RESUMO
BACKGROUND: Nevirapine prophylaxis has been found to lower the risk of HIV transmission in breastfed infants. While about 95% of HIV positive pregnant and lactating mothers use Antiretroviral therapy in Uganda, a smaller percentage of HIV exposed infants (HEI) receive nevirapine (NVP) prophylaxis. This study aimed to determine the proportion of HEI who missed NVP prophylaxis and associated factors. METHODS: This was a cross-sectional study done using quantitative methods, conducted at Mulago National Referral Hospital (MNRH). A total of 228 mother-infant pairs were enrolled. The proportion of HEI who missed NVP, maternal, infant and health facility factors associated were determined using a pre-tested questionnaire. Bivariate analysis and binary logistic regression model were used to determine the proportion and factors associated with missing NVP prophylaxis. RESULTS: The proportion of HEI who missed NVP prophylaxis was 50/228 (21.9%). Factors significantly associated with HEI missing NVP prophylaxis included delivery from outside government health facilities (AOR = 8.41; P = 0.001), mothers not undergoing PMTCT counselling (AOR = 12.01; P = 0.001), not on ART (AOR = 8.47; P = 0.003) and not having disclosed their HIV status to their partners (AOR = 2.80; P = 0.001). The HEI that missed nevirapine and were HIV positive were 35 (70.0%). The HEI that were HIV infected despite receiving nevirapine prophylaxis were 5 out of 40(12.5%). CONCLUSION: One in five HEI missed NVP prophylaxis and nearly three quarters of those who missed NVP prophylaxis were HIV infected. Improving uptake of nevirapine by HEI will require interventions that can aid to strengthen PMTCT counselling.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Transmissão Vertical de Doenças Infecciosas , Nevirapina , Humanos , Nevirapina/uso terapêutico , Estudos Transversais , Uganda , Feminino , Infecções por HIV/prevenção & controle , Infecções por HIV/tratamento farmacológico , Lactente , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Fármacos Anti-HIV/uso terapêutico , Adulto , Recém-Nascido , Masculino , Adulto Jovem , Gravidez , Adesão à Medicação/estatística & dados numéricos , Complicações Infecciosas na Gravidez/tratamento farmacológico , Complicações Infecciosas na Gravidez/prevenção & controleRESUMO
BACKGROUND: HIV is associated with an increased risk of progression to chronic kidney disease (CKD), and this risk is higher in people of West African descent than many other ethnicities. Our study assessed the rates of eGFR change and predictors of rapid eGFR progression in patients receiving antiretroviral therapy (ART), including tenofovir disoproxil fumarate (TDF), in central Ghana between 2003 and 2018. METHODS: This single-centre retrospective study enrolled people with HIV (PWH) initiating ART in Ghana between 2003-2018. Demographics, hepatitis B (HBsAg) status, ART regimens and estimated glomerular filtration rate (eGFR) measurements were recorded, and analyses including multi-level model linear regression were performed to determine predictors of greater levels of eGFR decline and risk of rapid eGFR decline. RESULTS: Six hundred and fifty-nine adult participants were included in the study with a median follow-up time of 6 years (IQR 3.6-8.9). 149 participants (22.6%) also had confirmed HBV co-infection. eGFR mean values were lowest at the point of diagnosis and highest on the second measurement taken; mean eGFR slowly decreased over subsequent measures thereafter. TDF use was associated with the highest mean rate of eGFR decline of all nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) with a statistically significant greater annual decline of -1.08 mL/min/1.73m2/year (CI: -1.92, -0.24) compared with zidovudine. Nevirapine (-0.78mL /min/173m2/year; CI: -1.39, -0.17) and protease inhibitors (-1.55mL/mil/173m2/year; CI: -2.68, -0.41) were associated with greater eGFR declines compared with efavirenz. Negative HBsAg status was associated with greater eGFR decline compared with positive HBsAg status (-1.25mL/mil/173m2/year; CI 0.29. -2.20). CONCLUSIONS: Increased rates of eGFR decline amongst PWH in Ghana were associated with TDF, nevirapine, and protease inhibitor use as well as negative HBsAg status. Additional research using mortality outcome data is needed to closely assess long-term predictors of eGFR decline in African populations.
