Adverse Drug Reactions and Prescription Patterns of Antiretroviral Drugs: A Longitudinal Observational Study From a Tertiary Care Hospital in Western India.

Background In 2018, the World Health Organisation (WHO) released interim guidelines, advising a change of regimens to dolutegravir-based first- and second-line antiretroviral therapy (ART), based on which, in 2021, the National Aids Control Organisation (NACO) updated its guidelines to include the tenofovir + lamivudine + dolutegravir (TLD) regimen as a first line of therapy for all people living with HIV (PLHIV) and second- and third-line regimens to dolutegravir-based regimens. Considering this change of regimen, the adverse drug reaction (ADR) profiling and longitudinal prescription pattern of antiretroviral and concomitant medications in adult patients at the ART centre of a tertiary care hospital were assessed in this study. Methods Ninety-seven PLHIV out of all the patients who attended the ART centre from September 2021 to July 2022 were enrolled and followed up for six months. The ADRs that occurred during this period were collected along with details of prescription patterns and analyzed by descriptive statistics. Causality assessment for ADR was done using the World Health Organisation-Uppsala Monitoring Centre (WHO-UMC) scale. Results Seventy-eight percent (n=76 out of 97) of patients experienced at least one ADR, and 128 ADRs were seen in 97 patients. The most common ADRs were increased alkaline phosphatase (39.0%, n=128), dyslipidaemia (12.5%, n=128), and nephrotoxicity (10.1%, n=128). The drug most suspected of causing ADRs was dolutegravir (27.5%, n=342). The most common therapeutic regimen was TLD (71.2%, n=97). The most prescribed drug was lamivudine (30.6%, n=1183). The most prescribed concomitant medication was cotrimoxazole (15%, n=312). Conclusions Dolutegravir-based regimens have been implemented for PLHIV in a phased-out manner from previous non-dolutegravir-based ART regimens, which is in line with the recent NACO guidelines. However, it has also led to an increase in dolutegravir-associated ADRs like increased alkaline phosphatase, dyslipidaemia, and nephrotoxicity. Continuous monitoring of prescriptions and ADRs can add to our knowledge regarding their use and ADRs.

Exploring Darunavir, Rilpivirine and Etravirine as Potential Therapies for Bladder Cancer: Efficacy and Synergistic Effects.

This research explores the therapeutic efficacy of Darunavir (DRV), Rilpivirine (RPV), and Etravirine (ETV) against UM-UC-5 bladder cancer cells, addressing the critical need for innovative treatments in bladder cancer research. Through a comprehensive assessment of their individual and combined effects across diverse time intervals, ETV emerges as the most potent drug, with a lowest IC50 of 5.9 µM, closely followed by RPV (lowest IC50 of 9.6 µM), while DRV exhibits the least effectiveness (lowest IC50 of 25.6 µM). Notably, a significant synergistic effect is evident in the ETV and RPV combination, especially at 48 and 72 h for low concentrations. Synergies are also observed with ETV and DRV, albeit to a lesser extent and primarily at 48 h. Conversely, the DRV and RPV combination yields minimal effects, predominantly additive in nature. In summary, this pre-clinical investigation underscores the promising therapeutic potential of ETV and RPV, both as standalone treatments and in combination, hinting at repurposing opportunities in bladder cancer therapy, which could give a new treatment method for this disease that is faster and without as severe side effects as anticancer drugs. These findings represent a substantial stride in advancing personalized medicine within cancer research and will be further scrutinized in forthcoming studies.

PROTAC-mediated degradation of HIV-1 Nef efficiently restores cell-surface CD4 and MHC-I expression and blocks HIV-1 replication.

The HIV-1 Nef accessory factor enhances the viral life cycle in vivo, promotes immune escape of HIV-infected cells, and represents an attractive antiretroviral drug target. However, Nef lacks enzymatic activity and an active site, complicating traditional occupancy-based drug development. Here we describe the development of proteolysis targeting chimeras (PROTACs) for the targeted degradation of Nef. Nef-binding compounds, based on an existing hydroxypyrazole core, were coupled to ligands for ubiquitin E3 ligases via flexible linkers. The resulting bivalent PROTACs induced formation of a ternary complex between Nef and the cereblon E3 ubiquitin ligase thalidomide-binding domain in vitro and triggered Nef degradation in a T cell expression system. Nef-directed PROTACs efficiently rescued Nef-mediated MHC-I and CD4 downregulation in T cells and suppressed HIV-1 replication in donor PBMCs. Targeted degradation is anticipated to reverse all HIV-1 Nef functions and may help restore adaptive immune responses against HIV-1 reservoir cells in vivo.

