RESUMEN

OBJECTIVE: This study examined the prevalence, severity and risk factors of anaemia among adult people living with HIV attending an antiretroviral therapy centre in Woreta Primary Hospital, Woreta town, Ethiopia. DESIGN: Hospital-based retrospective cross-sectional study. SETTING: Public health facility that provides HIV care in Woreta town. PARTICIPANTS: A total of 289 medical records of adults living with HIV/AIDS on highly active antiretroviral therapy from February 2019 to September 2023 at government hospital were reviewed using a systematic sampling method. The data were entered using Epi-info V.7 and exported to SPSS V.23 for data analysis. The data were analysed using bivariate and then multivariate logistic regression models in order to identify variables associated with anaemia. At the 95% CI level, variables having a p value of <0.05 were deemed to be statistically significant predictors. PRIMARY OUTCOME: Prevalence and severity of anaemia and its predictors among adult patients living with HIV on antiretroviral therapy in Woreta Primary Hospital. RESULTS: The total prevalence of anaemia was 31.5% (95% CI 28.9 to 33.8). The prevalence of mild, moderate and severe anaemia was 20.42%, 10.38% and 0.70%, respectively. Predictors independently linked with anaemia were female sex (adjusted OR (AOR) 1.08), age ≥40 years (AOR 1.21), lived with HIV >10 years (AOR 2.31), CD4 counts <200 cells/µL (AOR 3.81), non-suppressed viral load (AOR 1.28), history of opportunistic infections (AOR 1.54), WHO clinical stages III and IV (AOR 1.37 and 2.23, respectively) and history of parasitic infestation (AOR 2.81). CONCLUSIONS: A sizeable proportion of participants were found anaemic. Female sex, older age, longer periods lived with the virus, lower CD4 count, non-suppressed viral load, history of opportunistic infections, WHO clinical stages III and IV and history of parasitic infestation were the contributing factors. Therefore, to improve the anaemic status and living circumstances of patients living with HIV, immediate action on the linked factors is needed, such as monitoring for maintenance of CD4 counts >200 cells/µL and avoiding progression of HIV to the advanced WHO clinical stages, suppressed viral load, preventing opportunistic infections and parasitic infestation.

Asunto(s)

Anemia , Terapia Antirretroviral Altamente Activa , Infecciones por VIH , Compuestos Heterocíclicos con 3 Anillos , Oxazinas , Piridonas , Humanos , Femenino , Masculino , Adulto , Estudios Transversales , Estudios Retrospectivos , Anemia/epidemiología , Etiopía/epidemiología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Prevalencia , Persona de Mediana Edad , Factores de Riesgo , Piridonas/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Recuento de Linfocito CD4 , Adulto Joven , Inhibidores de Integrasa VIH/uso terapéutico , Índice de Severidad de la Enfermedad , Piperazinas

Asunto(s)

Fármacos Anti-VIH , Farmacorresistencia Viral , Emtricitabina , Infecciones por VIH , VIH-1 , Compuestos Heterocíclicos con 3 Anillos , Oxazinas , Piperazinas , Piridonas , Tenofovir , Humanos , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , VIH-1/genética , Emtricitabina/uso terapéutico , Piridonas/uso terapéutico , Piperazinas/uso terapéutico , Tenofovir/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Fármacos Anti-VIH/uso terapéutico , Oxazinas/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Hepatitis B/tratamiento farmacológico , Adenina/análogos & derivados , Adenina/uso terapéutico , Masculino , Femenino , Amidas

RESUMEN

BACKGROUND: An increase in the prevalence of HIV drug resistance (HIVDR) has been reported in recent years, especially in persons on non-nucleoside reverse transcriptase inhibitors (NNRTIs) due to their low genetic barrier to mutations. However, there is a paucity of epidemiological data quantifying HIVDR in the era of new drugs like dolutegravir (DTG) in sub-Saharan Africa. We, therefore, sought to determine the prevalence and correlates of viral load (VL) suppression in adult people with HIV (PWH) on a fixed-dose combination of tenofovir disoproxil fumarate/lamivudine/dolutegravir (TLD) or tenofovir alafenamide/emtricitabine/dolutegravir (TAFED) and describe patterns of mutations in individuals failing treatment. METHODS: We conducted a cross-sectional study among 384 adults living with HIV aged ≥15 years between 5th June 2023 and 10th August 2023. Demographic, laboratory and clinical data were collected from electronic health records using a data collection form. Viral load suppression was defined as plasma HIV-1 RNA VL of <1000 copies/ml after being on ART for ≥ 6 months. SPSS version 22 to analyze the data. Descriptive statistics and logistic regression were the statistical methods used. RESULTS: The median (interquartile range (IQR)) age was 22 (IQR 18, 38) years, and 66.1% (n = 254) were females. VL suppression was 90.4% (n = 347); (95% confidence interval (CI) 87.6%-93.6%) after switching to TLD/TAFED. Among the virally suppressed, the majority (67.1%, n = 233) were female. Those who missed ≥2 doses in the last 30 days prior to the most recent review were less likely to attain viral suppression compared to those who did not miss any dose (adjusted odds ratio (AOR) 0.047; 95% CI 0.016-0.136; p<0.001). Four participants had resistance mutations to lamivudine and tenofovir. The most common NRTI mutations were M184MV and K65R while K101E was the most common NNRTI mutation. CONCLUSION: Our findings show that viral suppression was high after switching to TLD/TAFED; but lower than the last 95% target of the UNAIDS. Adherence to antiretroviral therapy was a significant correlate of VL suppression. We, therefore, recommend prompt switching of PWH to TLD/TAFED regimen and close monitoring to enhance adherence to therapy.