Assuntos
Progressão da Doença , Taxa de Filtração Glomerular , Infecções por HIV , Insuficiência Renal Crônica , Tenofovir , Humanos , Masculino , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Infecções por HIV/complicações , Gana/epidemiologia , Adulto , Estudos Retrospectivos , Tenofovir/uso terapêutico , Prevalência , Pessoa de Meia-Idade , Insuficiência Renal Crônica/epidemiologia , Fármacos Anti-HIV/uso terapêutico , Ciclopropanos/uso terapêutico , Benzoxazinas/uso terapêutico , Nevirapina/uso terapêutico , Alcinos/uso terapêutico , Fatores de Risco , CoinfecçãoRESUMO
The implementation of pretreatment drug-resistance (PDR) surveillance among people living with HIV-1 (PLWH) is a top priority in countries using efavirenz (EFV)/nevirapine (NVP) for first-line ART. In this study, we assessed the prevalence of PDR among PLWH in Shanghai, China during 2017-2021, and to reveal PDR transmission between Shanghai and other regions of China. A total of 5050 PLWH not on ART during 2017-2021 were included. Partial HIV-1 pol sequences were amplified, sequenced, and analysed for drug-resistance mutations (DRMs). Besides, transmission network of PDR variants was inferred using HIV-TRACE. The overall prevalence of PDR was 4.8% (242/5050; 95% CI, 4.2-5.4). Prevalence of NNRTI-associated PDR was 3.9% (95% CI, 3.4-4.5), higher than those of NRTI-associated (0.8%; 95% CI, 0.5-1.1) and PI-associated PDR (0.9%; 95% CI, 0.6-1.2). High prevalence of PDR (especially high-level resistance) to EFV (132/5050, 2.6%) and NVP (137/5050, 2.7%) were found. CRF01_AE (46.0%) was the predominant HIV-1 genotype with any DRMs, followed by CRF55_01B (21.0%), and CRF07_BC (15.1%). Two NRTI-associated (S68G/N/R and T215A/N/S/Y), five NNRTI-associated (V179D/E/T/L, K103N/R/S/T, E138A/G/K, V106M/I/A and Y181C/I) and two PI-associated mutations (M46I/L/V and Q58E) were the most common observed DRMs in PDR patients in Shanghai. The vast majority of S68G occurred in CRF01_AE (45%). M46I/L/V and Q58E showed a relatively high prevalence in CRF01_AE (4.1%) and CRF07_BC (12.6%). Transmission network analyses demonstrated cross-regional transmission links of PDR variants between Shanghai and other regions of China, which was mainly driven by the potential low-level DRM V179D/E. These results provide crucial information for clinical decision making of first-line ART in PLWH with PDR.
Assuntos
Fármacos Anti-HIV , Farmacorresistência Viral , Infecções por HIV , HIV-1 , Humanos , China/epidemiologia , HIV-1/genética , HIV-1/efeitos dos fármacos , Infecções por HIV/transmissão , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Infecções por HIV/tratamento farmacológico , Masculino , Farmacorresistência Viral/genética , Feminino , Prevalência , Adulto , Pessoa de Meia-Idade , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Mutação , Adulto Jovem , Ciclopropanos , Alcinos , Benzoxazinas/uso terapêutico , Benzoxazinas/farmacologia , Adolescente , Genótipo , Nevirapina/uso terapêutico , Nevirapina/farmacologia , IdosoRESUMO
Chemical and pharmaceutical chemicals found in water sources create substantial risks to human health and the environment. The presence of pharmaceutical contaminants in water can cause antibiotic resistance development, toxicity to aquatic organisms, and endocrine disruption. Hence, the elimination of chemicals and other contaminants from wastewater prior to its release is a burgeoning concern in the domains of engineering and science. The use of treatment technologies in wastewater treatment plants can remove pharmaceutical contaminants through the oxidation process. However, many traditional wastewater treatment plants lack the advanced monitoring tools required to detect low concentrations of pharmaceuticals. Without the ability to detect these compounds, it's challenging to treat them effectively. The goal of this study was to use Response Surface Methodology (RSM) and Artificial Neural Networks (ANN) algorithms to model and improve how Nevirapine and Efavirenz break down in different chlorination conditions. The RSM analysis revealed statistically significant models (F-values: Nevirapine, pH-t: 108.15, T-t: 76.55, ICC-t: 110.84), indicating a strong correlation between operational parameters (pH, temperature, and initial chlorine concentration) and degradation behavior. The ANN model accurately predicted the degradation of both Nevirapine and Efavirenz under various chlorination conditions, as confirmed by analyzing actual-predicted graphs, residual plots, and Mean Squared Error (MSE) values. The ANN model using ICC-t achieved the highest MOD value of 31.31 % for Nevirapine. The ANN model based on ICC-t yielded a maximum MOD value of 16.06 % for Efavirenz. These findings provide valuable insights into optimizing chlorination processes for better removal of these pharmaceutical contaminants from water.