Lamivudine, Doravirine, and Cabotegravir Downregulate the Expression of Human Endogenous Retroviruses (HERVs), Inhibit Cell Growth, and Reduce Invasive Capability in Melanoma Cell Lines.

This study explores the impact of antiretroviral administration on the expression of human endogenous retroviruses (HERVs), cell growth, and invasive capability of human melanoma cell lines in culture. We investigated three antiretrovirals-lamivudine, doravirine, and cabotegravir-in A375, FO-1, and SK-Mel-28, BRAF-mutated, and in MeWo, P53-mutated, melanoma cell lines. The findings indicate a general capability of these drugs to downregulate the expression of HERV-K Pol and Env genes and hinder cell viability, mobility, and colony formation capacity of melanoma cells. The antiretroviral drugs also demonstrate selectivity against malignant cells, sparing normal human epithelial melanocytes. The study reveals that the integrase inhibitor cabotegravir is particularly effective in inhibiting cell growth and invasion across different cell lines in comparison with lamivudine and doravirine, which are inhibitors of the viral reverse transcriptase enzyme. The investigation further delves into the molecular mechanisms underlying the observed effects, highlighting the potential induction of ferroptosis, apoptosis, and alterations in cell cycle regulatory proteins. Our findings showed cytostatic effects principally revealed in A375, and SK-Mel-28 cell lines through a downregulation of retinoblastoma protein phosphorylation and/or cyclin D1 expression. Signs of ferroptosis were detected in both A375 cells and FO-1 cells by a decrease in glutathione peroxidase 4 and ferritin expression, as well as by an increase in transferrin protein levels. Apoptosis was also detected in FO-1 and SK-Mel-28, but only with cabotegravir treatment. Moreover, we explored the expression and activity of the stimulator of interferon genes (STING) protein and its correlation with programmed death-ligand 1 (PD-L1) expression. Both the STING activity and PD-L1 expression were decreased, suggesting that the antiretroviral treatments may counteract the detrimental effects of PD-L1 expression activation through the STING/interferon pathway triggered by HERV-K. Finally, this study underscores the potential therapeutic significance of cabotegravir in melanoma treatment. The findings also raise the prospect of using antiretroviral drugs to downregulate PD-L1 expression, potentially enhancing the therapeutic responses of immune checkpoint inhibitors.

Advances in the transdermal delivery of antiretroviral drugs.

Antiretroviral therapy regimens are successful in stopping the advancement of human immunodeficiency virus infection to acquired immunodeficiency syndrome, and other opportunistic infections. However, they do have significant disadvantages, including long-term treatment, limited oral bioavailability, inaccessibility to organs, non-adherence by patients, and the development of medication resistance. Because of the listed drawbacks of available routes and the availability of curative medicines for human immunodeficiency virus/acquired immunodeficiency syndrome, advanced solutions are required. Antiretroviral therapy transdermal delivery is one of the current strategies that have attracted much attention from many researchers. In this narrative review, various in vitro, in vivo, and ex vivo transdermal antiretroviral therapy delivery strategies were reviewed, such as transdermal patches and films, lipid-based nano-delivery systems, microneedles, chemical penetration enhancers, and iontophoresis, which showed promising results. Although the majority of studies on Antiretroviral transdermal delivery have produced hopeful findings, additional in-depth research on passive and physical enhancement techniques, both existing and new, is necessary to fully understand the potential of this route and to make it accessible to human immunodeficiency virus patients.

In vitro anti-HIV, cytotoxicity and nutritional analysis of Trianthema portulacastrum L. (Aizoaceae).