Asunto(s)

Fármacos Anti-VIH , Farmacorresistencia Viral , Infecciones por VIH , VIH-1 , Lamivudine , Mutación , Piperazinas , Piridonas , Tenofovir , Carga Viral , Humanos , Femenino , Adulto , VIH-1/genética , VIH-1/efectos de los fármacos , Masculino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Farmacorresistencia Viral/genética , Carga Viral/efectos de los fármacos , Zambia/epidemiología , Estudios Transversales , Tenofovir/uso terapéutico , Tenofovir/farmacología , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/farmacología , Piperazinas/uso terapéutico , Lamivudine/uso terapéutico , Lamivudine/farmacología , Piridonas/uso terapéutico , Oxazinas/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/farmacología , Emtricitabina/uso terapéutico , Persona de Mediana Edad , Adulto Joven , Adolescente , Combinación de Medicamentos

RESUMEN

Microplastic (MP) research faces challenges due to costly, time-consuming, and error-prone analysis techniques. Additionally, the variability in data quality across studies limits their comparability. This study addresses the critical need for reliable and cost-effective MP analysis methods through validation of a semi-automated workflow, where environmentally relevant MP were spiked into and recovered from marine fish gastrointestinal tracts (GITs) and blue mussel tissue, using Nile red staining and machine learning automated analysis of different polymers. Parameters validated include trueness, precision, uncertainty, limit of quantification, specificity, sensitivity, selectivity, and method robustness. For fish GITs a 95 ± 9 % recovery rate was achieved, and 87 ± 11 % for mussels. Polymer identification accuracies were 76 ± 8 % for fish GITs and 80 ± 13 % for mussels. Polyethylene terephthalate fragments showed more variability with lower accuracies. The proposed validation parameters offer a step towards quality management guidelines, as such aiding future researchers and fostering cross-study comparability.

Asunto(s)

Organismos Acuáticos , Monitoreo del Ambiente , Aprendizaje Automático , Microplásticos , Contaminantes Químicos del Agua , Animales , Contaminantes Químicos del Agua/análisis , Microplásticos/análisis , Monitoreo del Ambiente/métodos , Oxazinas , Peces , Mytilus edulis , Tracto Gastrointestinal , Plásticos

RESUMEN

The widespread application of neonicotinoid insecticides (NNIs) has attracted widespread attention to their potential ecotoxicological effects. In this study, we systematically evaluated the toxic effects of thiamethoxam (TMX) and its metabolite clothianidin (CLO) on earthworms (Eisenia fetida). Specifically, the antioxidant system responses and endogenous metabolite metabolism responses in earthworms were analyzed in the temporal dimension after 7, 14, 21 and 28 days of exposure to TMX and CLO. The results found that TMX and CLO could inhibit the growth phenotype of earthworms and cause significant changes in antioxidant system related indicators. More importantly, we found that TMX and CLO could cause significant changes in the metabolic profiles of earthworms through NMR-based metabolomics. From the changes in endogenous metabolites, the toxicity effects of TMX on earthworms gradually increases with prolonged exposure time. Differently, the toxicity effects of CLO on earthworms is significantly higher than that of TMX in the early stages of exposure. Meanwhile, these impacts will not weaken with prolonged exposure time. Furthermore, the results of KEGG enrichment pathway analysis indicated that TMX and CLO could significantly interfere with energy homeostasis, redox homeostasis, osmotic regulation, amino acid metabolism and protein synthesis in earthworms. These findings further deepen our understanding of the ecotoxicological effects of NNIs on soil organism.

Asunto(s)

Guanidinas , Insecticidas , Neonicotinoides , Oligoquetos , Tiametoxam , Tiazoles , Oligoquetos/efectos de los fármacos , Oligoquetos/metabolismo , Animales , Tiametoxam/toxicidad , Neonicotinoides/toxicidad , Tiazoles/toxicidad , Guanidinas/toxicidad , Insecticidas/toxicidad , Nitrocompuestos/toxicidad , Oxazinas/toxicidad , Antioxidantes/metabolismo , Metabolómica

RESUMEN

BACKGROUND: A dolutegravir (DTG)-based antiretroviral regimen has been rolled out for pregnant women in low- and middle-income countries since 2020. However, available safety data are limited to a few clinical trials and observational studies. Hence, we present real-world pregnancy and birth outcome safety data from a large sample multicenter cohort study in Ethiopia. METHODS: A retrospective cohort study was conducted in fourteen hospitals across Ethiopia from 2017 to 2022. HIV-infected pregnant women were followed from the date of prevention of mother-to-child transmission (PMTCT) care enrolment until the infant was 6-8 weeks old. The primary safety outcome was a composite of adverse pregnancy events comprising spontaneous abortion, intrauterine fetal death (IUFD) before onset of labor, preterm birth, and maternal death. Additionally, a composite adverse birth outcome was assessed, comprising intrapartum fetal demise, low birth weight, and neonatal death. Finally, a composite of adverse pregnancy or birth outcome was also investigated. The exposure of interest was the antiretroviral treatment (ART) regimen used during pregnancy for PMTCT of HIV. RESULTS: During the study period, 2643 women were enrolled in routine PMTCT care. However, 2490 (92.2%) participants were eligible for the study. A total of 136/1724 (7.9%, 95% CI: 6.7-9.3%) women experienced adverse pregnancy outcomes. Fewer women in the DTG-based group (5.4%, 95% CI: 3.7-7.5%) had adverse pregnancy outcomes than in the Efavirenz (EFV)-based group (8.3%, 95% CI: 6.6-10.3%), P = 0.004. After controlling for baseline differences, the DTG group had a 43% lower risk of adverse pregnancy outcomes (adjusted odd ratio (AOR), 0.57; 95% CI, 0.32-0.96%) and a 53% lower risk of preterm birth (AOR, 0.47; 95% CI, 0.22-0.98%) compared to the EFV group. A total of 103/1616 (6.4%, 95% CI: 5.2-7.7%) women had adverse birth outcomes. Although the difference was not statistically significant, fewer women in the DTG group (30/548; 5.5%, 95% CI: 3.7-7.7%) than in the EFV group (57/830; 6.9%, 95% CI: 5.2-8.8%) had adverse birth outcomes. CONCLUSIONS: In this study, we observed that DTG-based regimens were associated with better pregnancy and birth outcome safety profiles, reaffirming the WHO recommendation. However, a prospective study is recommended to assess uncaptured maternal and perinatal adverse outcomes, such as congenital abnormalities, and infant growth and neurocognitive development.