Assuntos
Antirretrovirais , Ciclopropanos , Halogenação , Redes Neurais de Computação , Eliminação de Resíduos Líquidos , Águas Residuárias , Poluentes Químicos da Água , Poluentes Químicos da Água/análise , Águas Residuárias/química , Antirretrovirais/análise , Eliminação de Resíduos Líquidos/métodos , Alcinos , Benzoxazinas/análise , Nevirapina/análiseRESUMO
In this work, exfoliated graphite was used to adsorb antiretroviral drugs from river water and wastewater. The exfoliated graphite was prepared from natural graphite by intercalating it with the acids and exfoliating it at 800 °C. It was characterized using Fourier Transform Infrared Spectroscopy which showed phenolic, alcoholic, and carboxylic functional groups between 1000 cm-1 and 1700 cm-1. Energy-dispersive X-ray spectroscopy results showed carbon as the main element with splashes of oxygen. The Scanning Electron Microscopy images showed increased c-axis distance between graphene layers after intercalation, which further increased after the exfoliation. The exfoliation resulted in elongated distorted cylinders, which were confirmed by the lower density (0.0068 g/mL) of exfoliated graphite material compared to the natural graphite (0.54 g/mL). The X-ray diffraction pattern showed the characteristics of hexagonal phase graphitic structure by the diffraction plane (002) at 26.74°. Raman spectroscopy results showed the natural graphite, graphite intercalated, and exfoliated graphite contained the D, G, D', and G' peaks at about 1350 cm-1, 1570 cm-1, 2440 cm-1, and 2720 cm-1, respectively indicating that the material's crystallinity was not affected by the modification. The highest antiretroviral drugs removal (95-99%), from the water was achieved with a solution pH of 7, an adsorbent mass of 30 mg, and an adsorption time of 30 min. The kinetic model and adsorption isotherm studies showed that the experimental data fit well in pseudo-second-order kinetics and is well explained by Freundlich's adsorption isotherm. The maximum adsorption capacity of the exfoliated graphite for antiretroviral drugs ranges between 1.660 and 197.0, 1.660-232.5, and 1.650-237.7 mg/g for abacavir, nevirapine, and efavirenz, respectively. The obtained removal percentages were 100% in river water, 63-100% in influent and 70-100% in effluent wastewater unspiked samples.
Assuntos
Antirretrovirais , Grafite , Nevirapina , Rios , Águas Residuárias , Grafite/química , Adsorção , Cinética , Águas Residuárias/química , Antirretrovirais/química , Rios/química , Nevirapina/química , Poluentes Químicos da Água/química , Espectroscopia de Infravermelho com Transformada de Fourier , Benzoxazinas/química , Alcinos , CiclopropanosRESUMO
Idiosyncratic drug reactions (IDRs) are associated with significant patient morbidity/mortality and lead to considerable drug candidate attrition in drug development. Their idiosyncratic nature makes the study of IDRs difficult. In particular, nevirapine is associated with a relatively high risk of serious skin rash and liver injury. We previously found that nevirapine causes a similar skin rash in female Brown Norway rats, but these animals do not develop significant liver injury. Programmed cell death protein-1 (PD-1) is an immune checkpoint involved in immune tolerance, and anti-PD-1 antibodies have been used to treat cancer. However, they increase the risk of liver injury caused by co-administered drugs. We found that PD-1-/- mice are more susceptible to drug-induced liver injury, but PD-1-/- mice are not a good model for all drugs. In particular, they do not develop a skin rash when treated with nevirapine, at least in part because they lack the sulfotransferase in their skin that forms the reactive metabolite responsible for the rash. Therefore, we developed a PD-1 mutant (PD-1m/m) rat, with an excision in the ligand-binding domain of PD-1, to test whether nevirapine would cause a more serious skin rash in these animals. The PD-1m/m rat was based on a Sprague Dawley background, which has a lower incidence of skin rash than Brown Norway rats. The treated PD-1m/m rats developed more severe liver injury than PD-1-/- mice, but in contrast to expectations, they did not develop a skin rash. Functional knockouts provide a unique tool to study the mechanisms of IDRs.
Assuntos
Nevirapina , Receptor de Morte Celular Programada 1 , Ratos Endogâmicos BN , Animais , Nevirapina/toxicidade , Feminino , Receptor de Morte Celular Programada 1/genética , Ratos , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Técnicas de Inativação de Genes , MasculinoRESUMO
Antiretroviral drugs (ARVDs) have been extensively employed in health care to improve the quality of life and lifecycle longevity. However, overuse and improper disposal of ARVDs have been recognized as an emerging concern whereby wastewater treatment major recipients. Therefore, in this work, the activated macadamia nutshells (MCNs) were explored as low-cost adsorbents for the removal of ARVDs in wastewater samples. Fourier transform infrared spectroscopy (FTIR), Scanning Electron microscopy (SEM), Brunauer-Emmet-Teller (BET), and Powder X-ray diffraction (PXRD). The highest removal efficiency (R.E) was above 86% for the selected analytes nevirapine, abacavir, and efavirenz. The maximum adsorption capacity of the functionalized MCN adsorbent was 10.79, 27.44, and 38.17 mg/g for nevirapine, abacavir, and efavirenz for HCl-modified adsorbent. In contrast, NaOH modified had adsorption capacities of 13.67, 14.25, and 20.79 mg/g. The FTIR showed distinct functional groups OH and CO, which facilitate the removal of selected ARVDs. From studying kinetics parameters, the pseudo-second-order (R2 = 0.990-0.996) was more dominant than the pseudo-first-order (R2 = 0.872-0.994). The experimental data was most fitted in the Freundlich model with (R2 close to 1). The thermodynamic parameters indicated that the adsorption process was spontaneous and exothermic. The study indicated that MCNs are an eco-friendly, low-cost, and effective adsorbent for the removal of nevirapine, abacavir, and efavirenz. PRACTITIONER POINTS: Modification macadamia nutshell with HCl and NaOH improved physio-chemical properties that yielded high removal efficiency compared with raw macadamia nutshells. Modification of macadamia by HCl showed high removal efficiency, which could be attributed to high interaction such as H-bonding that improves adsorption. The macadamia nutshell as an adsorbent showed so much robustness with regeneration studies yielding to about 69.64% of selected compounds.
