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Radiology. Cardiothoracic Imaging Apr 2024Purpose To assess early subclinical coronary artery disease (CAD) burden and its relation to myocardial function in asymptomatic persons living with HIV (PLWH) who are...
Purpose To assess early subclinical coronary artery disease (CAD) burden and its relation to myocardial function in asymptomatic persons living with HIV (PLWH) who are at low risk for cardiovascular disease (CVD). Materials and Methods In this prospective, HIPAA-compliant study (ClinicalTrials.gov NCT01656564 and NCT01399385) conducted from April 2010 to May 2013, 74 adult PLWH without known CVD and 25 matched healthy controls underwent coronary MRI to measure coronary vessel wall thickness (VWT) and echocardiography to assess left ventricular function. Univariable and multivariable linear regression analyses were used to evaluate statistical associations. Results For PLWH, the mean age was 49 years ± 11 (SD), and the median Framingham risk score was 3.2 (IQR, 0.5-6.6); for matched healthy controls, the mean age was 46 years ± 8 and Framingham risk score was 2.3 (IQR, 0.6-6.1). PLWH demonstrated significantly greater coronary artery VWT than did controls (1.47 mm ± 0.22 vs 1.34 mm ± 0.18; = .006) and a higher left ventricular mass index (LVMI) (77 ± 16 vs 70 ± 13; = .04). Compared with controls, PLWH showed altered association between coronary artery VWT and both E/A (ratio of left ventricular-filling peak blood flow velocity in early diastole [E wave] to that in late diastole [A wave]) ( = .03) and LVMI ( = .04). In the PLWH subgroup analysis, coronary artery VWT increase was associated with lower E/A ( < .001) and higher LVMI ( = .03), indicating restricted diastolic function. In addition, didanosine exposure was associated with increased coronary artery VWT and decreased E/A ratio. Conclusion Asymptomatic low-CVD-risk PLWH demonstrated increased coronary artery VWT in association with impaired diastolic function, which may be amenable to follow-up studies of coronary pathogenesis to identify potential effects on the myocardium and risk modification strategies. Coronary Vessel Wall Thickness, Diastolic Function, HIV, MRI, Echocardiography, Atherosclerosis Clinical trial registration nos. NCT01656564 and NCT01399385 © RSNA, 2024.
Topics: Adult; Humans; Middle Aged; Cardiovascular Diseases; Diastole; Heart; HIV Infections; Prospective Studies
PubMed: 38573125
DOI: 10.1148/ryct.230102 -
American Journal of Ophthalmology Case... Sep 2020To report the case 47-year-old patient presenting with severe maculopathy associated with long-term ritonavir treatment.
PURPOSE
To report the case 47-year-old patient presenting with severe maculopathy associated with long-term ritonavir treatment.
METHODS
Observational case report of one patient and literature review.
RESULTS
A 47 year-old Caucasian man presented with progressive bilateral vision loss for the past 5 years. His medical history included Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV) coinfection since 1992. He was treated by highly active antiretroviral therapy for 24 years including 4 years of didanosine treatment and 18 years of ritonavir treatment. Bilateral extensive macular atrophy with foveal sparing on the left eye and absence of midperipheral/peripheral retina involvement was confirmed on multimodal imaging and functional testing including swept-source OCT angiography and electroretinography.
CONCLUSION
Ritonavir associated maculopathy is a scarcely described medication-associated retinopathy. In this case, an extensive macular atrophy (with complete loss of photoreceptor, RPE and choriocapillaris layers) and subsequent cone-rod dysfunction appeared after 18 years of ritonavir exposure.
PubMed: 32803017
DOI: 10.1016/j.ajoc.2020.100783 -
Southern African Journal of HIV Medicine 2019The extent of disclosure of HIV status to children and adolescents and the context facilitating their disclosure process have received little attention.
BACKGROUND
The extent of disclosure of HIV status to children and adolescents and the context facilitating their disclosure process have received little attention.