The development of antiretroviral therapy has brought a tremendous relief to the world as it minimizes mortality, reduces HIV transmission, and suppresses progression in infected patients. However, the orthodox antiretroviral therapy is faced with limitations which have necessitated a continuous search for more novel plant-based antiviral compounds, which can bypass the existing barriers created by drug resistance and target more viral proteins. Despite the edibility and enormous pharmacological benefits of T. portulacastrum, little is known about its nutrient profiles and potential use as a natural source of antiviral drug. This study focuses on the full feed analysis and anti-HIV potential of two biotypes of T. portulacastrum. Ethanolic extracts of both biotypes of T. portulacastrum (T01 and T02) had significant inhibitory effects on the level of replication of the HIV-1. Both extracts induced the inhibition of at least 50% of the HIV-1 viral load at considerably low IC50 values of 1.757 mg/mL (T01) and 1.205 mg/mL (T02) which is comparable to the AZT standard. The protein composition ranged between 8.63-22.69%; fat (1.84-4.33%); moisture (7.89-9.04%); fibre (23.84-49.98%); and carbohydrate content (38.54-70.14%). Mineral contents of tested T. portulacastrum varied considerably in different parts of the plant. Nitrogen N mineral ranged between 13.8-36.3 mg/g; sodium Na (2.0-14.0 mg/g); potassium K (14.0-82.0 mg/g); magnesium Mg (2.8-7.1 mg/g); calcium Ca (9.1-24.7 mg/g); phosphorus P (1.3-3.6 mg/g); iron Fe (193.5-984.0 ppm); zinc Zn (42.5-96.0 ppm); manganese Mn (28.5-167.5 ppm); and copper Cu (2.0-8.5 ppm). These mineral values are comparable or higher than values quoted for common vegetables, suggesting that T. portulacastrum is a nutrient-dense vegetable that could provide alternative sources of antiviral nutrients to HIV-infected individuals. Further studies are recommended to unravel key metabolites responsible for high nutrient profiles and antiretroviral effects in T. portulacastrum.

Nicotine, THC, and Dolutegravir Modulate E-Cigarette-Induced Changes in Addiction- and Inflammation-Associated Genes in Rat Brains and Astrocytes.

E-cigarette use has been marketed as a safer alternative to traditional cigarettes, as a means of smoking cessation, and are used at a higher rate than the general population in people with HIV (PWH). Early growth receptor 2 (EGR2) and Activity-Regulated Cytoskeleton-Associated Protein (ARC) have a role in addiction, synaptic plasticity, inflammation, and neurodegeneration. This study showed that 10 days of exposure to e-cigarette vapor altered gene expression in the brains of 6-month-old, male, Sprague Dawley rats. Specifically, the e-cigarette solvent vapor propylene glycol (PG) downregulated EGR2 and ARC mRNA expression in frontal cortex, an effect which was reversed by nicotine (NIC) and THC, suggesting that PG could have a protective role against NIC and cannabis dependence. However, in vitro, PG upregulated EGR2 and ARC mRNA expression at 18 h in cultured C6 rat astrocytes suggesting that PG may have neuroinflammatory effects. PG-induced upregulation of EGR2 and ARC mRNA was reversed by NIC but not THC. The HIV antiretroviral DTG reversed the effect NIC had on decreasing PG-induced upregulation of EGR2, which is concerning because EGR2 has been implicated in HIV latency reversal, T-cell apoptosis, and neuroinflammation, a process that underlies the development of HIV-associated neurocognitive disorders.

A Comparative Study of Antiretroviral (Lopinavir/Ritonavir) and Remdesivir Used in the Pandemic in Iraq on the Clinical Outcome in Patients with SARS-CoV-2.

