Molecular mechanisms underpinning the protection against antiretroviral drug-induced sperm-endocrine aberrations and testicular toxicity: A review.

The introduction of highly active antiretroviral therapy (HAART) has revolutionized the treatment of HIV/AIDS worldwide. The HAART approach is the combination of two or more antiretroviral drugs of different classes and are responsible for patient's survival and declining death rates from HIV/AIDS and AIDS-related events. However, the severe and persistent reproductive side effect toxicity of HAART regimens is of great concern to patients within the reproductive age. Till date, the underlying pathophysiology of the HAART-induced reproductive toxicity remains unraveled. Nevertheless, preclinical studies show that oxidative stress and inflammation may be involved in HAART-induced sperm-endocrine deficit and reproductive aberrations. Studies are emerging demonstrating the efficacy of plant-based and non-plant products against the molecular alterations and testicular toxicity of HAART. The testicular mechanisms of mitigation by these products are associated with enhancement of testicular steroidogenesis, spermatogenesis, inhibition of oxidative stress and inflammation. This review presents the toxic effects of HAART on spermatogenesis, reproductive hormones and testis integrity. It also provides insights on the molecular mechanisms underlying the mitigation of HAART testicular toxicity by plant-based and non-plant agents. However, effect of repurposing clinical drugs to combat HAART toxicity is unknown, and more mechanistic studies are evidently needed. Altogether, plant-based and non-plant products are potential agents for prevention of rampant endocrine dysfunction and testicular toxicity of HAART.

Evaluation of Testicular Function and Structural Changes of Wistar Rats Following Antiretroviral Exposure: Protective Role of Cyperus Esculentus.

Long-term antiretroviral drug toxicity may exacerbate the impact of HAART-Cyperus esculentus (C. esculentus) interactions on testicular function in HIV-infected individuals. This study examined the ability of C. esculentus plants to treat testicular dysfunction, which is thought to be a probable side effect of antiretroviral toxicity. Adult Wistar male rats weighing 90-110 g were divided into six groups and administered the prescribed treatments. In addition to testicular histology and stereological parameters, testosterone levels, follicle-stimulating hormone levels, antioxidant markers, malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione levels were also evaluated. The adverse consequences of highly active antiretroviral therapy (HAART) include considerable loss of germ cells, enlargement of the tubular lumen, widening of interstitial gaps, and severe hypocellularity. Compared to the other treatment groups, MDA levels dramatically increased, whereas GSH and antioxidant enzyme (SOD) levels significantly decreased. Testicular architecture was largely conserved after treatment with C. esculentus, with a notable increase in the cellular densities of germinal and interstitial cells and a notable decrease in the tubular lumen. Vacuolation, architectural malformations, and hypoplastic changes were reduced. Significant improvements were also observed in C. esculentus in terms of elevated antioxidant SOD and GSH levels and decreased MDA levels. C. esculentus reduced architectural distortions and testicular dysfunction caused by HAART, and improved testicular morphology. Further exploration of these pathways is required.

Dolutegravir Inhibition of Matrix Metalloproteinases Affects Mouse Neurodevelopment.

Dolutegravir (DTG) is a first-line antiretroviral drug (ARV) used in combination therapy for the treatment of human immunodeficiency virus type-1 (HIV-1) infection. The drug is effective, safe, and well tolerated. Nonetheless, concerns have recently emerged for its usage in pregnant women or those of child-bearing age. Notably, DTG-based ARV regimens have been linked to birth defects seen as a consequence of periconceptional usages. To this end, uncovering an underlying mechanism for DTG-associated adverse fetal development outcomes has gained clinical and basic research interest. We now report that DTG inhibits matrix metalloproteinases (MMPs) activities that could affect fetal neurodevelopment. DTG is a broad-spectrum MMPs inhibitor and binds to Zn++ at the enzyme's catalytic domain. Studies performed in pregnant mice show that DTG readily reaches the fetal central nervous system during gestation and inhibits MMP activity. Postnatal screenings of brain health in mice pups identified neuroinflammation and neuronal impairment. These abnormalities persist as a consequence of in utero DTG exposure. We conclude that DTG inhibition of MMPs activities during gestation has the potential to affect prenatal and postnatal neurodevelopment.