OBJECTIVES
To assess disclosure and provide a comprehensive analysis of characteristics associated with disclosure to children (3-14 years) receiving antiretroviral treatment in a South African semi-urban clinic.
METHODS
This cross-sectional study used structured interview administered questionnaires which were supplemented with medical record data. Predictors included child, caregiver, clinical and socio-economic characteristics, viral suppression, immune response, adherence, health-related quality of life and family functioning.
RESULTS
We included 190 children of whom 45 (23.7%) received disclosure about their HIV status, of whom 28 (14.7%) were partially disclosed and 17 (8.9%) were fully disclosed. Older age of the child and higher education of the caregiver were strongly associated with disclosure. Female caregivers, detectable viral load, syrup formulation, protease inhibitor (PI) regimens with stavudine and didanosine, and self-reported non-adherence were strongly associated with non-disclosure.
CONCLUSION
When children do well on treatment, caregivers feel less stringent need to disclose. Well-functioning families, higher educated caregivers and better socio-economic status enabled and promoted disclosure. Non-disclosure can indicate a sub-optimal social structure which could negatively affect adherence and viral suppression. There is an urgent need to address disclosure thoughtfully and proactively in the long-term disease management. For the disclosure process to be beneficial, an enabling supportive context is important, which will provide a great opportunity for future interventions.
PubMed: 31534786
DOI: 10.4102/sajhivmed.v20i1.884 -
Journal Francais D'ophtalmologie Jun 2023
Topics: Humans; Didanosine; Follow-Up Studies; HIV Infections; Eye Diseases; Multimodal Imaging; Anti-HIV Agents
PubMed: 37088626
DOI: 10.1016/j.jfo.2022.12.018 -
Mini Reviews in Medicinal Chemistry Nov 2023Nucleoside analogs have been widely used as antiviral, antitumor, and antiparasitic agents due to their ability to inhibit nucleic acid synthesis. Adenosine, cytidine,...
Nucleoside analogs have been widely used as antiviral, antitumor, and antiparasitic agents due to their ability to inhibit nucleic acid synthesis. Adenosine, cytidine, guanosine, thymidine and uridine analogs such as didanosine, vidarabine, remdesivir, gemcitabine, lamivudine, acyclovir, abacavir, zidovusine, stavudine, and idoxuridine showed remarkable anticancer and antiviral activities. In our previously published articles, our main intention was to develop newer generation nucleoside analogs with acylation-induced modification of the hydroxyl group and showcase their biological potencies. In the process of developing nucleoside analogs, in silico studies play an important role and provide a scientific background for biological data. Molecular interactions between drugs and receptors followed by assessment of their stability in physiological environments, help to optimize the drug development process and minimize the burden of unwanted synthesis. Computational approaches, such as DFT, FMO, MEP, ADMET prediction, PASS prediction, POM analysis, molecular docking, and molecular dynamics simulation, are the most popular tools to culminate all preclinical study data and deliver a molecule with maximum bioactivity and minimum toxicity. Although clinical drug trials are crucial for providing dosage recommendations, they can only indirectly provide mechanistic information through researchers for pathological, physiological, and pharmacological determinants. As a result, in silico approaches are increasingly used in drug discovery and development to provide mechanistic information of clinical value. This article portrays the current status of these methods and highlights some remarkable contributions to the development of nucleoside analogs with optimized bioactivity.
PubMed: 37957918
DOI: 10.2174/0113895575258033231024073521 -
BMC Infectious Diseases Aug 2019Thymidine analogues (TA) and didanosine (ddI) are associated with long-lasting adipose tissue redistribution. Adiponectin is a widely used marker of adipocyte activity,... (Observational Study)
Observational Study
BACKGROUND
Thymidine analogues (TA) and didanosine (ddI) are associated with long-lasting adipose tissue redistribution. Adiponectin is a widely used marker of adipocyte activity, and adipose tissue density assessed by CT-scan is associated with adipocyte size and function. We hypothesized that prior exposure to TA and ddI was associated with long-lasting adipose tissue dysfunction in people living with HIV (PLWH). Thus, we tested possible associations between markers of adipose tissue dysfunction (adipose tissue density and adiponectin) and prior exposure to TA and/or ddI, years after treatment discontinuation.