The SARS-CoV-2 virus, which emerged in December 2019, has infected millions worldwide and caused many deaths. Due to its high mortality rate, several studies assessed the effectiveness of different drugs against COVID-19, mainly in reducing the hospitalization rate among the elderly and compromised patients. Lopinavir-ritonavir combination and remdesivir were among the medications used to treat COVID-19. Due to considerable differences in the effectiveness and clinical outcomes of the two treatments, this study aimed to compare the clinical outcomes between COVID-19 patients treated with antiretrovirals (lopinavir-ritonavir) and remdesivir. A total of 33 patients on lopinavir-ritonavir and 35 on remdesivir were selected for this study. A retrospective comparative analysis was conducted based on demographic characteristics, hospital stay, laboratory parameters of C-reactive protein (CRP) and plasma blood oxygen saturation (SPO2), clinical treatment, and a clinical outcome assessment extracted from hospital archive data. Both treatments improved patient outcomes, yet there was a significant difference between lopinavir-ritonavir and remdesivir groups in platelet count, CRP, SPO2, and monocyte results, with remdesivir showing better clinical outcomes. No significant difference was reported in white blood cells, lymphopenia, and lactate dehydrogenase between the two treatments. It is still necessary to conduct further research to determine how effective the two treatments are in treating severe COVID-19 cases due to the limited number of available studies and the inconsistency in research methods and measurements.

The Impact of Contemporary Antiretroviral Drugs on Atherosclerosis and Its Complications in People Living With HIV: A Systematic Review.

With the advent of modern antiretroviral therapy (ART), human immunodeficiency virus (HIV) infection has been modified into a chronic manageable condition, prolonging the lifespan of people living with HIV (PLHIV). This has resulted in an increased non-AIDS-related morbidity in the HIV-infected population. Our aim is to study the role of contemporary ART in tackling the risk of atherosclerosis and cardiovascular disease (CVD) in PLHIV. We searched through the databases of PubMed, PubMed Central, and Cochrane Library for pertinent articles using the medical subject headings (MeSH) "HIV infection", "Atherosclerosis", and "Antiretroviral agents". The articles published in the past five years were retrieved, screened for relevance, and assessed for quality before being included in the review. This review was performed following the PRISMA 2020 guidelines. The results indicate that the incidence of dyslipidemia with integrase strand transfer inhibitors (INSTIs) is greater than with non-nucleoside reverse transcriptase inhibitors (NNRTIs) and lesser than with protease inhibitors (PIs). INSTIs are indispensably associated with weight gain and obesity. High triglyceride (TG) and oxidized low-density lipoproteins to low-density lipoproteins (oxLDL/LDL) ratio levels and low high-density lipoprotein (HDL) levels are seen in patients taking PIs. A higher incidence of hypertension and metabolic syndrome (MetS) was noticed with INSTIs compared to NNRTIs. PI intake for >5 years increases the risk of subclinical atherosclerosis. Increased risk of myocardial infarction with INSTIs was observed in a study, while another study reported decreased risk. HIV infection independently increases the risk for atherosclerosis and CVD. Although contemporary ART decreases this enhanced risk, it inherently increases the risk for abnormal lipid profile, MetS, weight gain, and obesity. Further research into the risk of atherosclerosis and CVD with newer ART drugs is essential for decoding the underlying mechanisms and preventing adverse cardiac outcomes in PLHIV.

The Impact of Certain Pharmacogenetic Differences on the Metabolism of Antiretroviral Drugs Used in A Black South African Population.

BACKGROUND: Genetic polymorphism of drug-metabolising enzymes and transporters may influence the effect and toxicity of antiretroviral drugs. OBJECTIVES: To determine and compare the minimum allele frequency of 20 single nucleotide polymorphisms (SNPs) with possible involvement in the metabolism of the antiretroviral drugs with other populations. To investigate the influence of these variants on Reverse transcriptase, Protease and Integrase strand transfer inhibitor drugs. METHOD: DNA samples were collected from 1489 subjects. All SNPs with a gene call score of > 0.6 were selected for genotyping. The R package calculated call rates, MAF and Hardy-Weinberg equilibrium (HWE), test p-values, and Chi-squared analysis were performed on the data. The Fisher's exact test compared the allele frequencies between the populations. RESULTS: The highest similarities in minimum allele frequency (MAF) were between the Prospective Urban and Rural Epidemiological group (PURE), a Black population in South Africa, and the Yoruba and Luhya populations in Africa. The following SNPs were identified with a possible effect on metabolism: CYP2B6 rs28399494 (MAF 11%) is indicated in the toxicity of Efavirenz and Nevirapine. CYP3A5 rs776746 (MAF 17%) and CYP3A4 rs2749674 (MAF 23%) both cause an increase in the metabolism of the protease inhibitors. The very low MAF values for both SCL01B1 rs4149056 (MAF 0.6%) and ABCC rs717620 (MAF 2.8%) are indications that OATP1B1 transport function and glomerular filtration tempo will not be compromised. The high MAF value of 30% for UGTA1 rs10929302 can result in hyperbilirubinemia, which can decrease the clearance of Dolutegravir. CONCLUSION: These results show a possibility of kidney protection and an increase in bilirubin in this population.

