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European Review For Medical and... Feb 2020The current study was designed to investigate the effects of some nucleoside reverse transcriptase inhibitors (NRTIs) on HSV-1 infection.
OBJECTIVE
The current study was designed to investigate the effects of some nucleoside reverse transcriptase inhibitors (NRTIs) on HSV-1 infection.
MATERIALS AND METHODS
Initially, the SwissTargetPrediction server was used to predict the interactions between HSV-1 thymidine kinase and acyclovir, stavudine, zidovudine, didanosine, and entecavir. The effect of each component on Vero cell viability was assessed by the MTT assay. After treatment, the cell supernatants were collected, and HSV-1 replication was analyzed by quantitative real-time PCR.
RESULTS
The qPCR results revealed that viral titers were reduced 41, 40, 19, 44, and 31-fold in the presence of acyclovir, zidovudine, stavudine, didanosine, and entecavir, respectively.
CONCLUSIONS
Our findings indicate that NRTIs significantly reduce HSV-1 replication in cell culture.
Topics: Animals; Antiviral Agents; Chlorocebus aethiops; Dose-Response Relationship, Drug; Herpesvirus 1, Human; Reverse Transcriptase Inhibitors; Vero Cells; Virus Replication
PubMed: 32096195
DOI: 10.26355/eurrev_202002_20204 -
Annals of Medicine and Surgery (2012) Dec 2023The risk of falls in people living with HIV (PLHIVs) on antiretroviral therapy (ART) has received little attention in the literature. The aim of the meta-analysis is to... (Review)
Review
OBJECTIVE
The risk of falls in people living with HIV (PLHIVs) on antiretroviral therapy (ART) has received little attention in the literature. The aim of the meta-analysis is to quantify the association between fall risk and various categories of drugs used in ART.
MATERIAL AND METHODS
PubMed, Google Scholar, Embase, and the Cochrane Central Register of Controlled Trials were systematically searched from inception to January 2023. Any observational study or controlled trial that reported on the relationship of at least one antiretroviral drug with falls in PLHIVs was included. Data on the frequency of single fallers, multiple fallers (≥2 falls), and non-fallers were extracted and studied for each drug and drug category. The pooled results were reported as an odds ratio (OR) with a 95% confidence interval (CI).
RESULTS
A total of five observational studies (51 675 participants) were included out of 414 articles obtained through a literature review. Stavudine use was found to be associated with an increased risk of single falls in PLHIVs (OR: 1.69, 95% CI: 1.08-2.66, =0.02). However, efavirenz (OR: 0.82, 95% CI=0.76-0.89, <0.001) and zidovudine (OR: 0.82, 95% CI=0.77-0.92, <0.001) were found protective against the single falls. Didanosine had no significant association with fall risk (OR: 1.23, 95% CI: 0.78-1.93, =0.37). Likewise, protease inhibitors, integrase inhibitors, nucleoside reverse transcriptase inhibitors, and non-nucleoside reverse transcriptase inhibitors were discovered to have no significant association with fall risk.
CONCLUSION
Most drug categories of ART have no significant association with the risk of falls in PLHIVs. However, certain drugs, such as didanosine and stavudine, which have the inherent effect of causing balance deficits and neuropathy, should be used cautiously.
PubMed: 38098550
DOI: 10.1097/MS9.0000000000001411 -
AIDS Research and Human Retroviruses Mar 2020Mitochondrial DNA (mtDNA) haplogroup has been associated with disease risk and longevity. Among persons with HIV (PWH), mtDNA haplogroup has been associated with AIDS... (Observational Study)
Observational Study
Mitochondrial DNA (mtDNA) haplogroup has been associated with disease risk and longevity. Among persons with HIV (PWH), mtDNA haplogroup has been associated with AIDS progression, neuropathy, cognitive impairment, and gait speed decline. We sought to determine whether haplogroup is associated with frailty and its components among older PWH. A cross-sectional analysis was performed of AIDS Clinical Trials Group A5322 (HAILO) participants with available genome-wide genotype and frailty assessments. Multivariable logistic regression models adjusted for age, gender, education, smoking, hepatitis C, and prior use of didanosine/stavudine. Among 634 participants, 81% were male, 49% non-Hispanic white, 31% non-Hispanic black, and 20% Hispanic. Mean age was 51.0 (standard deviation 7.5) years and median nadir CD4 count was 212 (interquartile range 72, 324) cells/μL; 6% were frail, 7% had slow gait, and 21% weak grip. H haplogroup participants were more likely to be frail/prefrail ( = .064), have slow gait ( = .09), or weak grip ( = .017) compared with non-H haplogroup participants (not all comparisons reached statistical significance). In adjusted analyses, PWH with haplogroup H had a greater odds of being frail versus nonfrail [odds ratio (OR) 4.0 (95% confidence interval 1.0-15.4)] and having weak grip [OR 2.1 (1.1, 4.1)], but not slow gait [OR 1.6 (0.5, 5.0)] compared with non-H haplogroup. Among black and Hispanic participants, haplogroup was not significantly associated with frailty, grip, or gait. Among antiretroviral therapy (ART)-treated PWH, mtDNA haplogroup H was independently associated with weak grip and frailty. This association could represent a mechanism of weakness and frailty in the setting of HIV and ART.