METHODS
Eight hundred forty-eight PLWH from the COCOMO study were included and stratified according to prior exposure to TA and/or ddI (with, n = 451; without n = 397). Visceral (VAT) and subcutaneous (SAT) adipose tissue area and density were determined by single slice abdominal CT-scan at lumbar 4th level. Venous blood was collected and analyzed for adiponectin. Multivariable linear and logistic regression analyses were used to test our hypotheses. Multivariable models were adjusted for age, sex, smoking, origin, physical activity, BMI, and adipose tissue area (VAT or SAT area, accordingly to the outcome).
RESULTS
prior exposure to TA and/or ddI was associated with excess risk of low VAT (adjusted OR (aOR) 1.74 [1.14; 2.67]) and SAT density (aOR 1.74 [1.18; 2.58]), for a given VAT and SAT area, respectively. No association between VAT and SAT density with time since TA and/or ddI discontinuation was found. 10 HU increase in VAT density was associated with higher adiponectin plasma level and this association was not modified by prior exposure to TA and/or ddI. Prior exposure to TA and/or ddI was associated with 9% lower [- 17;-2] plasma adiponectin levels and with excess risk of low adiponectin (aOR 1.74 [1.10; 2.76]).
CONCLUSIONS
We described low adipose tissue density and impaired adiponectin production to be associated with prior exposure to TA and/or ddI even years after treatment discontinuation and independently of adipose tissue area. These findings suggest that prior TA and ddI exposure may have long-lasting detrimental effects on adipose tissue function and, consequently, on cardiometabolic health in PLWH.
Topics: Adiponectin; Adipose Tissue; Adult; Anti-HIV Agents; Biomarkers; Cross-Sectional Studies; Didanosine; Female; HIV Infections; Humans; Intra-Abdominal Fat; Longitudinal Studies; Male; Middle Aged; Subcutaneous Fat; Thymidine
PubMed: 31399063
DOI: 10.1186/s12879-019-4347-y -
PloS One 2023Pharmacotherapy is necessary for many people with psychiatric disorders and polypharmacy is common. The psychotropic drug-drug interaction (DDI) should be concerned and...
BACKGROUND
Pharmacotherapy is necessary for many people with psychiatric disorders and polypharmacy is common. The psychotropic drug-drug interaction (DDI) should be concerned and efficiently monitored by a proper instrument.
OBJECTIVES
This study aimed to investigate the prevalence and associated factors of psychotropic DDI and to compare the identification utility from three databases: Drugs.com®, Lexicomp®, and Epocrates®.
METHODS
This was a retrospective cohort design. We collected demographic and clinical data of all patients hospitalised in the psychiatric inpatient unit in 2020. Psychotropic DDI profiles were examined through three databases. Descriptive statistics were used to report comprehensiveness of each database and prevalence of psychotropic DDI. The Fleiss' kappa index would be analysed to indicate agreement strength of DDI severity classification among three databases.
RESULTS
From 149 total admissions, the psychotropic DDIs were found in 148 admissions (99.3%). Thorough the study, there were 182 of both psychotropic and other agents prescribed under 1,357 prescriptions. In total, 2,825 psychotropic DDIs were identified by using Drugs.com® 2,500 times, Epocrates® 2,269 times, and Lexicomp® 2,265 times. Interactions with clonazepam was the three most frequent agents when co-administrated with quetiapine (n = 56), risperidone (n = 36), and valproic acid and derivatives (n = 36). Serious DDIs were comparatively lower in incidence and there was no evidence of its association with reported clinical adverse consequences. The study revealed slight and fair agreement regarding severity classification among the three databases was found. DDI events detected by Drugs.com® were greatest in number, but Lexicomp® provided the broadest list of medications prescribed in our study.
