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Journal of the International AIDS... Apr 2024Liver disease is a leading cause of morbidity and mortality among persons living with HIV (PLHIV). While chronic viral hepatitis has been extensively studied in low- and...
INTRODUCTION
Liver disease is a leading cause of morbidity and mortality among persons living with HIV (PLHIV). While chronic viral hepatitis has been extensively studied in low- and middle-income countries (LMICs), there is limited information about the burden of metabolic disorders on liver disease in PLHIV.
METHODS
We conducted a cross-sectional analysis of baseline data collected between October 2020 and July 2022 from the IeDEA-Sentinel Research Network, a prospective cohort enrolling PLHIV ≥40 years on antiretroviral treatment (ART) for ≥6 months from eight clinics in Asia, Americas, and central, East, southern and West Africa. Clinical assessments, laboratory testing on fasting blood samples and liver stiffness measurement (LSM)/controlled attenuation parameter (CAP) by vibration-controlled transient elastography were performed. Multivariable logistic regression models assessed factors associated with liver fibrosis (LSM ≥7.1 kPa) and steatosis (CAP ≥248 dB/m). Population attributable fraction (PAF) of each variable associated with significant liver fibrosis was estimated using Levin's formula.
RESULTS
Overall, 2120 PLHIV (56% female, median age 50 [interquartile range: 45-56] years) were included. The prevalence of obesity was 19%, 12% had type 2 diabetes mellitus (T2DM), 29% had hypertension and 53% had dyslipidaemia. The overall prevalence of liver fibrosis and steatosis was 7.6% (95% confidence interval [CI] 6.1-8.4) and 28.4% (95% CI 26.5-30.7), respectively, with regional variability. Male sex at birth (odds ratio [OR] 1.62, CI 1.10-2.40), overweight/obesity (OR = 2.50, 95% CI 1.69-3.75), T2DM (OR 2.26, 95% CI 1.46-3.47) and prolonged exposure to didanosine (OR 3.13, 95% CI 1.46-6.49) were associated with liver fibrosis. Overweight/obesity and T2DM accounted for 42% and 11% of the PAF for liver fibrosis, while HBsAg and anti-HCV accounted for 3% and 1%, respectively. Factors associated with steatosis included overweight/obesity (OR 4.25, 95% CI 3.29-5.51), T2DM (OR 2.06, 95% CI 1.47-2.88), prolonged exposure to stavudine (OR 1.69, 95% CI 1.27-2.26) and dyslipidaemia (OR 1.68, 95% CI 1.31-2.16).
CONCLUSIONS
Metabolic disorders were significant risk factors for liver disease among PLHIV in LMICs. Early recognition of metabolic disorders risk factors might be helpful to guide clinical and lifestyle interventions. Further prospective studies are needed to determine the causative natures of these findings.
Topics: Adult; Infant, Newborn; Humans; Male; Female; Middle Aged; Cross-Sectional Studies; Developing Countries; Diabetes Mellitus, Type 2; Overweight; HIV Infections; Liver Cirrhosis; Obesity; Dyslipidemias
PubMed: 38566493
DOI: 10.1002/jia2.26238 -
Therapeutics and Clinical Risk... 2024Scaling up antiretroviral treatment (ART) reduces morbidity and mortality among people living with HIV/AIDS (PLHA). This success is challenged by the constellation of...
PURPOSE
Scaling up antiretroviral treatment (ART) reduces morbidity and mortality among people living with HIV/AIDS (PLHA). This success is challenged by the constellation of interrelated metabolic disorders such as metabolic syndrome (MetS). Given the changing ART regimens and schedules, increasing patient age and methodological limitations, existing evidence regarding the determinants of MetS remains inconclusive. Therefore, in the current study, we aimed to identify the determinants of MetS in patients receiving ART at a tertiary hospital in central Ethiopia.
