48. We also assessed safety, particularly bone, renal and metabolic abnormalities. RESULTS: We randomised 1002 eligible patients. The baseline characteristics were well balanced between groups. After a median 48 weeks of treatment, the non-inferiority criterion was met in all analysis sets. In the HBeAg-positive population, 50.2% of patients receiving TMF and 53.7% receiving TDF achieved HBV DNA less than 20 IU/mL. In the HBeAg-negative population, 88.9% and 87.8%, respectively, achieved HBV DNA less than 20 IU/mL in the TMF and TDF groups. Patients receiving TMF had significantly less decrease in bone mineral density at both hip (P < 0.001) and spine (P < 0.001), and a smaller increase in serum creatinine at week 48 (P < 0.05). Other safety results were similar between groups. CONCLUSION: TMF was non-inferior to TDF in terms of anti-HBV efficacy and showed better bone and renal safety. (NCT03903796).


Assuntos
Hepatite B Crônica , Antivirais/efeitos adversos , DNA Viral , Antígenos E da Hepatite B , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Humanos , Tenofovir/efeitos adversos , Resultado do Tratamento , Carga Viral
12.
Clin Drug Investig ; 41(11): 955-965, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34546533

RESUMO

BACKGROUND AND OBJECTIVE: Many people living with HIV (PLWH) on stable tenofovir disoproxil fumarate (TDF)-containing regimens have switched to tenofovir alafenamide (TAF), despite the potential lipid-lowering effect of TDF. We aimed to assess the impact of switching from TDF to TAF on lipids in real-world clinical practice. METHODS: PLWH prescribed TDF for ≥ 4 weeks who switched to TAF were identified in the OPERA cohort. Patterns of dyslipidemia were compared before and after switch based on NCEP ATPIII guidelines. Elevated 10-year risk of atherosclerotic cardiovascular disease (ASCVD ≥ 7.5%) and statin use were assessed. RESULTS: Among 6423 PLWH switched from TDF to TAF, the proportion with dyslipidemia/severe dyslipidemia observed after switch from TDF to TAF increased statistically significantly (p < 0.0001) with total cholesterol (5-10%), low-density lipoprotein cholesterol (16-23%), and triglycerides (21-27%), but decreased statistically significantly with high-density lipoprotein cholesterol (35-30%, p < 0.0001). These patterns of dyslipidemia persisted in sensitivity analyses restricted to PLWH who maintained all other antiretrovirals (N = 4328) or stratified by pharmaco-enhancer use before and after switch. An elevated ASCVD risk was detected in 29% before and 31% after switch. As many as 59% of PLWH with an elevated ASCVD risk were not prescribed a statin after switch from TDF to TAF. CONCLUSIONS: In this large, diverse population of PLWH in the USA, the switch from TDF to TAF was associated with development of less favorable lipid profiles, regardless of pharmaco-enhancers or third-agent use. Statins remained underutilized after a switch from TDF to TAF.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Inibidores de Hidroximetilglutaril-CoA Redutases , Alanina , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipídeos , Estudos Retrospectivos , Tenofovir/análogos & derivados , Tenofovir/uso terapêutico
13.
Medicine (Baltimore) ; 100(38): e27330, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34559154

RESUMO

ABSTRACT: Approximately 50% of people living with HIV (PLWH) in the United States are ≥50 years old. Clinical trials of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) demonstrated potent efficacy and favorable safety in older PLWH; however, real-world data would be useful to validate these results.Retrospective cohort study.We evaluated records from PLWH aged ≥50 years at the Orlando Immunology Center who were switched to B/F/TAF between February 2018 and August 2019. Eligible patients had baseline HIV-1 RNA <50 copies/mL and 48 weeks of follow-up data. The primary endpoint was maintenance of HIV-1 RNA <50 copies/mL at Week 48. The impact of switching to B/F/TAF on drug-drug interactions (DDIs) and safety parameters were also assessed.Three-hundred and fifty patients met inclusion criteria, median age was 57 years, 20% were women, and 43% were non-White. Fifty-five percent of patients switched from integrase inhibitor-based regimens; the most common reason for switch was simplification. At Week 48, 330 (94%) patients maintained an HIV-1 RNA <50 copies/mL and 20 (6%) had an HIV-1 RNA between 50 and 400 copies/mL. One-hundred and forty potential DDIs were identified in 121 (35%) patients taking a boosting agent or rilpivirine at baseline that were resolved after switching to B/F/TAF. Treatment-related adverse events occurred in 51 (15%) patients (all Grade 1-2) and led to 8 discontinuations.In this real-world cohort, switching to B/F/TAF was associated with maintenance of virologic control, and avoidance of DDIs in a large proportion of patients. These data support use of B/F/TAF as a treatment option in older PLWH.