Antiretroviral Drugs Impact Autophagy with Toxic Outcomes.

Antiretroviral drugs have dramatically improved the morbidity and mortality of people living with HIV (PLWH). While current antiretroviral therapy (ART) regimens are generally well-tolerated, risks for side effects and toxicity remain as PLWH must take life-long medications. Antiretroviral drugs impact autophagy, an intracellular proteolytic process that eliminates debris and foreign material, provides nutrients for metabolism, and performs quality control to maintain cell homeostasis. Toxicity and adverse events associated with antiretrovirals may be due, in part, to their impacts on autophagy. A more complete understanding of the effects on autophagy is essential for developing antiretroviral drugs with decreased off target effects, meaning those unrelated to viral suppression, to minimize toxicity for PLWH. This review summarizes the findings and highlights the gaps in our knowledge of the impacts of antiretroviral drugs on autophagy.

Colitis apoptótica por dolutegravir / Apoptotic colitis owing to dolutegravir

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Antiretroviral and cytotoxic activities of Tityus obscurus synthetic peptide.

New drugs are constantly in demand, and nature's biodiversity is a rich source of new compounds for therapeutic applications. Synthetic peptides based on the transcriptome analysis of scorpion venoms of Tityus obscurus, Opisthacanthus cayaporum, and Hadrurus gertschi were assayed for their cytotoxic and antiretroviral activity. The Tityus obscurus scorpion-derived synthetic peptide (FFGTLFKLGSKLIPGVMKLFSKKKER), in concentrations ranging from 6.24 to 0.39 µM, proved to be the most active one against simian immunodeficiency virus (SIV) replication in the HUT-78 cell line and in primary human leukocytes, with the lowest toxicity for these cells. The immune cellular response evaluated in primary human leukocytes treated with the most promising peptide and challenged with SIV infection exhibited production of cytokines such as interleukin (IL)-4, IL-6, IL-8, IL-10, and interferon-γ, which could be involved in cell defense mechanisms to overcome viral infection through proinflammatory and anti-inflammatory pathways, similar to those evoked for triggering the mechanisms exerted by antiviral restriction factors.

Investigating the importance of individual mitochondrial genotype in susceptibility to drug-induced toxicity.

The mitochondrion is an essential organelle responsible for generating cellular energy. Additionally, mitochondria are a source of inter-individual variation as they contain their own genome. Evidence has revealed that mitochondrial DNA (mtDNA) variation can confer differences in mitochondrial function and importantly, these differences may be a factor underlying the idiosyncrasies associated with unpredictable drug-induced toxicities. Thus far, preclinical and clinical data are limited but have revealed evidence in support of an association between mitochondrial haplogroup and susceptibility to specific adverse drug reactions. In particular, clinical studies have reported associations between mitochondrial haplogroup and antiretroviral therapy, chemotherapy and antibiotic-induced toxicity, although study limitations and conflicting findings mean that the importance of mtDNA variation to toxicity remains unclear. Several studies have used transmitochondrial cybrid cells as personalised models with which to study the impact of mitochondrial genetic variation. Cybrids allow the effects of mtDNA to be assessed against a stable nuclear background and thus the in vitro elucidation of the fundamental mechanistic basis of such differences. Overall, the current evidence supports the tenet that mitochondrial genetics represent an exciting area within the field of personalised medicine and drug toxicity. However, further research effort is required to confirm its importance. In particular, efforts should focus upon translational research to connect preclinical and clinical data that can inform whether mitochondrial genetics can be useful to identify at risk individuals or inform risk assessment during drug development.

A year-long extended release nanoformulated cabotegravir prodrug.