PATIENT AND METHODS
We conducted an unmatched case-control study that included 393 patients with a case-to-control ratio of 1 to 2. Data were collected by interviewing patients, reviewing charts, physical examinations, and laboratory testing. The data were entered into Epi-Info version 7.2 and analyzed using SPSS version 26. A binary logistic regression analysis was used to identify the determinants of MetS. The adjusted odds ratio (AOR) with a 95% confidence interval (CI) was used to estimate the strength of the association between MetS and its determinants. Statistical significance was set at p-value < 0.05.
RESULTS
In this study, higher odds of developing MetS were identified among patients aged 40-60 years (AOR 3.75; 95% CI: 1.66-8.49) and those older than 60 years (AOR 6.18; 95% CI: 2.12-17.95) than among those aged < 40 years. Similarly, higher odds were observed among patients who frequently consumed animal source foods than among those who consumed cereals or vegetables (AOR, 1.94; 95% CI, 1.03-3.63), those who had HIV lipodystrophy (AOR 1.73; 95% CI: 1.05-2.86), those who were treated with stavudine (AOR 3.08; 95% CI: 1.89-5.04), and those who were treated with zidovudine (AOR 1.71, 95% CI: 1.02-2.88) compared to their counterparts.
CONCLUSION
Older age, diet from animal sources, exposure to zidovudine or stavudine, and the presence of lipodystrophy were independent determinants of MetS.
PubMed: 38524687
DOI: 10.2147/TCRM.S453699 -
Journal of Medicinal Chemistry Feb 2024We report on the synthesis and characterization of three types of nucleoside tetraphosphate derivatives - acting as potential prodrugs of d4T nucleotides: (i) the...
We report on the synthesis and characterization of three types of nucleoside tetraphosphate derivatives - acting as potential prodrugs of d4T nucleotides: (i) the δ-phosph(on)ate is modified by two alkyl residues and ; (ii) the δ-phosph(on)ate is esterified covalently by one acyloxybenzyl moiety and a moiety and ; or (iii) the δ-phosphate of nucleoside tetraphosphate is masked by two prodrug groups and . We were able to prove the efficient release of d4T triphosphate (d4TTP, (i)), δ-monoalkylated d4T tetraphosphates ( and , (ii)), and d4T tetraphosphate (d4T4P, (iii)), respectively, by chemical or enzymatic processes. Surprisingly, δ-dialkylated d4T tetraphosphates, δ-monoalkylated d4T tetraphosphates, and d4T4P were substrates for HIV-RT. Remarkably, the antiviral activity of Tetraro-prodrug was improved by 7700-fold (SI 5700) as compared to the parent d4T in CEM/TK cells, denoting a successful cell membrane passage of these lipophilic prodrugs and an intracellular delivery of the nucleotide metabolites.
Topics: Anti-HIV Agents; Nucleosides; Stavudine; HIV-1; Nucleotides; Prodrugs
PubMed: 38345794
DOI: 10.1021/acs.jmedchem.3c02022 -
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 -
BMJ Open Dec 2023HIV-induced chronic inflammation, immune activation and combination antiretroviral therapy (cART) are linked with adverse metabolic changes known to cause cardiovascular...
OBJECTIVES
HIV-induced chronic inflammation, immune activation and combination antiretroviral therapy (cART) are linked with adverse metabolic changes known to cause cardiovascular adversities. This study evaluates the prevalence of lipodystrophy, and metabolic syndrome (MetS), and analyses risk factors in HIV-infected Ethiopians taking cART.
METHODS
A multicentre cross-sectional study was conducted at tertiary-level hospitals. Eligible participants attending the HIV clinics were enrolled. Sociodemographic, anthropometric, clinical, HIV treatment variables, lipid profile, fasting blood glucose level, risk factors and components of MetS, also lipodystrophy, were studied. Data were analysed by SPSS statistical package V.25 with descriptive and analytical statistics. For multivariable analysis of risk factors, a logistic regression model was used. Results were presented in frequency and percentages, mean±SD, or median+IQR. Statistical significance was taken as p<0.05.