Assuntos
Alanina/uso terapêutico , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Piperazinas/uso terapêutico , Piridonas/uso terapêutico , Tenofovir/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Combinação de Medicamentos , Substituição de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
14.
Ann Agric Environ Med ; 28(3): 458-462, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34558270

RESUMO

INTRODUCTION: Epidemiological data indicate that one-third of the world's population have serological markers of hepatitis B virus infection. Hepatic steatosis is often observed in patients with chronic liver diseases. The exact mechanisms of hepatic steatosis progression and the efficacy of antiviral therapy in patients with CHB and hepatic steatosis are not yet fully understood. OBJECTIVE: The aim of the study was to investigate the LDLR concentration and degree of hepatic fibrosis and hepatic steatosis in patients with chronic hepatitis B infection during tenofovir disoproxil fumarate therapy. MATERIAL AND METHODS: The study group consisted of 54 patients with CHB. The LDLR concentration, assessment of the degree of hepatic fibrosis, hepatic steatosis, total cholesterol, low density lipoprotein, high density lipoprotein and triglyceride concentrations, were assessed at the beginning of therapy, 6 months later, and 12 months after commencement of therapy. The control group consisted of 18 healthy individuals. RESULTS: The mean LDLR concentration in the studied groups was statistically significantly lower (p<0.05) than in the controls. The antiviral therapy based on TDF had no influence on the LDLR concentration and HBsAg level. CONCLUSIONS: The results indicate a statistically significant lower(p<0.05) concentration of LDLR in patients with chronic hepatitis B infection. Negative correlations between HBsAg level and LDLR concentration in patients with chronic HBV, at all stages of the study may indicate, that HBsAg protects hepatocytes from LDL accumulation.


Assuntos
Antivirais/administração & dosagem , Fígado Gorduroso/sangue , Hepatite B Crônica/tratamento farmacológico , Cirrose Hepática/sangue , Receptores de LDL/sangue , Tenofovir/administração & dosagem , Adulto , Idoso , Fígado Gorduroso/etiologia , Fígado Gorduroso/virologia , Feminino , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/genética , Vírus da Hepatite B/metabolismo , Hepatite B Crônica/sangue , Hepatite B Crônica/complicações , Hepatite B Crônica/virologia , Humanos , Lipoproteínas HDL/sangue , Cirrose Hepática/etiologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangue
15.
Cells ; 10(9)2021 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-34571970

RESUMO

Current treatment options for patients infected with hepatitis B virus (HBV) are suboptimal, because the approved drugs rarely induce cure due to the persistence of the viral DNA genome in the nucleus of infected hepatocytes, and are associated with either severe side effects (pegylated interferon-alpha) or require life-long administration (nucleos(t)ide analogs). We report here the evaluation of the safety and therapeutic efficacy of a novel, humanized antibody (hzVSF) in the woodchuck model of HBV infection. hzVSF has been shown to act as a viral entry inhibitor, most likely by suppressing vimentin-mediated endocytosis of virions. Targeting the increased vimentin expression on liver cells by hzVSF after infection with HBV or woodchuck hepatitis virus (WHV) was demonstrated initially. Thereafter, hzVSF safety was assessed in eight woodchucks naïve for WHV infection. Antiviral efficacy of hzVSF was evaluated subsequently in 24 chronic WHV carrier woodchucks by monotreatment with three ascending doses and in combination with tenofovir alafenamide fumarate (TAF). Consistent with the proposed blocking of WHV reinfection, intravenous hzVSF administration for 12 weeks resulted in a modest but transient reduction of viral replication and associated liver inflammation. In combination with oral TAF dosing, the antiviral effect of hzVSF was enhanced and sustained in half of the woodchucks with an antibody response to viral proteins. Thus, hzVSF safely but modestly alters chronic WHV infection in woodchucks; however, as a combination partner to TAF, its antiviral efficacy is markedly increased. The results of this preclinical study support future evaluation of this novel anti-HBV drug in patients.