Marcadores lipídicos en los pacientes con VIH/sida en tratamiento con inhibidores de la proteasa

Introducción: Las enfermedades cardiovasculares constituyen la principal causa de morbimortalidad a escala mundial. Otra enfermedad con impacto significativo en los sistemas de salud pública es el VIH/sida. Los pacientes infectados con el virus de la inmunodeficiencia humana, tienen mayor riesgo de desarrollar enfermedades cardiovasculares. Posterior al tratamiento antirretroviral ha disminuido la incidencia de enfermedades oportunistas asociadas al VIH/sida, y se ha elevado la incidencia de enfermedades asociadas al envejecimiento, como la enfermedad cardiovascular. El uso de antirretrovirales inhibidores de la proteasa se asocia a hiperlipidemia y, por consiguiente, al aumento de complicaciones cardiovasculares. Objetivo: Determinar los marcadores lipídicos en pacientes con VIH/sida en tratamiento con inhibidores de la proteasa. Materiales y métodos: Se realizó un estudio observacional, analítico, transversal en los pacientes con VIH/sida de la provincia de Matanzas, durante el período comprendido entre marzo y agosto de 2020, en el Laboratorio Clínico del Hospital Universitario Clínico Quirúrgico Comandante Faustino Pérez Hernández. Resultados: Se evaluaron los marcadores lipídicos como factor de riesgo cardiovascular asociado al tratamiento antirretroviral, siendo los triglicéridos el de mayor incidencia. Conclusiones: Se identificaron los marcadores lipídicos como factores de riesgo cardiovascular, en este caso la hipertrigliceridemia.

Introduction: Cardiovascular diseases are the main risk of morbidity and mortality worldwide. Another disease with significant impact on public health systems is HIV/AIDS. Patients infected with the human immunodeficiency virus have a higher risk of developing cardiovascular diseases. After antiretroviral treatment, the incidence of opportunistic diseases associated with HIV/AIDS has decreased and the incidence of diseases associated with aging such as cardiovascular disease has increased. The use of protease inhibitor antiretroviral drugs is associated with hyperlipidemia and a consequent increase in cardiovascular complications. Objective: To determine lipid markers in patients with HIV/AIDS undergoing treatment with protease inhibitors. Materials and method: An observational, analytical, cross-sectional study was carried out in patients with HIV/AIDS from the province of Matanzas during the period from March to August 2020, in the Clinical Laboratory of the Provincial Teaching Clinical Surgical Hospital Faustino Pérez Hernandez. Results: Lipid markers were evaluated as cardiovascular risk factor associated with antiretroviral treatment, with triglycerides being the one of highest incidence. Conclusions: Lipid markers were identified as cardiovascular risk factors; in this case hypertriglyceridemia.

Resistencia genotípica del HIV a los antirretrovirales en niños de Argentina entre 2006 y 2021 / HIV genotypic drug resistance to antiretrovirals in children in Argentina between 2006 and 2021