Asunto(s)

Infecciones por VIH , Compuestos Heterocíclicos con 3 Anillos , Transmisión Vertical de Enfermedad Infecciosa , Oxazinas , Piperazinas , Complicaciones Infecciosas del Embarazo , Resultado del Embarazo , Piridonas , Humanos , Embarazo , Femenino , Etiopía/epidemiología , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Adulto , Estudios Retrospectivos , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Recién Nacido , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Adulto Joven , Ciclopropanos , Benzoxazinas/uso terapéutico , Benzoxazinas/efectos adversos , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/efectos adversos , Alquinos , Estudios de Cohortes , Nacimiento Prematuro/epidemiología

RESUMEN

We report a novel system consisting of a redox reaction and a highly efficient reductase-like nanozyme, silica-palladium nanoparticles (Pd@SiO2 NPs), as a novel detection platform for fluorometric sensing. In a proof-of-concept demonstration using an oligonucleotide as the detection target, a glass fiber-based sensor is fabricated by covalently conjugating two oligo probes, which are complementary to the adjacent segments of the target oligonucleotide, on Pd@SiO2 NPs and glass fiber, respectively. In the presence of the target oligonucleotide, the two probes are drawn together by the target through sequence-specific hybridization, bringing the Pd@SiO2 NPs to the glass fiber. When the glass fiber is subsequently immersed in a mixture of resazurin and ammonia borane solution, the Pd@SiO2 NPs on the glass fiber trigger the catalytic conversion of resazurin (blue, slightly fluorescent) to resorufin (pink, highly fluorescent) with massive signal amplification, indirectly signaling the presence of the target oligonucleotide. We show that the glass fiber-based fluorometric sensor can detect a target oligonucleotide associated with the BRAF mutation linearly in the concentration range of 20 to 400 pM with a detection limit (LOD) of 15 pM and the specificity to differentiate targets with single-base difference. These results demonstrate a new frontier for the development of a sensitive, specific, and inexpensive nonenzyme-based fluorometric sensing platform as an alternative to conventional enzyme-based assays.

Asunto(s)

Fluorometría , Oxazinas , Xantenos , Oxazinas/química , Xantenos/química , Boranos/química , Dióxido de Silicio/química , Paladio/química , Amoníaco/análisis , Amoníaco/química , Oxidorreductasas/química , Oxidorreductasas/metabolismo , Nanopartículas del Metal/química , Límite de Detección , Técnicas Biosensibles/métodos , Humanos

RESUMEN

Neonicotinoid pesticides are a relatively new class of pesticides that have garnered significant attention owing to their potential ecological risks to nontarget organisms. A method combining solid phase extraction with liquid chromatography-tandem mass spectrometry (SPE-LC-MS/MS) was developed for the rapid and accurate detection of eight neonicotinoid pesticides (dinotefuran, E-nitenpyram, thiamethoxam, clothianidin, imidacloprid, imidaclothiz, acetamiprid, and thiacloprid) in wastewater. The chromatographic mobile phase and MS parameters were selected, and a single-factor method was used to determine the optimal column type, extraction volume, sample loading speed, and pH for SPE. The optimal parameters were as follows: column type, HLB column (500 mg/6 mL); sample extraction volume, 500 mL; sample loading speed, 10 mL/min; and sample pH, 6-8. The matrix effects of the wastewater samples were reduced by optimizing the chromatographic gradient-elution program, examining the dilution factor of the samples, and using the isotope internal standard calibration method. Prior to analysis, the wastewater samples were diluted 5-fold with ultrapure water for pretreatment. Subsequently, 2 mmol/L ammonium acetate aqueous solution containing 0.1% (v/v) formic acid and methanol was used as mobile phases for gradient elution on a ZORBAX Eclipse Plus C18 column (100 mm×2.1 mm, 1.8 µm). The samples were quantified using positive-ion multiple reaction monitoring (MRM) mode for 10 min. Imidacloprid-d4 was used as the isotope internal standard. The SPE process was further optimized by applying response surface methodology to select the type and mass of rinsing and elution solvents. The optimal pretreatment of the SPE column included rinsing with 10% methanol aqueous solution and elution with methanol-acetonitrile (1∶1, v/v) mixture (7 mL). The eight neonicotinoid pesticides showed satisfactory linearity within the relevant range, with linear correlation coefficients (r) all greater than 0.9990. The method detection limits (MDLs) ranged from 0.2 to 1.2 ng/L, and the method quantification limits (MQLs) ranged from 0.8 to 4.8 ng/L. The average recoveries of the eight neonicotinoid pesticides were in the range of 82.6%-94.2% at three spiked levels, with relative standard deviations (RSDs) ranging from 3.9% to 9.4%. Finally, the optimized method was successfully applied to analyze wastewater samples collected from four sewage treatment plants. The results indicated that the eight neonicotinoid pesticides could be generally detected at concentrations ranging from not detected (ND) to 256 ng/L. The developed method has a low MDL and high accuracy, rendering it a suitable choice for the trace detection of the eight neonicotinoid pesticides in wastewater when compared with other similar methods. The proposed method can be utilized to monitor the environmental impact and assess the potential risks of neonicotinoid pesticides in wastewater, thus promoting the protection of nontarget organisms and the sustainable use of these pesticides in agriculture.