Topics: Adult; Aging; CD4 Lymphocyte Count; Cohort Studies; Cross-Sectional Studies; DNA, Mitochondrial; Female; Frailty; HIV Infections; Haplotypes; Hispanic or Latino; Humans; Logistic Models; Male; Middle Aged; Odds Ratio; Risk Factors; Walking Speed
PubMed: 31822125
DOI: 10.1089/AID.2019.0233 -
Scientific Reports Oct 2019We investigated the effects of treating differentiated retinal pigment epithelial (RPE) cells with didanosine (ddI), which is associated with retinopathy in individuals...
We investigated the effects of treating differentiated retinal pigment epithelial (RPE) cells with didanosine (ddI), which is associated with retinopathy in individuals with HIV/AIDS. We hypothesized that such treatment would cause depletion of mitochondrial DNA and provide insight into the consequences of degradation of RPE mitochondrial function in aging and disease. Treatment of differentiated ARPE-19 or human primary RPE cells with 200 µM ddI for 6-24 days was not cytotoxic but caused up to 60% depletion of mitochondrial DNA, and a similar reduction in mitochondrial membrane potential and NDUFA9 protein abundance. Mitochondrial DNA-depleted RPE cells demonstrated enhanced aerobic glycolysis by extracellular flux analysis, increased AMP kinase activation, reduced mTOR activity, and increased resistance to cell death in response to treatment with the oxidant, sodium iodate. We conclude that ddI-mediated mitochondrial DNA depletion promotes a glycolytic shift in differentiated RPE cells and enhances resistance to oxidative damage. Our use of ddI treatment to induce progressive depletion of mitochondrial DNA in differentiated human RPE cells should be widely applicable for other studies aimed at understanding RPE mitochondrial dysfunction in aging and disease.
Topics: Adenylate Kinase; Cell Differentiation; Cell Line; DNA, Mitochondrial; Didanosine; Epithelial Cells; Glycolysis; Humans; Mechanistic Target of Rapamycin Complex 1; Membrane Potential, Mitochondrial; Mitochondria; Oxidative Stress; Retinal Pigment Epithelium
PubMed: 31653972
DOI: 10.1038/s41598-019-51761-1 -
Journal of Acquired Immune Deficiency... Feb 2022Little is known regarding the long-term effects of antiretroviral (ARV) exposure on body composition for people living with HIV (PLWH) since early childhood. This study...
BACKGROUND
Little is known regarding the long-term effects of antiretroviral (ARV) exposure on body composition for people living with HIV (PLWH) since early childhood. This study explores changes in body fat distribution in relation to ARV exposure.
METHODS
We conducted a prospective study of adults with perinatal HIV (n = 70) using dual-energy X-ray absorptiometry and standard anthropometrics. Trunk to limb fat ratio and waist to hip ratio were compared cross-sectionally to 47 matched controls. Furthermore, changes in body composition and ARV exposure were evaluated longitudinally in a subset of 40 PLWH with a median follow-up of 7 years.