RESULTS
Among 518 studied participants, two-thirds were females, and the mean age of the study population was 45 years (SD=11). The mean duration of cART was 10 years (SD=4). Median CD4 count was 460 cells/mm. The prevalence of MetS according to the Adult Treatment Panel III (2005) criteria was 37.6%. In multivariable analysis, independent risk factors for MetS were age >45 years (aHR 1.8, 95% CI 1.2 to 2.4), female sex (aHR 1.8, 95% CI 1.1 to 2.8), body mass index (BMI)25 kg/m (aHR 2.7, 95% CI 1.8 to 4.1), efavirenz-based cART (aHR 2.8, 95% CI 1.6 to 4.8) and lopinavir/ritonavir-based cART (aHR 3.7, 95% CI 1.0 to 13.3). The prevalence of lipodystrophy was 23.6%. Prior exposure to a stavudine-containing regimen was independently associated with lipodystrophy (aHR 3.1, 95% CI 1.6 to 6.1).
CONCLUSION
Our study revealed 38% of the participants had MetS indicating considerable cardiovascular disease (CVD) risks. Independent risk factors for MetS were BMI≥25 kg/m, efavirenz and lopinavir/ritonavir-based cART, female sex and age ≥45 years. In addition to prevention, CVD risk stratification and management will reduce morbidity and mortality in people with HIV infection.
Topics: Adult; Humans; Female; Middle Aged; Male; HIV Infections; Metabolic Syndrome; Lopinavir; Ritonavir; Cross-Sectional Studies; Prevalence; Ethiopia; Risk Factors; Lipodystrophy; Cardiovascular Diseases
PubMed: 38070936
DOI: 10.1136/bmjopen-2022-069637 -
Pharmaceutics Sep 2023Erythrocytes have been thoroughly investigated as drug delivery systems for a wide range of therapeutic molecules and using different kinds of loading methods,...
Erythrocytes have been thoroughly investigated as drug delivery systems for a wide range of therapeutic molecules and using different kinds of loading methods, outstanding the osmosis-based methods as the most used ones. Most of them involve too much handling of blood components and the immediate obtention of fresh blood. Based on our group's considerable experience in dialysis-based carrier erythrocyte preparation, this study details a simple method based on hypotonic dilution and subsequent resealing that has been developed for stavudine using packed erythrocytes from a local blood bank. Properties of the obtained carrier erythrocytes were studied in comparison to those prepared by dialysis. Erythrocytes' morphology, osmotic fragility, hematological parameters, and in vitro release profiles were evaluated. Loaded erythrocytes obtained with the proposed method did not show impaired properties in comparison with those obtained with our reference method, provided that the buffer composition remained the same. In the present work, we have optimized a simplified method for erythrocytes' drug loading, which can use blood transfusion products and could be easily automatized and scalable.
PubMed: 37765250
DOI: 10.3390/pharmaceutics15092281 -
Molecules (Basel, Switzerland) Aug 2023The behavior of four drugs from the family of nucleoside analog reverse-transcriptase inhibitors (zalcitabine, stavudine, didanosine, and apricitabine) in a membrane...
The behavior of four drugs from the family of nucleoside analog reverse-transcriptase inhibitors (zalcitabine, stavudine, didanosine, and apricitabine) in a membrane environment was traced using molecular dynamics simulations. The simulation models included bilayers and monolayers composed of POPC and POPG phospholipids. It was demonstrated that the drugs have a higher affinity towards POPG membranes than POPC membranes due to attractive long-range electrostatic interactions. The results obtained for monolayers were consistent with those obtained for bilayers. The drugs accumulated in the phospholipid polar headgroup region. Two adsorption modes were distinguished. They differed in the degree of penetration of the hydrophilic headgroup region. Hydrogen bonds between drug molecules and phospholipid heads were responsible for adsorption. It was shown that apricitabine penetrated the hydrophilic part of the POPC and POPG membranes more effectively than the other drugs. Van der Waals interactions between S atoms and lipids were responsible for this.