Asunto(s)

Neonicotinoides , Nitrocompuestos , Extracción en Fase Sólida , Espectrometría de Masas en Tándem , Aguas Residuales , Contaminantes Químicos del Agua , Espectrometría de Masas en Tándem/métodos , Extracción en Fase Sólida/métodos , Aguas Residuales/química , Aguas Residuales/análisis , Neonicotinoides/análisis , Contaminantes Químicos del Agua/análisis , Cromatografía Liquida/métodos , Nitrocompuestos/análisis , Tiametoxam/análisis , Guanidinas/análisis , Tiazoles/análisis , Plaguicidas/análisis , Tiazinas/análisis , Oxazinas/análisis

RESUMEN

Specific cancer therapy remains a problem to be solved. Breast and colorectal cancer are among the cancers with the highest prevalence and mortality rates. Although there are some therapeutic options, there are still few effective agents for those cancers, which constitutes a clinical problem that requires further research efforts. Lysosomes play an important role in cancer cells' survival, and targeting lysosomes has gained increased interest. In recent years, our team has been synthetizing and testing novel benzo[a]phenoxazine derivatives, as they have been shown to possess potent pharmacological activities. Here, we investigated the anticancer activity of three of the most potent derivatives from our library, C9, A36, and A42, on colorectal- and breast-cancer-derived cell lines, and compared this with the effect on non-neoplastic cell lines. We observed that the three compounds were selective for the cancer cells, namely the RKO colorectal cancer cell line and the MCF7 breast cancer cell line. In both models, the compounds reduced cell proliferation, cell survival, and cell migration, accumulated on the lysosome, and induced cell death accompanied by lysosomal membrane permeabilization (LMP), increasing the intracellular pH and ROS accumulation. Our results demonstrated that these compounds specifically target lysosomes from cancer cells, making them promising candidates as LMP inducers for cancer therapy.

Asunto(s)

Antineoplásicos , Proliferación Celular , Lisosomas , Oxazinas , Humanos , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Oxazinas/farmacología , Oxazinas/uso terapéutico , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Especies Reactivas de Oxígeno/metabolismo , Células MCF-7 , Supervivencia Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos

RESUMEN

INTRODUCTION: Millions of people living with HIV (PLWH) take oral antiretroviral therapy (ART), which requires a lifetime of consistent medication adherence. The relationship between adherence and poor HIV outcomes is well documented. Newer ART regimens that include dolutegravir (DTG) could be more forgiving, but empirical evidence on the relationship between adherence and viral suppression under DTG is only emerging. METHODS: In this observational cohort study (secondary analysis of data from a randomized trial), we used data from 313 ART clients from a large HIV clinic in Kampala, Uganda. Over the 4-year study period (January 2018-January 2022), 91% switched from non-DTG regimens to DTG regimens. We measured adherence using Medication Event Monitoring Systems-caps and extracted prescription information and viral load measures from electronic health records. We estimated unadjusted linear regressions and adjusted models that included individual and time fixed-effects. RESULTS: Under non-DTG regimens, 96% of participants were virally suppressed (defined as viral load < 200 copies/ml) when adherence was 90% or higher in the 3 months before viral load measurement. Viral suppression was 32 percentage points lower when adherence was between 0% and 49% (95% CI -0.44, -0.20, p < 0.01), 12 percentage points lower when adherence was between 50% and 79% (95% CI -0.23, -0.02, p < 0.01), and not significantly different when adherence was between 80% and 89% (effect of 0.00, 95% CI -0.06, 0.07, p = 0.81). In contrast, for participants taking DTG, there was no statistically significant difference in viral suppression among any of the four adherence levels; more than 95% were virally suppressed at each adherence level. On average, switching to DTG increased viral suppression by 6 percentage points in our adjusted models (95% CI 0.00, 0.13, p = 0.03). CONCLUSIONS: There was no significant association between adherence levels and viral suppression among PLWH taking DTG regimens, suggesting a high degree of forgiveness for missed doses. The use of DTG should be prioritized over older regimens, particularly for those with low adherence. CLINICAL TRIAL NUMBER: NCT03494777.

Asunto(s)

Infecciones por VIH , Compuestos Heterocíclicos con 3 Anillos , Cumplimiento de la Medicación , Oxazinas , Piperazinas , Piridonas , Carga Viral , Humanos , Uganda , Piridonas/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Masculino , Femenino , Cumplimiento de la Medicación/estadística & datos numéricos , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Adulto , Carga Viral/efectos de los fármacos , Oxazinas/uso terapéutico , Piperazinas/uso terapéutico , Estudios de Cohortes , Persona de Mediana Edad , Fármacos Anti-VIH/uso terapéutico