Assuntos
Alcinos , Benzoxazinas , Ciclopropanos , Didesoxiadenosina/análogos & derivados , Infecções por HIV , Poluentes Químicos da Água , Águas Residuárias , Macadamia , Adsorção , Nevirapina , Qualidade de Vida , Hidróxido de Sódio , Termodinâmica , Cinética , Poluentes Químicos da Água/química , Espectroscopia de Infravermelho com Transformada de Fourier , Concentração de Íons de HidrogênioRESUMO
Background Australia imposes restrictions for people living with HIV (PLHIV) applying for permanent residency (PR), including spending less than AUD51,000 on medical costs over 10years. Some PLHIV opted for suboptimal and cheaper antiretroviral therapy (ART) regimens to increase their chances of receiving PR. We collated a case series to examine PLHIV on suboptimal ART because of visa issues. Methods We identified all patients applying for a PR in Australia who obtained nevirapine, efavirenz or zidovudine between July 2022 and July 2023 from the Melbourne Sexual Health Centre. Pathology results and records detailing psychological issues relating to the patients' wishes to remain on suboptimal ART were extracted from clinical records by two researchers. Results We identified six patients with a mean age of 39years migrating from Asian and European countries. Three patients used efavirenz, and three used nevirapine. All desired to remain on cheaper, suboptimal ART to stay below visa cost thresholds, which they considered to aid favourably with their application. Four displayed stress and anxiety arising from visa rejections, appeal deadlines and the lengthy visa application process. Conclusions Despite access to more effective and safer ART, we identified patients who chose to remain on cheaper ART to improve chances of obtaining an Australian visa, potentially putting their health at risk. We found significant evidence of stress and anxiety among patients. There is a need to review and revise current migration policies and laws in Australia that discriminate against PLHIV and jeopardise public health.
Assuntos
Infecções por HIV , Humanos , Infecções por HIV/tratamento farmacológico , Adulto , Masculino , Austrália , Feminino , Emigração e Imigração/legislação & jurisprudência , Pessoa de Meia-Idade , Fármacos Anti-HIV/uso terapêutico , Alcinos , Ciclopropanos/uso terapêutico , Benzoxazinas/uso terapêutico , Nevirapina/uso terapêutico , Zidovudina/uso terapêuticoRESUMO
Nevirapine, an antiretroviral used in the treatment of HIV, is associated with idiosyncratic drug-induced liver injury (IDILI), a potentially life-threatening adverse drug reaction. Its usage has decreased due to this concern, but it is still widely used in lower-resource settings. In general, the mechanisms underlying idiosyncratic drug reactions (IDRs) are poorly understood, but evidence indicates that most are immune-mediated. There is very limited understanding of the early immune response following administration of drugs associated with IDRs, which likely occurs due to reactive metabolite formation. In this work, we aimed to characterize the links between covalent binding of nevirapine, the development of an early immune response, and the subsequent liver injury using a mouse model. We describe initial attempts to characterize an early immune response to nevirapine followed by the discovery that nevirapine induced the release of corticosterone. Corticosterone release was partially associated with the degree of drug covalent binding in the liver but was also likely mediated by additional mechanisms at higher drug doses. Transcriptomic analysis confirmed metabolic activation, glucocorticoid signaling, and decreased immune activation; GDF-15 also warrants further investigation as part of the immune response to nevirapine. Finally, glucocorticoid blockade preceding the first dose of nevirapine attenuated nevirapine-induced liver injury at 3 weeks, suggesting that acute glucocorticoid signaling is harmful in the context of nevirapine-induced liver injury. This work demonstrates that nevirapine induces acute corticosterone release, which contributes to delayed-onset liver injury. It also has implications for screening drug candidates for IDILI risk and preventing nevirapine-induced IDILI.
Assuntos
Fármacos Anti-HIV , Doença Hepática Induzida por Substâncias e Drogas , Corticosterona , Fígado , Nevirapina , Nevirapina/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Fármacos Anti-HIV/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
The global prevalence of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) has been an environmental menace. Tons of drug wastes from antiretroviral therapy are released into the environment annually. We, for the first time, employed the novel dielectric barrier atmospheric non-thermal plasma (DBANP) discharge, to mitigate the inadvertent pollution arising from the antiretroviral therapy. A 40-min treatment of nevirapine achieved >94 % (0.075 min-1) removal efficiency at discharge power of 63.5 W and plasma working gas of atmospheric air. Chemical probes confirmed â¢OH, ONOO- and eaq- as the dominant reactive species whilst further revealing the reaction acceleration role of NaNO3 and CCl4 which are known reaction terminators. The commonly coexisting inorganic anions potentiated nevirapine removal with over 98 % efficiency, achieving the highest rate constant of 0.148 min-1 in this study. Moreover, the initial solution pH (1.5-11.1) was no limiting factor either. The insensitivity of the DBANP discharge to actual water matrices was an eminent inference of its potential applicability in practical conditions. With reference to data obtained from the liquid chromatography-mass spectrometer analysis, nevirapine degradation pathway was proposed. A nucleophilic attack by ONOO- at the cyclopropyl group and â¢OH attack at the carbonyl carbon of the amide group, respectively, initiated nevirapine degradation process. It is anticipated that the findings herein, will provide new insights into antiretroviral drug waste management in environmental waters using the innovative and green non-thermal plasma process.