Introducción: La resistencia del HIV a los antirretrovirales (ARVs) es una de las principales causas de fallo terapéutico en niños, niñas y adolescentes que conviven con el virus. Desde el año 2006, el Laboratorio de Biología Celular y Retrovirus del Hospital Garrahan realiza el estudio genotípico de resistencia (ER) del HIV-1 a los ARVs a fin de identificar mutaciones que disminuyen la susceptibilidad del virus a los fármacos que componen el tratamiento ARV. Objetivos: El objetivo del trabajo fue estudiar el tipo y frecuencia de resistencia del HIV a los ARVs, a través de un análisis de 371 ER realizados entre los años 2006 y 2021 en niños, niñas y adolescentes con HIV-1 adquirido por transmisión vertical y con solicitud médica de ER por presentar fallo terapéutico. Resultados: Entre los años 2006 y 2013 la proporción de casos con resistencia a al menos una clase de fármaco ARV fue mayor al 90%, sugiriendo una asociación directa entre el fallo virológico y la disminución en la susceptibilidad del HIV-1 a uno o más componentes del TARV. A partir del año 2012, se observa una disminución progresiva del nivel de resistencia de HIV-1, llegando al 50% en 2021 (p<0.0001). La frecuencia de mutaciones de resistencia fue diferente para cada una de las clases de ARVs. Mientras que la resistencia a INNTR no sufrió cambios significativos a lo largo del período de estudio, oscilando entre 27% y 75%. La proporción de mutaciones a IPs en pacientes con fallo virológico disminuyó de 87% en 2006 a 17% en 2021 y para los INTR, disminuyó de 79% en 2006 a 45% en 2021. Conclusión: El nivel de resistencia a los ARVs ha disminuido de manera sustancial a lo largo de los últimos 16 años, probablemente por el uso de nuevos fármacos ARV con alta potencia que posibilitaron la intensificación de los tratamientos ARV y la implementación de criterios de fallo terapéutico más estrictos tanto a nivel clínico como virológico (AU)

Introduction: HIV resistance to antiretroviral (ARV) drugs is one of the main causes of therapeutic failure in children and adolescents living with the virus. Since 2006, the Cell Biology and Retrovirus Laboratory of the Garrahan Hospital has been performing the genotypic study of HIV-1 resistance to ARV drugs in order to identify mutations that reduce the susceptibility of the virus to the drugs that constitute ARV treatment. Objectives: The aim of this study was to assess the type and frequency of HIV resistance to ARV drugs through an analysis of 371 genotype studies performed between 2006 and 2021 in children and adolescents with HIV-1 acquired through motherto-child transmission and with medical request for genotype study due to therapeutic failure. Results: Between 2006 and 2013, the proportion of cases with resistance to at least one ARV drug class was greater than 90%, suggesting a direct association between virologic failure and decreased susceptibility of HIV-1 to one or more components of ART. From 2012 onwards, a progressive decrease in the level of HIV-1 resistance was observed, reaching 50% in 2021 (p<0.0001). The frequency of resistant mutations was different for each of the ARV classes, while resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) did not change significantly over the study period, ranging from 27% to 75%. The proportion of drug-resistant mutations to protease inhibitors (PI) in patients with virologic failure decreased from 87% in 2006 to 17% in 2021 and for NNRTIs from 79% in 2006 to 45% in 2021. Conclusion: The level of resistance to ARV drugs has decreased substantially over the last 16 years, probably due to the use of new ARV drugs with high potency that allowed the intensification of ARV treatments and the implementation of stricter criteria for therapeutic failure both clinically and virologically (AU)

Central nervous system disorders after use of dolutegravir: evidence from preclinical and clinical studies.

The evaluation of dolutegravir based on available preclinical and clinical studies reveals a risk of central nervous system (CNS) disorders associated with long-term use of the drug. The available literature on the pharmacokinetics of the drug, including its penetration of the blood-brain barrier, was reviewed, as well as clinical trials assessing the incidence of adverse effects in the CNS and the frequency of its discontinuation. This paper also summarizes the impact of factors affecting the occurrence of CNS disorders and indicates the key role of pharmacovigilance in the process of supplementing knowledge on the safety of drugs, especially those that are newly registered.

Acceptability of a Combination Adherence Strategy to Support HIV Antiretroviral Therapy and Pre-exposure Prophylaxis Adherence During Pregnancy and Breastfeeding in Malawi.

In two parallel pilot studies, we implemented a combination adherence intervention of patient-centered counselling and adherence supporter training, tailored to support HIV treatment (i.e., antiretroviral therapy) or prevention (i.e., pre-exposure prophylaxis, or PrEP) during pregnancy and breastfeeding. Using a mixed-methods approach, we evaluated the intervention's acceptability. We investigated engagement, satisfaction, and discussion content via survey to all 151 participants assigned to the intervention arm (51 women living with HIV, 100 PrEP-eligible women without HIV). We also conducted serial in-depth interviews with a subgroup (n = 40) at enrollment, three months, and six months. In the quantitative analysis, the vast majority reported high satisfaction with intervention components and expressed desire to receive it in the future, if made available. These findings were supported in the qualitative analysis, with favorable comments about counselor engagement, intervention content and types of support received from adherence supporters. Overall, these results demonstrate high acceptability and provide support for HIV status-neutral interventions for antiretroviral adherence.