RESUMEN

INTRODUCTION: Dolutegravir (DTG)-based antiretroviral therapy is the World Health Organization's preferred first-line regimen for all persons with HIV, including pregnant women. While DTG has been implicated as an obesogen associated with greater weight gain compared to other antiretrovirals, there is a paucity of data in pregnant women and their children. The Obesogenic oRigins of maternal and Child metabolic health Involving Dolutegravir (ORCHID) study is investigating associations between DTG, weight gain, and metabolic outcomes in the context of HIV. MATERIALS & METHODS: ORCHID is a prospective observational study taking place in Cape Town, South Africa (NCT04991402). A total of 1920 pregnant women with and without HIV infection are being followed from ≤18 weeks gestational age to 24 months postpartum with their children. Participants attend eleven study visits: 3 antenatal, delivery, and 7 postnatal visits. Several embedded sub-studies address specific scientific aims. Primary outcome measurements in mothers include anthropometry, blood pressure, body composition, dysglycemia, insulin resistance (IR), and dyslipidemia. Other maternal measures include demographics, resting energy expenditure, viral load, physical activity, dietary intake, hepatic steatosis, and repository specimens. Sub-study measurements include markers of adipose inflammation, gut integrity, and satiety/hunger, subcutaneous adipose tissue morphology and mitochondrial function, and metabolomics. Primary outcome measurements in children include anthropometry, adipose tissue mass, dysglycemia, IR, and dyslipidemia. Other variables include fetal growth, birth outcomes, medical/breastfeeding history, caloric intake, neurodevelopment, and repository specimens. Sub-study measurements include metabolites/lipid subspecies in umbilical cord blood, as well as breast milk composition and DTG exposure. DISCUSSION: ORCHID will play a pivotal role in defining obesogenic mechanisms and clinical consequences of DTG use in pregnancy in women with HIV and their children. It will provide insights into metabolic disease risk reduction in the context of HIV/DTG, identify intervention targets, and inform public health approaches to diminish chronic metabolic co-morbidities for women and children.

Asunto(s)

Infecciones por VIH , Compuestos Heterocíclicos con 3 Anillos , Oxazinas , Piperazinas , Piridonas , Humanos , Femenino , Embarazo , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Piperazinas/efectos adversos , Piperazinas/uso terapéutico , Adulto , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Complicaciones Infecciosas del Embarazo/virología , Estudios Prospectivos , Inhibidores de Integrasa VIH/efectos adversos , Inhibidores de Integrasa VIH/uso terapéutico , Preescolar , Lactante , Recién Nacido , Obesidad/inducido químicamente , Obesidad/epidemiología , Resistencia a la Insulina , Masculino , Aumento de Peso/efectos de los fármacos , Estudios de Cohortes , Sudáfrica/epidemiología

RESUMEN

Dolutegravir (DLG) has become a distinctive first-line antiretroviral therapy for the treatment of HIV in most countries due to its affordability, high efficacy, and low drug-drug interactions. However, the evaluation of genotoxic impurities (GTIs) in DLG and their toxicity assessment has not been explored thoroughly. Thus, in this study, a simple, fast, and selective analytical methodology was developed for the identification and determination of 7 GTIs in the comprehensive, explicit route of synthesis for the dolutegravir sodium (DLG-Na) drug. A facile, fast ultrasonication-assisted liquid-liquid extraction procedure was adapted to isolate the GTIs in DLG-Na and then analyzed using the gas chromatography (GC)-electron impact (EI)/mass spectrometer (MS) quantification (using selective ion monitoring mode) technique. This EI-GC/MS method was validated as per the current requirements of ICH Q2 (R1) guidelines. Under optimal method conditions, excellent linearities were achieved with R between 0.9959 and 0.9995, and high sensitivity was obtained in terms of detection limits (LOD) between 0.15 to 0.63 µg/g, and quantification limits (LOQ) between 0.45 to 1.66 µg/g for the seven GTIs in DLG. The obtained recoveries ranged from 98.2 to 104.3 % at LOQ, 15 µg/g, and 18 µg/g concentration levels (maximum daily dose of 100 mg). This developed and validated method is rapid, easy to adopt, specific, sensitive, and accurate in estimating the seven GTIs in a relatively complex sodium matrix of the DLG-Na drug moiety. As a method application, two different manufactured samples of DLG-Na drug substances were analyzed for the fate of the GTIs and drug safety for the intended dosage applications. Moreover, an in-silico QSAR toxicity prediction assessment was carried out to prove scientifically the potential GTI nature of each impurity from the alerting functional groups.

Asunto(s)

Contaminación de Medicamentos , Cromatografía de Gases y Espectrometría de Masas , Compuestos Heterocíclicos con 3 Anillos , Límite de Detección , Oxazinas , Piperazinas , Piridonas , Compuestos Heterocíclicos con 3 Anillos/química , Compuestos Heterocíclicos con 3 Anillos/análisis , Piperazinas/química , Piperazinas/análisis , Piridonas/química , Piridonas/análisis , Cromatografía de Gases y Espectrometría de Masas/métodos , Oxazinas/química , Reproducibilidad de los Resultados , Modelos Lineales , Mutágenos/análisis , Fármacos Anti-VIH/análisis , Fármacos Anti-VIH/química , Extracción Líquido-Líquido/métodos , Sonicación/métodos , Simulación por Computador , Humanos

RESUMEN

This study used the brilliant cresyl blue (BCB) staining method to group buffalo oocytes (BCB+ and BCB-) and perform in vitro maturation, in vitro fertilization and embryo culture. At the same time, molecular biology techniques were used to detect gap junction protein expression and oxidative stress-related indicators to explore the molecular mechanism of BCB staining to predict oocyte developmental potential. The techniques of buffalo oocytes to analyse their developmental potential and used immunofluorescence staining to detect the expression level of CX43 protein, DCFH-DA probe staining to detect ROS levels and qPCR to detect the expression levels of the antioxidant-related genes SOD2 and GPX1. Our results showed that the in vitro maturation rate, embryo cleavage rate and blastocyst rate of buffalo oocytes in the BCB+ group were significantly higher than those in the BCB- group and the control group (p < .05). The expression level of CX43 protein in the BCB+ group was higher than that in the BCB- group both before and after maturation (p < .05). The intensity of ROS in the BCB+ group was significantly lower than that in the BCB- group (p < .05), and the expression levels of the antioxidant-related genes SOD2 and GPX1 in the BCB+ group were significantly higher than those in the BCB- group (p < .05). Brilliant cresyl blue staining could effectively predict the developmental potential of buffalo oocytes. The results of BCB staining were positively correlated with the expression of gap junction protein and antioxidant-related genes and negatively correlated with the reactive oxygen species level, suggesting that the mechanism of BCB staining in predicting the developmental potential of buffalo oocytes might be closely related to antioxidant activity.