Assuntos
Síndrome da Imunodeficiência Adquirida , Infecções por HIV , Humanos , Nevirapina/uso terapêutico , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Carbono , Cromatografia LíquidaAssuntos
Fármacos Anti-HIV , Infecções por HIV , Compostos Heterocíclicos com 3 Anéis , Compostos Heterocíclicos de 4 ou mais Anéis , Metadona , Nevirapina , Humanos , Feminino , Infecções por HIV/tratamento farmacológico , Nevirapina/uso terapêutico , Nevirapina/administração & dosagem , Metadona/uso terapêutico , Metadona/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Piperazinas/uso terapêutico , Piperazinas/administração & dosagem , Adulto , Piridonas/uso terapêutico , Piridonas/administração & dosagem , Tratamento de Substituição de Opiáceos/métodos , AmidasRESUMO
INTRODUCTION: The large number of deaths among children with HIV is driven by poor antiretroviral treatment (ART) coverage among this cohort. The aim of the study was to assess the availability and stock-outs of paediatric and adult ART formulations in Kenya and Uganda across various regions and types of health facilities. METHODS: A survey on availability and stock-outs of paediatric ART at health facilities was adapted from the standardized Health Action International-WHO Medicine Availability Monitoring Tool. All preferred and limited-use formulations, and three phased-out formulations according to the 2021 WHO optimal formulary list were included in the survey, as well as a selection of adult ART formulations suitable for older children, adolescents, and adults. Availability data were collected in June-July 2022 and stock-out data were obtained over the previous year from randomly selected public and private-not-for-profit (PNFP) facilities registered to dispense paediatric ART across six districts per country. All data were analysed descriptively. RESULTS: In total, 144 health facilities were included (72 per country); 110 were public and 34 PNFP facilities. Overall availabilities of preferred paediatric ART formulations were 52.2% and 63.5% in Kenya and Uganda, respectively, with dolutegravir (DTG) 10 mg dispersible tablets being available in 70.2% and 77.4% of facilities, respectively, and abacavir/lamivudine dispersible tablets in 89.8% and 98.2% of facilities. Of note, availability of both formulations was low (37.5% and 62.5%, respectively) in Kenyan PNFP facilities. Overall availabilities of paediatric limited-use products were 1.1% in Kenya and 1.9% in Uganda. At least one stock-out of a preferred paediatric ART formulation was reported in 40.0% of Kenyan and 74.7% of Ugandan facilities. Nevirapine solution stock-outs were reported in 43.1% of Ugandan facilities, while alternative formulations for postnatal HIV prophylaxis were not available. CONCLUSIONS: Recommended DTG-based first-line ART for children across all ages was reasonably available at health facilities in Kenya and Uganda, with the exception of Kenyan PNFP facilities. Availability of paediatric ART formulations on the limited-use list was extremely low across both countries. Stock-outs were reported regularly, with the high number of reported stock-outs of neonatal ART formulations in Uganda being most concerning.
Assuntos
Infecções por HIV , Instalações de Saúde , Uganda , Quênia , Humanos , Infecções por HIV/tratamento farmacológico , Criança , Instalações de Saúde/estatística & dados numéricos , Fármacos Anti-HIV/provisão & distribuição , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , Piridonas/provisão & distribuição , Piridonas/uso terapêutico , Antirretrovirais/provisão & distribuição , Antirretrovirais/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/provisão & distribuição , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Adolescente , Pré-Escolar , Acessibilidade aos Serviços de Saúde , Nevirapina/provisão & distribuição , Nevirapina/uso terapêutico , Nevirapina/administração & dosagem , Lactente , Masculino , Feminino , Lamivudina/provisão & distribuição , Lamivudina/uso terapêutico , Lamivudina/administração & dosagem , Oxazinas , PiperazinasRESUMO
Parkinson's disease (PD) is a complex neurodegenerative disorder with an unclear etiology. Despite significant research efforts, developing disease-modifying treatments for PD remains a major unmet medical need. Notably, drug repositioning is becoming an increasingly attractive direction in drug discovery, and computational approaches offer a relatively quick and resource-saving method for identifying testable hypotheses that promote drug repositioning. We used an artificial intelligence (AI)-based drug repositioning strategy to screen an extensive compound library and identify potential therapeutic agents for PD. Our AI-driven analysis revealed that efavirenz and nevirapine, approved for treating human immunodeficiency virus infection, had distinct profiles, suggesting their potential effects on PD pathophysiology. Among these, efavirenz attenuated α-synuclein (α-syn) propagation and associated neuroinflammation in the brain of preformed α-syn fibrils-injected A53T α-syn Tg mice and α-syn propagation and associated behavioral changes in the C. elegans BiFC model. Through in-depth molecular investigations, we found that efavirenz can modulate cholesterol metabolism and mitigate α-syn propagation, a key pathological feature implicated in PD progression by regulating CYP46A1. This study opens new avenues for further investigation into the mechanisms underlying PD pathology and the exploration of additional drug candidates using advanced computational methodologies.