Long-acting cabotegravir (CAB) extends antiretroviral drug administration from daily to monthly. However, dosing volumes, injection site reactions and health-care oversight are obstacles towards a broad usage. The creation of poloxamer-coated hydrophobic and lipophilic CAB prodrugs with controlled hydrolysis and tissue penetrance can overcome these obstacles. To such ends, fatty acid ester CAB nanocrystal prodrugs with 14, 18 and 22 added carbon chains were encased in biocompatible surfactants named NMCAB, NM2CAB and NM3CAB and tested for drug release, activation, cytotoxicity, antiretroviral activities, pharmacokinetics and biodistribution. Pharmacokinetics studies, performed in mice and rhesus macaques, with the lead 18-carbon ester chain NM2CAB, showed plasma CAB levels above the protein-adjusted 90% inhibitory concentration for up to a year. NM2CAB, compared with NMCAB and NM3CAB, demonstrated a prolonged drug release, plasma circulation time and tissue drug concentrations after a single 45 mg per kg body weight intramuscular injection. These prodrug modifications could substantially improve CAB's effectiveness.

Use of pre-ART laboratory screening to identify renal, hepatic and haematological abnormalities in Côte d'Ivoire.

BACKGROUND: High demand for HIV-services and extensive clinical guidelines force health systems in low-resource settings to dedicate resources to service delivery at the expense of other priorities. Simplifying services may reduce the burden on health systems and pre-antiretroviral therapy (ART) laboratory screening is among the services under consideration for simplification. METHODS: We assessed the frequencies of conditions linked to ART toxicities among 34,994 adult, ART-naïve patients with specimens referred to the RETRO-CI laboratory in Abidjan, Côte d'Ivoire between 1998 and 2017. Screening included tests for serum creatinine, alanine aminotransferase (ALT) and haemoglobin (Hb) to identify renal dysfunction (estimated glomerular filtration rate < 50 mL/min), hepatic abnormalities (ALT > 5× upper limit of normal) and severe anaemia (Hb < 6.5 g/dL), respectively. We considered screening results across four eras and identified factors associated with the conditions in question. RESULTS: The prevalence of renal dysfunction, hepatic abnormalities and severe anaemia were largely unchanged over time and just 8.4% of patients had any of the three conditions. Key factors associated with renal dysfunction and severe anaemia were age > 50 years (adjusted odds ratio (aOR): 2.53; 95% confidence interval (CI): 2.19-2.92; P < 0.001) and CD4 < 100 cells/µl (aOR: 2.57; 95% CI: 2.30-2.88; P < 0.001). CONCLUSION: The relative infrequency of conditions linked to toxicity in Côte d'Ivoire supports the notion that simplification of pre-ART laboratory screening may be undertaken with limited negative impact on identification of adverse events. Targeted screening may be a feasible strategy to balance detection of conditions associated with ART toxicities with simplification of services.

CONTEXTE: La forte demande de services VIH et les directives cliniques détaillées obligent les systèmes de santé des pays à faibles ressources à consacrer des ressources à la prestation de services au détriment d'autres priorités. La simplification des services peut réduire la charge pesant sur les systèmes de santé et les analyses de laboratoire avant la thérapie antirétrovirale (ART) fait partie des services envisagés pour la simplification. MÉTHODES: Nous avons évalué la fréquence des conditions liées aux toxicités dues à l'ART chez 34.994 patients adultes naïfs pour l'ART avec des échantillons référés au laboratoire RETRO-CI à Abidjan, en Côte d'Ivoire entre 1998 et 2017. Les analyses comprenaient les tests de créatinine sérique, d'alanine aminotransférase (ALT) et d'hémoglobine (Hb) pour identifier respectivement la dysfonction rénale (débit de filtration glomérulaire estimé <50 mL/min), les anomalies hépatiques (ALT >5x la limite supérieure normale) et l'anémie sévère (Hb <6,5 g/dL). Nous avons examiné les résultats des analyses sur quatre époques et identifié les conditions associées aux conditions en question. RÉSULTATS: La prévalence de la dysfonction rénale, des anomalies hépatiques et de l'anémie sévère est restée largement inchangée au fil du temps et seulement 8,4% des patients présentaient l'une des trois conditions. Les facteurs clés associés à la dysfonction rénale et à l'anémie sévère étaient l'âge >50 ans (odds ratio ajusté (aOR): 2,53; intervalle de confiance (IC) à 95%: 2,19 à 2,92; p <0,001) et les CD4 <100 cellules/µl (aOR: 2,57; IC95%: 2,30 à 2,88; P < 0,001). CONCLUSION: La relativement faible fréquence des conditions liées à la toxicité en Côte d'Ivoire soutient la notion selon laquelle une simplification des analyses de laboratoire pré-ART peut être entreprise avec un impact négatif limité sur l'identification des événements adverses. Le ciblage des analyses peut être une stratégie réalisable pour aligner la détection des conditions associées aux toxicités ART à la simplification des services.