RESULTS
Cross-sectional comparisons of PLWH with controls revealed significantly higher waist to hip ratio, trunk to limb fat ratio, HOMA-IR, and triglycerides, whereas BMI did not differ. Among PLWH with longitudinal follow-up, the prevalence of overweight increased from 27.5% to 52.5% and obesity from 12.5% to 25%; waist to hip and trunk to limb fat ratios also increased (P < 0.0001). Changes in waist to hip ratio were positively correlated with longer exposure during follow-up to darunavir (r = 0.36; P = 0.02), whereas increases in trunk to limb fat ratio were positively correlated with longer exposure to stavudine (r = 0.39; P = 0.01) and didanosine (r = 0.39; P = 0.01) but inversely associated with emtricitabine (r = -0.33; P = 0.04). Increases in waist to hip ratio were correlated with increases in triglyceride levels (r = 0.35; P = 0.03).
CONCLUSION
This study presents strong evidence for persistent and worsening central adiposity in young adults with lifelong HIV and extensive ARV exposure. As this cohort ages, continued evaluation of the body composition and metabolic impact of lifelong ARV therapy is warranted to optimize long-term health.
Topics: Absorptiometry, Photon; Antiviral Agents; Body Composition; Body Mass Index; Child, Preschool; Cross-Sectional Studies; HIV Infections; Humans; Obesity; Obesity, Abdominal; Prospective Studies; Young Adult
PubMed: 34693931
DOI: 10.1097/QAI.0000000000002841 -
AIDS Research and Therapy Mar 2022The authors recently performed plastic surgeries for a small number of patients with hemophilia, HIV infection, and morphologic evidence of lipodystrophy. Because the...
BACKGROUND
The authors recently performed plastic surgeries for a small number of patients with hemophilia, HIV infection, and morphologic evidence of lipodystrophy. Because the pathophysiological mechanism of HIV-associated lipodystrophy remains to be elucidated, we analyzed subcutaneous adipose tissues from the patients.
METHODS
All six patients had previously been treated with older nucleoside analogue reverse-transcriptase inhibitors (NRTIs; stavudine, didanosine or zidovudine). Abdominal and inguinal subcutaneous fat samples were obtained from the HIV+ patients with hemophilia and HIV- healthy volunteers (n = 6 per group), and analyzed via DNA microarray, real-time PCR, flow cytometry and immunohistochemistry.
RESULTS
The time from initial NRTI treatment to collecting samples were 21.7 years in average. Cytometric analysis revealed infiltration of inflammatory M1 macrophages into HIV-infected adipose tissue and depletion of adipose-derived stem cells, possibly due to exhaustion following sustained adipocyte death. Genetic analysis revealed that adipose tissue from HIV+ group had increased immune activation, mitochondrial toxicity, chronic inflammation, progressive fibrosis and adipocyte dysfunction (e.g. insulin resistance, inhibited adipocyte differentiation and accelerated apoptosis). Of note, both triglyceride synthesis and lipolysis were inhibited in adipose tissue from patients with HIV.
CONCLUSIONS
Our findings provide important insights into the pathogenesis of HIV-associated lipodystrophy, suggesting that fat redistribution may critically depend on adipocytes' sensitivity to drug-induced mitochondrial toxicity, which may lead either to atrophy or metabolic complications.
Topics: Anti-HIV Agents; DNA, Mitochondrial; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Hemophilia A; Humans; Lipodystrophy; Subcutaneous Fat
PubMed: 35246167
DOI: 10.1186/s12981-022-00432-9 -
Journal of Vitreoretinal Diseases 2022This article describes a case of didanosine (DDI)-associated retinal toxicity in a patient with a heterozygous pathogenic variant in the CRB1 gene.
PURPOSE
This article describes a case of didanosine (DDI)-associated retinal toxicity in a patient with a heterozygous pathogenic variant in the CRB1 gene.
METHODS
Case report.
RESULTS
A middle-aged patient with HIV controlled on HAART therapy, and a remote 10-year year history of treatment with DDI and tenofivir, presented with external ophthalmoplegia and well-circumscribed, midperipheral patterns of bilateral pigmentary retinopathy and chorioretinal atrophy in both eyes. Genetic testing revealed a heterozygous pathogenic variant in the gene that encodes a protein (Crumbs homolog 1) involved in regulation of cell polarity and junctions and is localized adjacent to mitochondria in the ellipsoid and myoid area.
CONCLUSIONS
This case highlights a potential role for genetic susceptibility to retinal toxicity in DDI-associated retinal toxicity. Large, prospective pharmacogenomics studies may be informative to further elucidate the role of genetic risk factors in drug-induced retinal toxicity.
PubMed: 37007923
DOI: 10.1177/24741264211044599 -
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 -
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