CONCLUSION
Among three databases, interactions detected by Drugs.com® were greatest in number, whereas Lexicomp® provided the broadest list of medications. Development of such databases, based on both theoretical and clinical conceptions, should be focused to balance safety of patients and weariness of healthcare providers.
Topics: Humans; Retrospective Studies; Databases, Factual; Didanosine; Fatigue; Drug Interactions
PubMed: 37347788
DOI: 10.1371/journal.pone.0287575 -
Drug Metabolism and Disposition: the... Jul 2020Equilibrative nucleoside transporters (ENTs) transport nucleosides across the blood-testis barrier (BTB). ENTs are of interest to study the disposition of nucleoside...
Equilibrative nucleoside transporters (ENTs) transport nucleosides across the blood-testis barrier (BTB). ENTs are of interest to study the disposition of nucleoside reverse-transcriptase inhibitors (NRTIs) in the human male genital tract because of their similarity in structure to nucleosides. HeLa S3 cells express ENT1 and ENT2 and were used to compare relative interactions of these transporters with selected NRTIs. Inhibition of [H]uridine uptake by NBMPR was biphasic, with IC values of 11.3 nM for ENT1 and 9.6 μM for ENT2. Uptake measured with 100 nM NBMPR represented ENT2-mediated transport; subtracting that from total uptake represented ENT1-mediated transport. The kinetics of ENT1- and ENT2-mediated [H]uridine uptake revealed no difference in J (16.53 and 30.40 pmol cm min) and an eightfold difference in K (13.6 and 108.9 μM). The resulting fivefold difference in intrinsic clearance (J/K) for ENT1- and ENT2 transport accounted for observed inhibition of [H]uridine uptake by 100 nM NBMPR. Millimolar concentrations of the NRTIs emtricitabine, didanosine, lamivudine, stavudine, tenofovir disoproxil, and zalcitabine had no effect on ENT transport activity, whereas abacavir, entecavir, and zidovudine inhibited both transporters with IC values of ∼200 µM, 2.5 mM, and 2 mM, respectively. Using liquid chromatography-tandem mass spectrometry and [H] compounds, the data suggest that entecavir is an ENT substrate, abacavir is an ENT inhibitor, and zidovudine uptake is carrier-mediated, although not an ENT substrate. These data show that HeLa S3 cells can be used to explore complex transporter selectivity and are an adequate model for studying ENTs present at the BTB. SIGNIFICANCE STATEMENT: This study characterizes an in vitro model using S-[(4-nitrophenyl)methyl]-6-thioinosine to differentiate between equilibrative nucleoside transporter (ENT) 1- and ENT2-mediated uridine transport in HeLa cells. This provides a method to assess the influence of nucleoside reverse-transcriptase inhibitors on natively expressed transporter function. Determining substrate selectivity of the ENTs in HeLa cells can be effectively translated into the activity of these transporters in Sertoli cells that comprise the blood-testis barrier, thereby assisting targeted drug development of compounds capable of circumventing the blood-testis barrier.
Topics: Blood-Testis Barrier; Drug Evaluation, Preclinical; Equilibrative Nucleoside Transporter 1; Equilibrative-Nucleoside Transporter 2; HeLa Cells; Humans; Inhibitory Concentration 50; Nucleosides; Reverse Transcriptase Inhibitors; Zidovudine
PubMed: 32393653
DOI: 10.1124/dmd.120.090720 -
Medicina (Kaunas, Lithuania) May 2022This article aims to describe a unique case of didanosine-induced retinal degeneration that was discovered 11 years after the drug withdrawal. The patient is a...