Assuntos
Alanina/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Antivirais/farmacologia , Vírus da Hepatite B da Marmota/efeitos dos fármacos , Hepatite B/tratamento farmacológico , Fígado/efeitos dos fármacos , Tenofovir/análogos & derivados , Vimentina/antagonistas & inibidores , Internalização do Vírus/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Quimioterapia Combinada , Endocitose/efeitos dos fármacos , Células Hep G2 , Hepatite B/metabolismo , Hepatite B/virologia , Vírus da Hepatite B da Marmota/patogenicidade , Interações Hospedeiro-Patógeno , Humanos , Fígado/metabolismo , Fígado/virologia , Marmota , Tenofovir/farmacologia , Vimentina/metabolismo , Carga Viral , Replicação Viral/efeitos dos fármacos
16.
AIDS Res Ther ; 18(1): 57, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488812

RESUMO

INTRODUCTION: Although individual antiretroviral drugs have been shown to be associated with elevated cardiovascular disease (CVD) risk, data are limited on the role of antiretroviral drug combinations. Therefore, we sought to investigate CVD risk associated with antiretroviral drug combinations. METHODS: Using an administrative health-plan dataset, risk of acute myocardial infarction (AMI) associated with current exposure to antiretroviral drug combinations was assessed among persons living with HIV receiving antiretroviral therapy (ART) across the U.S. from October 2009 through December 2014. To account for confounding-by-indication and for factors simultaneously acting as causal mediators and confounders, we applied inverse probability of treatment weighted marginal structural models to longitudinal data of patients. RESULTS: Over 114,417 person-years (n = 73,071 persons) of ART exposure, 602 cases of AMI occurred at an event rate of 5.26 (95% CI: 4.86, 5.70)/1000 person-years. Of the 14 antiretroviral drug combinations studied, persons taking abacavir-lamivudine-darunavir had the highest incidence rate (IR: 11/1000; 95% CI: 7.4-16.0) of AMI. Risk (HR; 95% CI) of AMI was elevated for current exposure to abacavir-lamivudine-darunavir (1.91; 1.27-2.88), abacavir-lamivudine-atazanavir (1.58; 1.08-2.31), and tenofovir-emtricitabine-raltegravir (1.35; 1.07-1.71). Tenofovir-emtricitabine-efavirenz was associated with reduced risk (0.65; 0.54-0.78). Abacavir-lamivudine-darunavir was associated with increased risk of AMI beyond that expected of abacavir alone, likely attributable to darunavir co-administration. We did not find an elevated risk of AMI when abacavir-lamivudine was combined with efavirenz or raltegravir. CONCLUSION: The antiretroviral drug combinations abacavir-lamivudine-darunavir, abacavir-lamivudine-atazanavir and tenofovir-emtricitabine-raltegravir were found to be associated with elevated risk of AMI, while tenofovir-emtricitabine-efavirenz was associated with a lower risk. The AMI risk associated with abacavir-lamivudine-darunavir was greater than what was previously described for abacavir, which could suggest an added risk from darunavir. The results should be confirmed in additional studies.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Infarto do Miocárdio , Fármacos Anti-HIV/efeitos adversos , Didesoxinucleosídeos/efeitos adversos , Combinação de Medicamentos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Lamivudina/uso terapêutico , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/epidemiologia , Tenofovir/efeitos adversos , Estados Unidos/epidemiologia
17.
Hepatol Int ; 15(5): 1083-1092, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34402025

RESUMO

BACKGROUND AND AIMS: Whether entecavir (ETV) or tenofovir alafenamide (TAF) is better at preventing hepatocellular carcinoma (HCC) development among patients with chronic hepatitis B (CHB) remains unclear. The present study was conducted to explore the ability of these two antivirals to prevent HCC. METHODS: From 2012 to 2019, treatment-naïve CHB patients undergoing ETV or TAF therapy were recruited at three academic teaching hospitals. The TAF group comprised patients starting TAF as first-line antiviral and those switching antivirals from tenofovir disoproxil fumarate to TAF. Patients with decompensated cirrhosis or HCC at enrollment were excluded from the analysis. Cumulative probabilities of HCC were assessed using the Kaplan-Meier method. RESULTS: In total, 1810 patients (1525 and 285 in ETV and TAF groups, respectively) were recruited. The annual HCC incidence was statistically not different between the ETV and TAF groups (1.67 vs. 1.19 per 100 person-years, respectively) with an adjusted hazard ratio (HR) of 0.681 (p = 0.255), as determined by multivariate analysis. Male, hypertension, liver cirrhosis, FIB-4 index, and albumin were independent prognostic factors for HCC development. Propensity score-matched and inverse probability of treatment weighting analyses yielded similar results, with non-statistically different HCC incidence between the ETV and TAF groups (1.07 vs. 1.19 per 100 person-years (HR = 0.973; p = 0.953) and 1.67 vs. 1.89 per 100 person-years, respectively (HR = 0.949; p = 0.743). CONCLUSIONS: These findings suggest that ETV- and TAF-treated CHB patients have similar risk of developing HCC. Further studies with the larger sample size and longer follow-up are needed to validate these results.