Topics: Molecular Dynamics Simulation; Reverse Transcriptase Inhibitors; Stavudine; Phospholipids; DNA-Directed RNA Polymerases
PubMed: 37687102
DOI: 10.3390/molecules28176273 -
Journal of Personalized Medicine Jul 2023Pharmacogenomics may improve patient care by guiding drug selection and dosing; however, this requires prior knowledge of the pharmacogenomics of drugs commonly used in...
Pharmacogenomics may improve patient care by guiding drug selection and dosing; however, this requires prior knowledge of the pharmacogenomics of drugs commonly used in a specific setting. The aim of this study was to identify a preliminary set of pharmacogenetic variants important in Southern Africa. We describe comorbidities in 3997 patients from Malawi, South Africa, and Zimbabwe. These patient cohorts were included in pharmacogenomic studies of anticoagulation, dyslipidemia, hypertension, HIV and breast cancer. The 20 topmost prescribed drugs in this population were identified. Using the literature, a list of pharmacogenes vital in the response to the top 20 drugs was constructed leading to drug-gene pairs potentially informative in translation of pharmacogenomics. The most reported morbidity was hypertension (58.4%), making antihypertensives the most prescribed drugs, particularly amlodipine. Dyslipidemia occurred in 31.5% of the participants, and statins were the most frequently prescribed as cholesterol-lowering drugs. HIV was reported in 20.3% of the study participants, with lamivudine/stavudine/efavirenz being the most prescribed antiretroviral combination. Based on these data, pharmacogenes of immediate interest in Southern African populations include , , , , , , , , and . Variants in these genes are a good starting point for pharmacogenomic translation programs in Southern Africa.
PubMed: 37623436
DOI: 10.3390/jpm13081185 -
Frontiers in Cardiovascular Medicine 2023Previous studies have reported impairment in systolic and diastolic function in people with HIV (PWHIV). Our aim was to determine if echocardiographically measured left...
BACKGROUND
Previous studies have reported impairment in systolic and diastolic function in people with HIV (PWHIV). Our aim was to determine if echocardiographically measured left ventricular (LV) global longitudinal strain (GLS) is abnormal in asymptomatic PWHIV.
METHODS
A cross-sectional study of PWHIV ( = 98, 89% male, median age 53 years) and HIV-negative people ( = 50, median age 53 years) without known cardiovascular disease were recruited from a single centre. All participants completed a health/lifestyle questionnaire, provided a fasting blood sample, and underwent a comprehensive echocardiogram for assessment of diastolic and systolic LV function, including measurement of GLS.
RESULTS
All PWHIV were receiving antiretroviral therapy (ART) for a median of 12 years (IQR: 6.9, 22.4), the majority with good virological control (87% suppressed) and without immunological compromise (median CD4 598 cells/µl, IQR: 388, 841). Compared with controls of similar age and gender, there was no difference in GLS [mean GLS -20.3% (SD 2.5%) vs. -21.0% (SD 2.5%), = 0.14] or left ventricular ejection fractions [65.3% (SD 6.3) vs. 64.8% (SD 4.8), = 0.62]. Following adjustment for covariates (gender, heart rate, systolic and diastolic blood pressure, and fasting glucose), the difference in GLS remained non-significant. There were no differences in LV diastolic function between the groups. Exposure to at least one mitochondrially toxic ART drug (didanosine, stavudine, zidovudine, or zalcitabine) was not associated with impairment of LV systolic function.
CONCLUSION
No clinically significant impairment of myocardial systolic function, as measured by LV GLS, was detected in this predominantly Caucasian male population of PWHIV on long-term ART, with no history of cardiovascular disease.
PubMed: 37547256
DOI: 10.3389/fcvm.2023.1198387