Bioaccumulation and glutathione S-transferase activity on Rhinella arenarum tadpoles after short-term exposure to antiretrovirals.

The aim of the present study was to investigate the bioaccumulation and toxicological effects of four antiretrovirals (lamivudine, stavudine, zidovudine and nevirapine) on Rhinella arenarum tadpoles, after short-term (48 h) exposure to these drugs at sublethal concentrations. The analytical procedure involved a simple extraction method followed by ultra-high performance liquid chromatography with diode array detection and chemometric analysis for data processing. Under the conditions studied, the analytes investigated, particularly nevirapine, showed possible bioaccumulation in tadpoles. Besides, an increase in the bioaccumulation was observed when increasing the exposure concentration. In addition, the enzymatic biomarkers measured to evaluate the toxicological effects showed that acethylcholinesterase activity was similar to that of the control group, while glutathione S-transferase activity was increased, indicating potential oxidative stress damage. Our results also allowed demonstrating the usefulness of chemometric algorithms to quantitate analytes in complex matrices, such as those absorbed by tadpoles in aquatic ecosystems. The results also evidenced the short-term antiretroviral bioaccumulation in tadpoles and the alteration of antioxidant systems, highlighting the need of environmental studies to elucidate the ecotoxicological risk of antiretrovirals in humans and wildlife.

HIV, aging, and adherence: an update and future directions.

PURPOSE OF REVIEW: To highlight recent data on antiretroviral adherence in older people living with HIV (PLWH), describe the most relevant pharmacokinetic antiretroviral studies, and identify critical research gaps in this population. RECENT FINDINGS: Overall, studies have found that older PLWH are more likely to be adherent to antiretroviral therapy (ART). Although multiple methods to measure adherence are available (self-report, pharmacy refills, electronic device monitors, drug concentrations), there is currently no 'gold standard' adherence measure or sufficient evidence to suggest a preferred method in older patients. Recently, studies evaluating antiretroviral concentrations in hair and dried blood spots in older patients identified no major differences when compared with younger individuals. Similarly, although pharmacokinetic studies in older PLWH are scarce, most data reveal no significant pharmacokinetic differences in the aging population. Furthermore, no specific guidelines or treatment recommendations regarding ART dose modification or long-term toxicity in aging PLWH are available, mostly because of the exclusion of this population in clinical trials. SUMMARY: How aging influences adherence and pharmacokinetics remains poorly understood. As the population of older PLWH increases, research focusing on adherence, toxicity, drug--drug interactions, and the influence of comorbidities is needed.

Toxic Myopathies.

PURPOSE OF REVIEW: This article reviews the pathogenesis, clinical features, and management of toxic myopathy related to common medications, critical illness, and illicit substances. RECENT FINDINGS: Muscle symptoms are common among statin users and are usually reversible after discontinuation of the statin; rarely, however, statins trigger an immune-mediated necrotizing myopathy that persists and requires immunomodulatory therapy. Autoantibodies targeting 3-hydroxy-3-methylglutaryl coenzyme A reductase can distinguish the toxic and immune-mediated forms. Immune checkpoint inhibitors, increasingly used in the treatment of advanced cancer, have recently been associated with the development of inflammatory myositis. A reversible mitochondrial myopathy has long been associated with zidovudine, but recent reports elucidate the risk of myopathy with newer antivirals, such as telbivudine and raltegravir. SUMMARY: The medications most commonly associated with myopathy include statins, amiodarone, chloroquine, hydroxychloroquine, colchicine, certain antivirals, and corticosteroids, and myopathy can occur with chronic alcoholism. Certain clinical, electrodiagnostic, and histologic features can aid in early recognition. Stopping the use of the offending agent reverses symptoms in most cases, but specific and timely treatment may be required in cases related to agents that trigger immune-mediated muscle injury.