Assuntos
Alcinos , Inteligência Artificial , Benzoxazinas , Ciclopropanos , Reposicionamento de Medicamentos , Doença de Parkinson , alfa-Sinucleína , Ciclopropanos/farmacologia , Ciclopropanos/uso terapêutico , Alcinos/farmacologia , Benzoxazinas/farmacologia , Reposicionamento de Medicamentos/métodos , Animais , alfa-Sinucleína/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Camundongos , Caenorhabditis elegans/efeitos dos fármacos , Camundongos Transgênicos , Humanos , Nevirapina/farmacologia , Modelos Animais de Doenças , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND OBJECTIVE: This study aimed to understand the basic situation of adults with human immunodeficiency virus (HIV) receiving antiretroviral therapy (ART) in Meigu County, Liangshan Yi Autonomous Prefecture. The information of patients who had been on ART for more than 6 months, the effect of ART, the possible reasons for ART failure, knowledge of drug resistance among patients with ART failure and the possible reasons for the emergence of drug resistance were analyzed. METHODS: A total of 2753 people living with HIV (PLWH) were collected for HIV-1 RNA virus nucleic acid testing. Plasma specimens with HIV-1 RNA ≥ 1000 copies/mL were sent to the laboratory for nucleic acid extraction, PCR, electrophoresis and sequencing, and the sequencing results were submitted to the HIV drug resistance database of Stanford University for subtyping to determine the drug resistance mutation sites and drug sensitivity levels. RESULTS: A total of 2753 patients were enrolled in this study. Antiviral therapy failed in 288 patients and was successfully amplified in 245, of which 111 had resistance genes. The resistance rate to failure of viral suppression was 45.3% (111/245). The highest rates of resistance to NNRTIs were found for efavirenz (EFV) and nevirapine (NVP) (42.9%), and the highest rates of resistance to NRTIs were found for 3TC and emtricitabine (FTC) (15.9%). The most common NNRTI resistance mutation site was K103N (20.8%), followed by V179D (9.4%) and V106M (7.8%); the most common NRTI resistance mutation site was M184V/I/MV (14.3%), followed by K65R (6.9%); three PI-associated resistance mutation sites were identified. The subtype of the resistant strain was CRF07-BC in almost all patients (98.9%). CONCLUSIONS: Compared with the previous low ART efficacy in the county, this study showed that the overall virological failure (VF) resistance rate in the county is still low, dominated by resistance to EFV, NVP, 3TC, FTC, and didanosine (DDI). Due to economic constraints, the core regimen is still 3TC + TDF, but before initiating ART, testing for HIV-1 subtypes and resistance should be conducted to avoid resistance that can lead to VF, especially for patients with high risk factors for resistance as shown by epidemiologic investigations.
Assuntos
Síndrome da Imunodeficiência Adquirida , Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Ácidos Nucleicos , Adulto , Humanos , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Emtricitabina/uso terapêutico , HIV-1/genética , Nevirapina/farmacologia , Nevirapina/uso terapêutico , Didanosina , Mutação , Resistência a Medicamentos , Farmacorresistência Viral/genéticaRESUMO
Idiosyncratic drug reactions are rare but serious adverse drug reactions unrelated to the known therapeutic properties of the drug and manifest in only a small percentage of the treated population. Animal models play an important role in advancing mechanistic studies examining idiosyncratic drug reactions. However, to be useful, they must possess similarities to those seen clinically. Although mice currently represent the dominant mammalian genetic model, rats are advantageous in many areas of pharmacologic study where their physiology can be examined in greater detail and is more akin to that seen in humans. In the area of immunology, this includes autoimmune responses and susceptibility to diabetes, in which rats more accurately mimic disease states in humans compared with mice. For example, oral nevirapine treatment can induce an immune-mediated skin rash in humans and rats, but not in mice due to the absence of the sulfotransferase required to form reactive metabolites of nevirapine within the skin. Using CRISPR-mediated gene editing, we developed a modified line of transgenic rats in which a segment of IgG-like ectodomain containing the core PD-1 interaction motif containing the native ligand and therapeutic antibody domain in exon 2 was deleted. Removal of this region critical for mediating PD-1/PD-L1 interactions resulted in animals with an increased immune response resulting in liver injury when treated with amodiaquine.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Nevirapina , Humanos , Ratos , Camundongos , Animais , Nevirapina/toxicidade , Nevirapina/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Sistemas CRISPR-Cas , Modelos Animais , Fígado/metabolismo , Mamíferos/metabolismoRESUMO