Assuntos
Carcinoma Hepatocelular , Hepatite B Crônica , Neoplasias Hepáticas , Alanina , Antivirais/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/prevenção & controle , Guanina/análogos & derivados , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/epidemiologia , Masculino , Estudos Retrospectivos , Tenofovir/análogos & derivados , Resultado do Tratamento
18.
Medicine (Baltimore) ; 100(30): e26588, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34397689

RESUMO

ABSTRACT: High cardiovascular disease risk in people living with HIV is partly attributed to antiretroviral therapy (ART). Lipid response to ART has been extensively studied, yet, little is known how small molecule lipids respond to Integrase inhibitor-based (INSTI-based) compared to Protease inhibitor-based (PI-based) ART regimens.Ancillary study to a phase 3, randomized, open-label trial [AIDS Clinical Trial Group A5257 Study] in treatment-naive HIV-infected patients randomized in a 1:1:1 ratio to receive ritonavir-boosted atazanavir (ATV/r), ritonavir-boosted darunavir (DRV/r) (both PI-based), or raltegravir with Tenofovir Disoproxil Fumarate-TDF plus emtricitabine (RAL, INSTI-based).We examined small molecule lipid response in a subcohort of 75 participants. Lipidomic assays of plasma samples collected pre- and post-ART treatment (48 weeks) were conducted using ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry. The effect of ART regimens was regressed on lipid species response adjusting for the baseline covariates (lipids, age, sex, race, CD4 level, BMI, and smoking). Results were validated in the Centers for AIDS Research Network of Integrated Clinical Systems study (N = 16).Out of 417 annotated lipids, glycerophospholipids (P = .007) and sphingolipids (P = .028) had a higher response to ATV/r and DRV/r compared to RAL. The lysophosphatidylcholine (LPCs(16:1),(17:1),(20:3)) and phosphophatidylcholine species (PCs(40:7),(38:4)) had an opposite response to RAL versus ATV/r in the discovery and validation cohort. The INSTI-based regimen had an opposite response of ceramide species ((d38:1), (d42:2)), PCs((35:2), (38:4)), phosphatidylethanolamines (PEs(38:4), (38:6)), and sphingomyelin(SMd38:1) species compared with the PI-based regimens. There were no differences observed between 2 PI-based regimens.We observed differences in response of small molecule lipid species by ART regimens in treatment-naive people living with HIV.


Assuntos
Antirretrovirais/efeitos adversos , Lipidômica/métodos , Adulto , Antirretrovirais/uso terapêutico , Sulfato de Atazanavir/efeitos adversos , Sulfato de Atazanavir/uso terapêutico , Distribuição de Qui-Quadrado , Darunavir/efeitos adversos , Darunavir/uso terapêutico , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/fisiopatologia , Humanos , Lipidômica/estatística & dados numéricos , Lipídeos , Masculino , Espectrometria de Massas/métodos , Pessoa de Meia-Idade , Plasma/efeitos dos fármacos , Raltegravir Potássico/efeitos adversos , Raltegravir Potássico/uso terapêutico , Tenofovir/efeitos adversos , Tenofovir/uso terapêutico
19.
N Engl J Med ; 385(7): 595-608, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34379922