Discontinuation of tenofovir due to nephrotoxicity: insight into 12 years of clinical practice

INTRODUCTION: Chronic kidney disease is a significant cause of morbidity and mortality among patients infected with human immunodeficiency virus (HIV). Tenofovir disoproxil fumarate (TDF) is widely used as the part of combination antiretroviral therapy (cART) and may cause renal function impairment. AIM: The primary objective of this analysis was to determine the rate of reversibility of kidney dysfunction and factors correlated with eGFR improvement in patients treated with TDF. MATERIALS AND METHODS: All patients who discontinued TDF between 2003 and 2015 were screened and included in the study if the reason for withdrawal was nephrotoxicity. Kidney function (eGFR, proteinuria, haematuria) was assessed on treatment and one year after discontinuation. Factors associated with not achieving eGFR recovery one year after discontinuing TDF were assessed. RESULTS: A total of 69 patients out of 1625 screened discontinued TDF due to nephrotoxicity and were included in the analysis. At the end of the study period eGFR (CKD-EPI) improved in 52 (75,4%) patients. The eGFR difference was 11,7 ml/min/1,73m2 (95% CI: 6,0 ­ 14,5). Two factors were associated with kidney function improvement: the length of TDF treatment and baseline eGFR. Better recovery was observed in patients treated with shorter (difference: 15,6 ml/min/1,73m2, 95% CI: 5,99 ­ 23,0) and in those with impaired renal function at baseline (difference: 21 ml/min/1,73m2, 95% CI: 11,0 ­ 27,99). CONCLUSIONS: In majority of patients who discontinue TDF therapy, kidney function improves during oneyear period. The drug withdrawal in case of eGFR deterioration should not be postponed.

Antiretroviral drug-induced endothelial dysfunction is improved by dual PPARα/γ stimulation in obesity.

Obesity rates are rising in HIV-infected populations; however, the putative role of highly active antiretroviral therapy (HAART) in the development of endothelial and cardiovascular derangements in the presence of pre-existing overweight/obesity is unclear. Although dual peroxisome proliferator-activated receptors-alpha/gamma (PPARα/γ) stimulation mitigates HAART-induced metabolic dysfunction, vascular effects are unresolved. To investigate whether HAART induces vascular dysfunction in obesity and to explore the underlying mechanisms of PPARα/γ stimulation, male Wistar rats were placed on a high-calorie diet for 16 weeks. After 10 weeks, HAART (lopinavir/ritonavir, azidothymidine/lamivudine) with/without PPARα/γ agonist, Saroglitazar, was administered daily for six weeks. Excised thoracic aorta rings were subjected to isometric tension studies and Western blot measurements. HAART+Saroglitazar-treated obese animals recorded lower adiposity indices (4.3 ±â€¯0.5%) vs. HAART only-treated obese rats (5.6 ±â€¯0.3%; p < .01). Maximum acetylcholine-induced vasorelaxation (Rmax), was lower in obese+HAART group (76.10 ±â€¯3.58%) vs. obese control (101.40 ±â€¯4.75%; p < .01). However, Rmax was improved in obese+ HAART+Saroglitazar (101.00 ±â€¯3.12%) vs. obese+HAART rats (p < .001). The mean LogEC50 was improved in obese+HAART+Saroglitazar vs. obese+HAART group; p = .003. Improved endothelial function in obese+ HAART+Saroglitazar group was associated with upregulation of eNOS, PKB/Akt and downregulated p22-phox expression vs. obese+HAART group. Therefore, PPARα/γ stimulation attenuated HAART-induced endothelial dysfunction by upregulating vasoprotective eNOS, PKB/Akt signaling and downregulating pro-oxidative p22-phox expression.