Asunto(s)

Búfalos , Conexina 43 , Técnicas de Maduración In Vitro de los Oocitos , Oocitos , Oxazinas , Estrés Oxidativo , Animales , Oocitos/metabolismo , Conexina 43/genética , Conexina 43/metabolismo , Femenino , Técnicas de Maduración In Vitro de los Oocitos/veterinaria , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa/genética , Glutatión Peroxidasa/metabolismo , Glutatión Peroxidasa/genética , Fertilización In Vitro/veterinaria , Técnicas de Cultivo de Embriones/veterinaria , Glutatión Peroxidasa GPX1 , Desarrollo Embrionario/fisiología , Coloración y Etiquetado , Antioxidantes/metabolismo

Asunto(s)

Fármacos Anti-VIH , Infecciones por VIH , Humanos , Infecciones por VIH/prevención & control , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/economía , Fármacos Anti-VIH/economía , Fármacos Anti-VIH/uso terapéutico , Costos de los Medicamentos , Piridonas/economía , Piridonas/uso terapéutico , Profilaxis Pre-Exposición/economía , Profilaxis Pre-Exposición/métodos , Compuestos Heterocíclicos con 3 Anillos/economía , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Oxazinas/uso terapéutico , Piperazinas

RESUMEN

BACKGROUND: There is a need to understand health care resource utilization (HCRU) and costs associated with treatment-experienced people with HIV (PWH) switching treatment regimens. OBJECTIVE: To describe HCRU and cost during lines of antiretroviral therapy (ART) for treatment-experienced PWH switching to or restarting guideline-recommended, integrase strand transfer inhibitor (INSTI)-based multitablet regimens and single-tablet regimens. METHODS: This retrospective claims study used data from Optum Research Database (January 1, 2010, to March 31, 2020) to identify lines of therapy (LOTs) for treatment-experienced adults who switched to or restarted INSTI-based regimens between January 1, 2018, and December 31, 2019. The first LOT during the study period was included in the analysis. We examined all-cause HCRU and costs and HIV-related HCRU and combined costs to the health plan and direct patient costs by site of service and compared between INSTI-based regimens: bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) (single tablet) vs dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) (single tablet), dolutegravir + emtricitabine/tenofovir alafenamide (DTG+FTC/TAF) (multitablet), and dolutegravir + emtricitabine/tenofovir disoproxil fumarate (DTG+FTC/TDF) (multitablet). Analysis of HCRU by site of service was conducted following inverse probability treatment weighting. Multivariable regression was conducted using a generalized linear model with stepwise covariate selection to estimate HIV-related medical costs and control for remaining differences after inverse probability treatment weighting. RESULTS: 4,251 PWH were identified: B/F/TAF (n = 2,727; 64.2%), DTG/ABC/3TC (n = 898; 21.1%), DTG+FTC/TAF (n = 539; 12.7%), and DTG+FTC/TDF (n = 87; 2.1%). PWH treated with DTG+FTC/TAF had a significantly higher mean of all-cause ambulatory visits than PWH treated with B/F/TAF (1.8 vs 1.6, P < 0.001). A significantly smaller proportion of PWH treated with DTG/ABC/3TC had an all-cause ambulatory visit vs PWH treated with B/F/TAF (90.6% vs 93.9%, P < 0.001). All-cause total costs were not significantly different between regimens. Mean (SD) medical HIV-related costs per month during the LOT were not significantly different between B/F/TAF $699 (3,602), DTG/ABC/3TC $770 (3,469), DTG+FTC/TAF $817 (3,128), and DTG+FTC/TDF $3,570 (17,691). After further controlling for unbalanced measures, HIV-related medical costs during the LOT were higher (20%) but did not reach statistical significance for DTG/ABC/3TC (cost ratio = 1.20, 95% CI = 0.851-1.694; P = 0.299), 49% higher for DTG+FTC/TAF (cost ratio = 1.489, 95% CI = 1.018-2.179; P = 0.040), and almost 11 times greater for DTG+FTC/TDF (cost ratio = 10.759, 95% CI = 2.182-53.048; P = 0.004) compared with B/F/TAF. CONCLUSIONS: HIV-related medical costs during the LOT were lowest for PWH treated with INSTI-based single-tablet regimens. Simplifying treatment regimens may help PWH maintain lower health care costs.