This article aims to describe a unique case of didanosine-induced retinal degeneration that was discovered 11 years after the drug withdrawal. The patient is a 42-year-old woman with a medical history of HIV and hepatitis C virus since 2004. She has been prescribed antiretroviral therapy since then. For the first seven years (2004-2011), the patient was prescribed a combination therapy consisting of didanosine, efavirenz, and lamivudine. The protocol was changed to atripla (efavirenz, emtricitabine, and tenofovir) from 2011 to 2021. Recently (October 2021-January 2021), the patient was prescribed eviplera (rilpivirin, emtricitabine, and tenofovir). In addition, her past medical history revealed Gougerot-Sjogren syndrome and rheumatoid arthritis. She was prescribed hydroxychloroquine (HCQ) (2009-2021) at a dose of 400 mg daily. She had no vision complaint. During her routine HCQ screening at the eye clinic, University Hospital Bretonneau, Tours, France, the widefield colour fundus photograph showed well-defined symmetric mid-peripheral areas of chorioretinal atrophy sparing the posterior pole of both eyes. Furthermore, the widefield fundus autofluorescence illustrated mid-peripheral round well-demarcation hypoautofluorescent areas of chorioretinal atrophy of both eyes. Conversely, the macular optical coherence tomography (OCT) was normal. Many of her drugs are known to be associated with retinopathy such as HCQ, tenofovir, efavirenz, and didanosine. Because our data corroborate peripheral retinal damage rather than posterior pole damage, this case report is compatible with didanosine-induced retinopathy rather than HCQ, efavirenz, or tenofovir retinal toxicity. All HIV patients who are presently or were previously on didanosine therapy should have their fundus examined utilising widefield fundus autofluorescence and photography.
Topics: Adult; Atrophy; Choroid Diseases; Didanosine; Emtricitabine; Female; HIV Infections; Humans; Hydroxychloroquine; Retinal Degeneration; Tenofovir; Tomography, Optical Coherence
PubMed: 35743998
DOI: 10.3390/medicina58060735 -
European Journal of Neurology Apr 2021Human immunodeficiency virus (HIV)-associated neurological syndromes occur in affected individuals as a consequence of primary HIV infection, opportunistic infections,... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND PURPOSE
Human immunodeficiency virus (HIV)-associated neurological syndromes occur in affected individuals as a consequence of primary HIV infection, opportunistic infections, inflammation and as an adverse effect of some forms of antiretroviral treatment (ART). The aim of this systematic review was to establish the epidemiological characteristics, clinical features, pathogenetic mechanisms and risk factors of HIV-related peripheral neuropathy (PN).
METHODS
A systematic, computer-based search was conducted using the PubMed database. Data regarding the above parameters were extracted. Ninety-four articles were included in this review.
RESULTS
The most commonly described clinical presentation of HIV neuropathy is the distal predominantly sensory polyneuropathy. The primary pathology in HIVPN appears to be axonal rather than demyelinating. Age and treatment with medications belonging in the nucleoside analogue reverse transcriptase class are risk factors for developing HIV-related neuropathy. The pooled prevalence of PN in patients naïve to ARTs was established to be 29% (95% CI: 9%-62%) and increased to 38% (95% confidence interval [CI]: 29%-48%) when looking into patients at various stages of their disease. More than half of patients with HIV-related neuropathy are symptomatic (53%, 95% CI: 41%-63%). Management of HIV-related neuropathy is mainly symptomatic, although there is evidence that discontinuation of some types of ART, such as didanosine, can improve or resolve symptoms.
CONCLUSIONS
Human immunodeficiency virus-related neuropathy is common and represents a significant burden in patients' lives. Our understanding of the disease has grown over the last years, but there are unexplored areas requiring further study.
Topics: HIV; HIV Infections; Humans; Peripheral Nervous System Diseases; Risk Factors
PubMed: 33226721
DOI: 10.1111/ene.14656