The inhibitory effect of antiretroviral drugs on the L-carnitine uptake in human placenta.

In spite of remarkable reduction in the number of children born with HIV due to antiretroviral therapy, concerns remain on the short- and long-term effects of antiretroviral drugs at the feto-placental unit. Cardio- and skeletal myopathies have been reported in children exposed to antiretroviral drugs prenatally. These conditions have also been described in perturbed placental transfer of l-carnitine, an essential co-factor in fatty acid oxidation. Due to limited fetal and placental synthesis, carnitine supply is maintained through the placental carnitine uptake from maternal blood by the organic cation/carnitine transporters OCTN1 and OCTN2 (SLC22A4 and SLC22A5, respectively). The aim of our study was to investigate potential inhibition of placental carnitine uptake by a broad range of antiretroviral drugs comprising nucleoside/nucleotide reverse transcriptase inhibitors (lamivudine, zidovudine, abacavir, tenofovir disoproxil fumarate), non-nucleoside reverse transcriptase inhibitors (rilpivirine, efavirenz, etravirine), protease inhibitors (ritonavir, lopinavir, atazanavir, saquinavir, tipranavir), integrase inhibitors (raltegravir, dolutegravir, elvitegravir) and viral entry inhibitor, maraviroc. Studies in choriocarcinoma BeWo cells and human placenta-derived models confirmed predominant expression and function of OCTN2 above OCTN1 in l-carnitine transport. Subsequent screenings in BeWo cells and isolated MVM vesicles revealed seven antiretroviral drugs as inhibitors of the Na+-dependent l-carnitine uptake, corresponding to OCTN2. Ritonavir, saquinavir and elvitegravir showed the highest inhibitory potential which was further confirmed for ritonavir and saquinavir in placental fresh villous fragments. Our data indicate possible impairment in placental and fetal supply of l-carnitine with ritonavir and saquinavir, while suggesting retained placental carnitine transport with the other antiretroviral drugs.

Stability behaviour of antiretroviral drugs and their combinations. 9: Identification of incompatible excipients.

Incompatibility studies of antiretroviral drugs, viz., lamivudine (3TC), emtricitabine (FTC), abacavir sulfate (ABC), tenofovir disoproxil fumarate (TDF), zidovudine (ZDV), efavirenz (EFV) and nevirapine (NVP) were carried out in the presence of ten selected excipients, i.e., microcrystalline cellulose, lactose monohydrate, starch, magnesium stearate, sodium lauryl sulfate, sodium starch glycolate, croscarmellose sodium, colloidal silica, povidone K-30 and hydroxypropyl cellulose. Among all, ABC showed reaction with lactose monohydrate, resulting in the formation of two interaction products, while sodium lauryl sulphate enhanced the degradation of TDF. The interaction products of ABC-Lactose were separated by high performance liquid chromatography (HPLC) and subjected to liquid chromatography-high resolution mass spectrometry (LC-HRMS) studies for their characterization. One of the products was also isolated and subjected to 1D and 2D nuclear magnetic resonance (NMR) studies for structural confirmation. The toxicity of both was predicted using TOPKAT and ADMET™ software and compared to the drug.

Improving the clinical relevance of a mouse pregnancy model of antiretroviral toxicity; a pharmacokinetic dosing-optimization study of current HIV antiretroviral regimens.

Animal models can be useful tools for the study of HIV antiretroviral (ARV) safety/toxicity in pregnancy and the mechanisms that underlie ARV-associated adverse events. The utility and translatability of animal model-based ARV safety/toxicity data is improved if ARVs are tested in clinically relevant concentrations. The objective of this work was to improve the clinical relevance of our mouse pregnancy model of ARV toxicity, by determining the doses of currently prescribed ARV regimens that would yield human therapeutic plasma concentrations. Pregnant mice were administered increasing doses of ARV combinations by oral gavage, followed by measurement of drug concentrations in the maternal plasma and amniotic fluid. Concentrations of ten different ARVs in maternal plasma and amniotic fluid samples of pregnant mice are presented, with dosing optimization to yield human pregnancy-relevant plasma drug concentrations. We have proposed optimal dosing for different regimen component drugs to achieve human therapeutic plasma levels, so that a clinically relevant standard dosing is established. A review of related ARV pharmacokinetic studies in (pregnant/non-pregnant) rodents and human pregnancy is also shown. We hope these data will inform and encourage the use of mouse pregnancy models in the study of ARV safety/toxicity.