Asunto(s)

Fármacos Anti-VIH , Infecciones por VIH , Piridonas , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/economía , Estudios Retrospectivos , Femenino , Masculino , Adulto , Persona de Mediana Edad , Piridonas/economía , Piridonas/uso terapéutico , Fármacos Anti-VIH/economía , Fármacos Anti-VIH/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/economía , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Tenofovir/uso terapéutico , Tenofovir/economía , Aceptación de la Atención de Salud/estadística & datos numéricos , Costos de la Atención en Salud/estadística & datos numéricos , Combinación de Medicamentos , Oxazinas/uso terapéutico , Oxazinas/economía , Emtricitabina/uso terapéutico , Emtricitabina/economía , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/economía , Piperazinas/economía , Piperazinas/uso terapéutico , Lamivudine/economía , Lamivudine/uso terapéutico , Inhibidores de Integrasa VIH/economía , Inhibidores de Integrasa VIH/uso terapéutico , Recursos en Salud/economía , Recursos en Salud/estadística & datos numéricos , Sustitución de Medicamentos/economía , Amidas , Ciclopropanos , Didesoxiadenosina/análogos & derivados

RESUMEN

Introduction: VESTED (NCT03048422) compared the safety and efficacy of three antiretroviral treatment (ART) regimens in pregnant and postpartum women: dolutegravir+emtricitabine/tenofovir alafenamide fumarate; dolutegravir+emtricitabine/tenofovir disoproxil fumarate (TDF); efavirenz/emtricitabine/TDF. Vertical HIV transmission (VT) occurred to 4/617 (0.60%) live-born infants, who were evaluated for HIV drug resistance (HIVDR) and other risk factors. Setting: In 2018-2020, pregnant (weeks-14-28) women living with HIV and ≤14 days of ART were enrolled at 22 international sites and followed with their infants through 50 weeks postpartum. Methods: HIV sequences derived by single genome amplification (SGA) from longitudinally collected specimens were assessed from VT Cases for HIVDR in protease, reverse transcriptase, integrase, and the nef 3'polypurine tract (3'PPT). Results: The four Case mothers were prescribed efavirenz-based-ART for 1-7 days prior to randomization to study ART. Their infants received postnatal nevirapine+/-zidovudine prophylaxis and were breastfed. A total of 833 SGA sequences were derived. The "major" (Stanford HIVDR Score ≥60) non-nucleoside reverse transcriptase inhibitor (NNRTI) mutation (K103N) was detected persistently in one viremic mother, and likely contributed to VT of HIVDR. Major NNRTI HIVDR mutations were detected in all three surviving infants. No integrase, nor high frequencies of 3'PPT mutations conferring dolutegravir HIVDR were detected. The timing of HIV infant diagnosis, plasma HIV RNA levels and HIVDR suggests one in utero, one peripartum, one early, and one late breastfeeding transmission. Conclusions: VT was rare. New-onset NNRTI HIVDR in Case mothers was likely from efavirenz-ART prescribed prior to study dolutegravir-ART, and in one case appeared transmitted to the infant despite nevirapine prophylaxis.

Asunto(s)

Fármacos Anti-VIH , Farmacorresistencia Viral , Infecciones por VIH , Transmisión Vertical de Enfermedad Infecciosa , Humanos , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/transmisión , Infecciones por VIH/virología , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Farmacorresistencia Viral/genética , Embarazo , Fármacos Anti-VIH/uso terapéutico , Adulto , Recién Nacido , Piperazinas/uso terapéutico , Ciclopropanos , VIH-1/genética , VIH-1/efectos de los fármacos , Tenofovir/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Alquinos , Piridonas/uso terapéutico , Emtricitabina/uso terapéutico , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Complicaciones Infecciosas del Embarazo/virología , Benzoxazinas/uso terapéutico , Oxazinas/uso terapéutico

RESUMEN

The neurotoxic effects of neonicotinoids (NEOs) have been widely reported in relation to the poisoning of wild birds, yet the underlying molecular mechanism has remained elusive. This study employed Japanese quails (Coturnix japonica) and primary quail embryonic neurons as in vivo and ex vivo models, respectively, to investigate the neurotoxic effects and mechanism of thiamethoxam (TMX), a representative neonicotinoid insecticide, at environmentally relevant concentrations. Following a 28-day exposure to TMX, metabolomic analysis of quail brain revealed TMX-induced changes in glutamatergic, GABA-ergic, and dopaminergic function. Subsequent ex vivo and in silico experimentation revealed that the activation of nicotinic acetylcholine receptors and calcium signaling, induced by clothianidin (CLO), the primary metabolite of TMX, served as upstream events for the alterations in neurotransmitter synthesis, metabolism, release, and uptake. Our findings propose that the disruption of the central nervous system, caused by environmentally significant concentrations of NEOs, may account for the avian poisoning events induced by NEOs.

Asunto(s)

Coturnix , Insecticidas , Tiametoxam , Animales , Tiametoxam/toxicidad , Coturnix/metabolismo , Insecticidas/toxicidad , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/metabolismo , Neonicotinoides/toxicidad , Tiazoles/toxicidad , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Simulación por Computador , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Guanidinas/toxicidad , Oxazinas/toxicidad , Receptores Nicotínicos/metabolismo

RESUMEN

INTRODUCTION: HIV drug resistance poses a challenge to the United Nation's goal of ending the HIV/AIDS epidemic. The integrase strand transfer inhibitor (InSTI) dolutegravir, which has a higher resistance barrier, was endorsed by the WHO in 2019 for first-line, second-line and third-line antiretroviral therapy (ART). This multiplicity of roles of dolutegravir in ART may facilitate the emergence of dolutegravir resistance. METHODS AND ANALYSIS: Nested within the International epidemiology Databases to Evaluate AIDS (IeDEA), DTG RESIST is a multicentre study of adults and adolescents living with HIV in sub-Saharan Africa, Asia, and South and Central America who experienced virological failure on dolutegravir-based ART. At the time of virological failure, whole blood will be collected and processed to prepare plasma or dried blood spots. Laboratories in Durban, Mexico City and Bangkok will perform genotyping. Analyses will focus on (1) individuals who experienced virological failure on dolutegravir and (2) those who started or switched to such a regimen and were at risk of virological failure. For population (1), the outcome will be any InSTI drug resistance mutations, and for population (2) virological failure is defined as a viral load >1000 copies/mL. Phenotypic testing will focus on non-B subtype viruses with major InSTI resistance mutations. Bayesian evolutionary models will explore and predict treatment failure genotypes. The study will have intermediate statistical power to detect differences in resistance mutation prevalence between major HIV-1 subtypes; ample power to identify risk factors for virological failure and limited power for analysing factors associated with individual InSTI drug resistance mutations. ETHICS AND DISSEMINATION: The research protocol was approved by the Biomedical Research Ethics Committee at the University of KwaZulu-Natal, South Africa and the Ethics Committee of the Canton of Bern, Switzerland. All sites participate in International epidemiology Databases to Evaluate AIDS and have obtained ethics approval from their local ethics committee to collect additional data. TRIAL REGISTRATION NUMBER: NCT06285110.