BACKGROUND: Infants born with HIV-1 require lifelong antiretroviral therapy (ART). We aimed to assess whether very early ART in neonates might restrict HIV-1 reservoirs, an important step towards ART-free remission. METHODS: IMPAACT P1115 is an ongoing, phase 1/2, proof-of-concept study in which infants were enrolled at 30 research clinics in 11 countries (Brazil, Haiti, Kenya, Malawi, South Africa, Tanzania, Thailand, Uganda, the USA, Zambia, and Zimbabwe) into two cohorts. Infants at least 34 weeks' gestational age at high risk for in-utero HIV-1 with either untreated maternal HIV-1 (cohort 1) or who were receiving pre-emptive triple antiretroviral prophylaxis outside of the study (maternal ART permissible; cohort 2) were included. All infants initiated treatment within 48 h of life. Cohort 1 initiated three-drug nevirapine-based ART, and cohort 2 initiated three-drug nevirapine-based prophylaxis then three-drug nevirapine-based ART following HIV diagnosis by age 10 days. We added twice-daily coformulated oral ritonavir 75 mg/m2 and lopinavir 300 mg/m2 from 14 days of life and 42 weeks postmenstrual age. We discontinued nevirapine 12 weeks after two consecutive plasma HIV-1 RNA levels below limit of detection. We tracked virological suppression, safety outcomes, and meeting a predetermined biomarker profile at age 2 years (undetectable RNA since week 48, HIV-1 antibody-negative, HIV-1 DNA not detected, and normal CD4 count and CD4 percentage) to assess qualification for analytical treatment interruption. This study is registered with ClinicalTrials.gov, NCT02140255. FINDINGS: Between Jan 23, 2015, and Dec 14, 2017, 440 infants were included in cohort 1 and 20 were included in cohort 2. 54 of these infants (34 from cohort 1 and 20 from cohort 2) had confirmed in-utero HIV-1 and were enrolled to receive study ART. 33 (61%) of 54 infants were female and 21 (39%) were male. The estimated probability of maintaining undetectable plasma RNA through to 2 years was 33% (95% CI 17-49) in cohort 1 and 57% (28-78) in cohort 2. Among infants maintaining protocol-defined virological control criteria through to study week 108, seven of 11 (64%, 95% CI 31-89) in cohort 1 and five of seven (71%, 29-96) in cohort 2 had no detected HIV-1 DNA. Ten of 12 (83%, 52-100) in cohort 1 and all seven (100%, 59-100) in cohort 2 tested HIV-1 antibody-negative at week 108. Among 54 infants initiated on very early ART, ten (19%; six in cohort 1 and four in cohort 2) met all criteria for possible analytical treatment interruption. Reversible grade 3 or 4 adverse events occurred in 15 (44%) of 34 infants in cohort 1 and seven (35%) of 20 infants in cohort 2. INTERPRETATION: Very early ART for in-utero HIV-1 can achieve sustained virological suppression in association with biomarkers indicating restricted HIV-1 reservoirs by age 2 years, which might enable potential ART-free remission. FUNDING: National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Soropositividade para HIV , HIV-1 , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Antirretrovirais/efeitos adversos , DNA/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Soropositividade para HIV/tratamento farmacológico , HIV-1/genética , Nevirapina/uso terapêutico , RNA/uso terapêutico , Estudo de Prova de ConceitoRESUMO
Globally, the environmental occurrence of Contaminants of Emerging Concern (CECs) including pharmaceuticals (PhACs), personal care products (PCPs) and modern polar pesticides has raised ecological and human health awareness. However, as the developed world races against time to establish regulatory measures to mitigate their effects, developing nations including Kenya are lagging behind, partly due to unavailability of adequate data. In this work, a multi-residue analysis of 86 CECs was carried out on 198 surface water and 18 effluent samples collected at 24 sites across the River Athi basin area, Kenya, in both dry and rainy seasons. Overall, 57 CECs comprising 31 PhACs (0.4 ng L-1-142 µg L-1), 6 PCPs (0.7-570 ng L-1) and 20 pesticides (0.3 ng L-1-8.3 µg L-1) were detected. The maximum loads varied from 217 g day-1 (PCPs) to 46 kg day-1 (PhACs). Individually, carbamazepine, nevirapine, sulfamethoxazole and DEET were the most ubiquitous CECs, with detection frequencies (DF) higher than 80 %. The highest concentrations were observed at river sites that are heavily impacted by informal settlements, highlighting the critical role of slums in urban rivers pollution. At least 8 CECs including acetamiprid, alachlor, atrazine, diuron, nevirapine and paracetamol show potential risk to algae, Daphnia magna and fish, as exemplified by Risk Quotients (RQ) up to 174. Similarly, potential risk of antibiotic resistant bacteria development is evident (RQ up to 64), being driven by metronidazole, sulfamethoxazole and trimethoprim. Ultimately, further studies on the occurrence and distribution of antibiotic resistant bacteria within the basin and among the communities consuming untreated river water for drinking is merited.