IL-1RN and IL-1ß Polymorphism and ARV-Associated Hepatotoxicity.

The severity of hepatic injury depends upon cytokines. Previous studies associated IL-1RN allele 2 with IL-1ß production. Hence, we examined the association of IL-1 RN and IL-1ß polymorphisms with ARV-associated hepatotoxicity. Genotyping of IL-1RN (VNTR), IL-1ß (-511C/T) polymorphisms was done in 162 HIV-infected patients, 34 with ARV hepatotoxicity, 128 without hepatotoxicity, and 152 healthy controls using PCR and PCR-RFLP method. The haplotypes 1T and 2C enhanced the risk for severe hepatotoxicity (OR = 1.41, P = 0.25; OR = 1.67, P = 0.31). IL-1ß-511TT genotype significantly represented among tobacco using HIV-infected individuals compared to nonusers (OR = 3.74, P = 0.05). IL-1ß-511TT genotype among alcohol users increased the risk for hepatotoxicity (OR = 1.80, P = 0.90). IL-1ß-511CT and -511TT genotypes overrepresented in alcohol using HIV-infected individuals (OR = 2.29, P = 0.27; OR = 2.64, P = 0.19). IL-RN 2/2 and 1/3 genotypes represented higher in nevirapine using hepatotoxicity patients (OR = 1.42, P = 0.64, OR = 8.79, P = 0.09). IL-1ß-511CT and -511 TT genotypes among nevirapine users enhanced the risk for severe hepatotoxicity (OR = 4.29, P = 0.20; OR = 1.95, P = 0.56). IL-1ß-511CT and -511TT genotypes were overrepresented in combined nevirapine and alcohol using HIV-infected individuals as compared to nevirapine users and alcohol nonusers (OR = 2.56, P = 0.26; OR = 2.84, P = 0.24). IL-1ß-511TT genotype with tobacco, alcohol, and nevirapine usage revealed a trend of risk for the development of ARV-associated hepatotoxicity and its severity.

Removal of antiretroviral drugs stavudine and zidovudine in water under UV254 and UV254/H2O2 processes: Quantum yields, kinetics and ecotoxicology assessment.

The concentration of antiretroviral drugs in wastewater treatment plants (WWTP) effluents and surface waters of many countries has increased significantly due to their widespread use for HIV treatment. In this study, the removal of stavudine and zidovudine under UV254 photolysis or UV254/H2O2 was investigated in a microcapillary film (MCF) photoreactor, using minimal water samples quantities. The UV254 quantum yield of zidovudine, (2.357 ±â€¯0.0589)·10-2 mol ein-1 (pH 4.0-8.0), was 28-fold higher that the yield of stavudine (8.34 ±â€¯0.334)·10-4 mol ein-1 (pH 6.0-8.0). The second-order rate constant kOH,iof reaction of hydroxyl radical with the antiretrovirals (UV254/H2O2 process) were determined by kinetics modeling: (9.98 ±â€¯0.68)·108 M-1 s-1 (pH 4.0-8.0) for zidovudine and (2.03 ±â€¯0.18)·109 M-1 s-1 (pH 6.0-8.0) for stavudine. A battery of ecotoxicological tests (i.e. inhibition growth, bioluminescence, mutagenic and genotoxic activity) using bacteria (Aliivibrio fischeri, Salmonella typhimurium), crustacean (Daphnia magna) and algae (Raphidocelis subcapitata) revealed a marked influence of the UV dose on the ecotoxicological activity. The UV254/H2O2 treatment process reduced the ecotoxicological risk associated to direct photolysis of the antiretrovirals aqueous solutions, but required significantly higher UV254 doses (≥2000 mJ cm-2) in comparison to common water UV disinfection processes.