Asunto(s)

Farmacorresistencia Viral , Infecciones por VIH , Inhibidores de Integrasa VIH , VIH-1 , Compuestos Heterocíclicos con 3 Anillos , Oxazinas , Piperazinas , Piridonas , Humanos , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Oxazinas/uso terapéutico , VIH-1/genética , VIH-1/efectos de los fármacos , Piperazinas/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Infecciones por VIH/epidemiología , Farmacorresistencia Viral/genética , Inhibidores de Integrasa VIH/uso terapéutico , Adulto , Adolescente , Estudios Multicéntricos como Asunto , Carga Viral , Genotipo , Femenino , Masculino , África del Sur del Sahara/epidemiología

RESUMEN

We describe and analyze resistance-associated mutations (RM) and virological failures (VF) on antiretroviral therapy using the latest approved integrase inhibitors (INIs) dolutegravir (DTG), bictegravir (BIC), and cabotegravir (CAB), together with their companion drugs in fixed-dose formulations: BIC/emtricitabine/tenofovir; CAB/rilpivirine; DTG/abacavir/lamivudine; DTG/emtricitabine/tenofovir; and DTG/lamivudine. Systematic literature searches were conducted in PubMed and other electronic databases for clinical studies published between January 2010 and May 2023, according to preferred reporting items for systematic reviews and meta-analyses guidelines (PRISMA), which analyzed VFs and RMs of INIs. Fifty clinical studies were included in the synthesis. VF in antiretroviral treatment (ART)-naïve patients occurred in 0.7-4.0%, 0.6-1.4%, and 0.6-9.0% of patients treated with DTG, BIC, and CAB, respectively. VF was reported in patients with previous ART in 0-8.1%, 0-2.0%, and 0.4-2.3% of those treated with DTG, BIC, and CAB, respectively. RMs were detected in ART-naïve patients in only one study with DTG (0.3%), none of the studies with BIC, and three of the studies with CAB (0.1-5.4%). In ART-experienced patients, RMs were detected in 0-1.9% of DTG-treated patients. No cases of RM were detected in the 11 BIC studies reviewed. In the case of CAB, RMs were detected in eight studies, ranging from 0.3% to 1.9% of patients. In conclusion, RM rates in the studies reviewed were generally low using the latest INIs. This review identified BIC as the INI with the lowest number of observed VF and lack of RM.

Asunto(s)

Farmacorresistencia Viral , Infecciones por VIH , Inhibidores de Integrasa VIH , VIH-1 , Compuestos Heterocíclicos con 3 Anillos , Compuestos Heterocíclicos de 4 o más Anillos , Oxazinas , Piperazinas , Piridonas , Humanos , Piridonas/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Oxazinas/uso terapéutico , Piperazinas/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Inhibidores de Integrasa VIH/uso terapéutico , Inhibidores de Integrasa VIH/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Piridazinas/uso terapéutico , Piridazinas/farmacología , Insuficiencia del Tratamiento , Amidas/uso terapéutico , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/farmacología , Dicetopiperazinas

RESUMEN

BACKGROUND: One major barrier to HIV cure is the persistence of virus, possibly linked to an insufficient antiretroviral drug (ARV) distribution into tissues. OBJECTIVES: To draw the whole-body distribution of three antiretroviral drugs-tenofovir disoproxil fumarate, emtricitabine and dolutegravir-in non-human primates (NHPs). METHODS: Eight uninfected NHPs received a single injection of a solution containing the three ARVs. Forty-five different tissues were sampled 24 h after injection. RESULTS: Median tissue penetration factors (TPFs) were 45.4, 5.8 and 0.5 for tenofovir, emtricitabine and dolutegravir, respectively, and were statistically different between the three ARVs. Tissues were grouped by system, because TPFs were consistent according to these groups, and ranked in order of decreasing TPFs. The digestive system was the system with the highest tissue concentrations. Next came the two main sites of elimination, the liver and the kidney, as well as the tissues of the cardiopulmonary and urinary systems. Then, it was the whole lymphatic system. The next group included the reproductive system, the adipose tissue and the skin. The last two systems were the muscle and the CNS. The intra-tissue variability was rather low with a median coefficient of variation of the concentrations around 15% and no value greater than 80%. CONCLUSIONS: Overall, this study determines the first whole-body distribution in a validated NHP model. These data have important implications for future preclinical and clinical studies for the development of novel HIV therapies towards an HIV cure.

Asunto(s)

Emtricitabina , Compuestos Heterocíclicos con 3 Anillos , Oxazinas , Piperazinas , Piridonas , Tenofovir , Animales , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Emtricitabina/farmacocinética , Tenofovir/farmacocinética , Distribución Tisular , Masculino , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/administración & dosificación , Femenino , Macaca mulatta