Assuntos
Praguicidas , Poluentes Químicos da Água , Animais , Humanos , Quênia , Poluentes Químicos da Água/análise , Estações do Ano , Nevirapina/análise , Monitoramento Ambiental , Praguicidas/análise , Antibacterianos/análise , Sulfametoxazol/análise , Água/análiseRESUMO
The mechanism of drug-induced skin rash is not well understood. Circumstantial evidence suggests that the covalent binding of a reactive metabolite is involved in the mechanism of most idiosyncratic drug reactions. However, there is a limited quantity of drug metabolizing enzymes in the skin, except for sulfotransferases. It is possible that some drugs are metabolized to reactive sulfate metabolites that are responsible for skin rashes. For example, nevirapine-induced skin rash involves metabolism of nevirapine to 12-hydroxy-nevirapine, which is further metabolized by sulfotransferase in the skin to a reactive benzylic sulfate that covalently binds to proteins. The working hypothesis is that lamotrigine, valdecoxib, and sertraline skin rashes involve the formation of reactive sulfate in the skin. Lamotrigine-N-oxide, hydroxy-valdecoxib, and hydroxy-sertraline were tested as substrates with known human sulfotransferases. Hydroxy-valdecoxib and the benzylic alcohol metabolite of sertraline were not substrates for human sulfotransferases. Therefore, this pathway is presumably not involved in the mechanism by which they cause skin rashes. In contrast, lamotrigine-N-oxide is a substrate for several human sulfotransferases and the sulfate is chemically reactive. Furthermore, lamotrigine-N-sulfate not only alkylates proteins as we described previously but also forms the sulfate of tyrosine, suggesting another possible mechanism for protein modification. This study has further added to the understanding of the potential of the sulfotransferase pathways and protein sulfation to play a role in drug-induced skin rash.
Assuntos
Toxidermias , Exantema , Humanos , Lamotrigina , Nevirapina , Sertralina/efeitos adversos , Exantema/induzido quimicamente , Sulfotransferases , Óxidos , SulfatosRESUMO
BACKGROUND: Feline immunodeficiency virus (FIV) causes an acquired immunodeficiency-like syndrome in cats. FIV is latent. No effective treatment has been developed for treatment the infected cats. The first and second generations non-nucleoside reverse transcriptase inhibitors (NNRTIs) for HIV treatment, nevirapine (NVP) and efavirenz (EFV), and rilpivirine (RPV), were used to investigate the potential of NNRTIs for treatment of FIV infection. OBJECTIVE: This study aims to use experimental and in silico approaches to investigate the potential of NNRTIs, NVP, EFV, and RPV, for inhibition of FIV reverse transcriptase (FIV-RT). METHODS: The FIV-RT and human immunodeficiency virus reverse transcriptase (HIV-RT) were expressed and purified using chromatography approaches. The purified proteins were used to determine the IC50 values with NVP, EFV, and RPV. Surface plasmon resonance (SPR) analysis was used to calculate the binding affinities of NNRTIs to HIV-RT and FIV-RT. The molecular docking and molecular dynamic simulations were used to demonstrate the mechanism of FIV-RT and HIV-RT with first and second generation NNRTI complexes. RESULTS: The IC50 values of NNRTIs NVP, EFV, and RPV against FIV-RT were in comparable ranges to HIV-RT. The SPR analysis showed that NVP, EFV, and RPV could bind to both enzymes. Computational calculation also supports that these NNRTIs can bind with both FIV-RT and HIV-RT. CONCLUSIONS: Our results suggest the first and second generation NNRTIs (NVP, EFV, and RPV) could inhibit both FIV-RT and HIV-RT.
Assuntos
Fármacos Anti-HIV , Doenças do Gato , Infecções por HIV , HIV-1 , Gatos , Animais , Humanos , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/uso terapêutico , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Simulação de Acoplamento Molecular , HIV-1/metabolismo , Rilpivirina/farmacologia , Rilpivirina/uso terapêutico , Nevirapina/farmacologia , Nevirapina/uso terapêutico , Transcriptase Reversa do HIV/metabolismo , Transcriptase Reversa do HIV/farmacologia , Transcriptase Reversa do HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/veterinária , Doenças do Gato/tratamento farmacológicoRESUMO
Despite the proven virological advantages, there remains some controversy regarding whether first-line integrase strand transfer inhibitors (INSTIs)-based antiretroviral therapy (ART) contributes to reducing mortality of people living with HIV (PLHIV) in clinical practice. Here we report a retrospective study comparing all-cause mortality among PLHIV in China who were on different initial ART regimens (nevirapine, efavirenz, dolutegravir, lopinavir, and others [including darunavir, raltegravie, elvitegravir and rilpivirine]) between 2017 and 2019. A total of 41,018 individuals were included across China, representing 21.3% of newly reported HIV/AIDS cases collectively in the country during this period. Only the differences in all-cause mortality of PLHIV between the efavirenz group and the nevirapine group, the dolutegravir group and the nevirapine group, and the lopinavir group and the nevirapine group, were observed in China. After stratifying the cause of mortality, we found that the differences in mortality between initial ART regimens were mainly observed in AIDS-related mortality.