RESUMO

BACKGROUND: Safe and effective long-acting injectable agents for preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection are needed to increase the options for preventing HIV infection. METHODS: We conducted a randomized, double-blind, double-dummy, noninferiority trial to compare long-acting injectable cabotegravir (CAB-LA, an integrase strand-transfer inhibitor [INSTI]) at a dose of 600 mg, given intramuscularly every 8 weeks, with daily oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) for the prevention of HIV infection in at-risk cisgender men who have sex with men (MSM) and in at-risk transgender women who have sex with men. Participants were randomly assigned (1:1) to receive one of the two regimens and were followed for 153 weeks. HIV testing and safety evaluations were performed. The primary end point was incident HIV infection. RESULTS: The intention-to-treat population included 4566 participants who underwent randomization; 570 (12.5%) identified as transgender women, and the median age was 26 years (interquartile range, 22 to 32). The trial was stopped early for efficacy on review of the results of the first preplanned interim end-point analysis. Among 1698 participants from the United States, 845 (49.8%) identified as Black. Incident HIV infection occurred in 52 participants: 13 in the cabotegravir group (incidence, 0.41 per 100 person-years) and 39 in the TDF-FTC group (incidence, 1.22 per 100 person-years) (hazard ratio, 0.34; 95% confidence interval, 0.18 to 0.62). The effect was consistent across prespecified subgroups. Injection-site reactions were reported in 81.4% of the participants in the cabotegravir group and in 31.3% of those in the TDF-FTC group. In the participants in whom HIV infection was diagnosed after exposure to CAB-LA, INSTI resistance and delays in the detection of HIV infection were noted. No safety concerns were identified. CONCLUSIONS: CAB-LA was superior to daily oral TDF-FTC in preventing HIV infection among MSM and transgender women. Strategies are needed to prevent INSTI resistance in cases of CAB-LA PrEP failure. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 083 ClinicalTrials.gov number, NCT02720094.).


Assuntos
Infecções por HIV/prevenção & controle , Inibidores de Integrase de HIV/administração & dosagem , Profilaxia Pré-Exposição , Piridonas/administração & dosagem , Tenofovir/uso terapêutico , Administração Oral , Adulto , Idoso , Fármacos Anti-HIV/uso terapêutico , Preparações de Ação Retardada/administração & dosagem , Método Duplo-Cego , Esquema de Medicação , Resistência a Medicamentos/genética , Feminino , Inibidores de Integrase de HIV/efeitos adversos , Homossexualidade Masculina , Humanos , Injeções Intramusculares/efeitos adversos , Análise de Intenção de Tratamento , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Piridonas/efeitos adversos , Pessoas Transgênero , Adulto Jovem
20.
BMC Pregnancy Childbirth ; 21(1): 551, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34384374

RESUMO

BACKGROUND: We encourage Hepatitis B virus-infected mothers to breastfeed postpartum, even when continuing pregnancy category B nucleos(t)ide analogs (NAs) treatment. However, a large proportion of the Hepatitis B virus-infected mothers were noncompliant with this breastfeeding recommendation. This study aimed to investigate the factors associated with noncompliance with breastfeeding recommendation in Hepatitis B virus-infected mothers who had received NAs treatment during pregnancy. METHODS: A total of 155 mothers with chronic hepatitis B receiving NAs treatment for preventing mother-to-child transmission during the late gestation period were included and divided into exclusive breastfeeding (n = 63), mixed feeding (n = 34), and artificial feeding (n = 58) groups according to the postpartum feeding methods. Independent variables associated with feeding methods were analyzed using logistic regression analysis. RESULTS: Compared to the breastfeeding and mixed feeding groups, the artificial feeding group had significantly more multiparity, later postpartum timing of stopping NAs treatment, and a lower proportion of having knowledge of NAs medications (all P < 0.05). In addition, multivariable logistic regression analysis confirmed that multiparity, later postpartum timing of stopping NAs treatment, and lacking knowledge of medication were independent factors associated with noncompliance with breastfeeding recommendation. CONCLUSIONS: Hepatitis B virus-infected mothers who stopped NAs treatment at late postpartum period or had less knowledge of medication were more likely to be noncompliant with breastfeeding recommendation. Strengthening health education for participants taking NAs may be an important method to improve compliance with breastfeeding recommendation.


Assuntos
Antivirais/uso terapêutico , Aleitamento Materno , Nucleosídeos/uso terapêutico , Cooperação do Paciente , Período Pós-Parto , Telbivudina/uso terapêutico , Tenofovir/uso terapêutico , Adulto , China/epidemiologia , Feminino , Hepatite B Crônica/prevenção & controle , Humanos , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Gravidez , Complicações Infecciosas na Gravidez/prevenção & controle , Estudos Retrospectivos , Fatores de Risco
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