Female Sex Hormones Upregulate the Replication Activity of HIV-1 Sub-Subtype A6 and CRF02_AG but Not HIV-1 Subtype B.

More than 50% of all people living with HIV worldwide are women. Globally, HIV/AIDS is the leading cause of death among women aged 15 to 44. The safe and effective methods of hormonal contraception are an essential component of preventive medical care in order to reduce maternal and infant mortality. However, there is limited knowledge regarding the effect of hormones on the rate of viral replication in HIV infection, especially non-B subtypes. The goal of the present work was to study in vitro how the female hormones ß-estradiol and progesterone affect the replication of the HIV-1 subtypes A6, CRF02_AG, and B. The findings show that high doses of hormones enhanced the replication of HIV-1 sub-subtype A6 by an average of 1.75 times and the recombinant variant CRF02_AG by 1.4 times but did not affect the replication of HIV-1 subtype B. No difference was detected in the expression of CCR5 and CXCR4 co-receptors on the cell surface, either in the presence or absence of hormones. However, one of the reasons for the increased viral replication could be the modulated TLRs secretion, as it was found that high doses of estradiol and progesterone upregulated, to varying degrees, the expression of TLR2 and TLR9 genes in the PBMCs of female donors infected with HIV-1 sub-subtype A6.

Uptake of selected antiretrovirals by pepper (Capsicum annum), radish (Raphanus sativus), and ryegrass (Lolium perenne) grown on two contrasting soils and fertilized with human urine-derived fertilizers.

The use of urine-derived fertilizers has several economic and environmental advantages. However, there is concern that pharmaceutical residues present in urine could enter the food chain after plant uptake and pose potential risks to human and animal health. A pot experiment was conducted to evaluate the uptake of nine target antiretroviral drugs (ARVDs) by pepper (Capsicum annum), ryegrass (Lolium perenne) and radish (Raphanus sativus) grown in two soils of contrasting texture and organic matter content and fertilized with stored urine, nitrified urine concentrate (NUC), and struvite. Nevirapine was the only ARVD detected in crops grown with NUC and struvite on both soils, but the concentrations were below the limit of quantification. Plants fertilized with stored urine absorbed lamivudine, ritonavir, stavudine, emtricitabine, nevirapine, and didanosine, while abacavir, efavirenz and zidovudine were not detected. The ARVDs detected in the soils after harvest were significantly higher in the soil with high organic matter and clay content. To assess direct human exposure the estimated daily dietary intake (DDI) of ARVDs by consumption of the pepper and radish fertilized with stored urine was compared with the Threshold of Toxicological Concern (TTC) values based on the Cramer classification tree. The calculated DDI values for all ARVDs were about 300-3000 times lower than the TTC values for class III compounds. Therefore, daily consumption of these crops fertilized with stored urine does not pose a health risk to the consumer. Future research is required to assess the impact of ARVD metabolites, which may be more harmful to human health than the parent compounds.

Human adenovirus DNA polymerase is evolutionarily and functionally associated with human telomerase reverse transcriptase based on in silico molecular characterization that implicate abacavir and zidovudine.

Human adenoviruses (HAdVs) are non-enveloped, small double stranded DNA (dsDNA) viruses that cause asymptomatic infections, clinical syndromes and significant susceptibility to infections in immunocompromised people. The aim of the present study was to identify critical host proteins and HAdV hypothetical proteins that could be developed as potential host-viral targets for antiHAdV therapy. Here, the function of selected hypothetical proteins of HAdV based on phylogenetic relationship with the therapeutic targets of antiretroviral drugs of human immunodeficiency virus (HIV) was predicted computationally, and characterized the molecular dynamics and binding affinity of DNA polymerase of HAdV. Thirty-eight hypothetical proteins (HPs) of human adenovirus (HAdV) were used in this study. The results showed that HAdV DNA polymerase (P03261) is related to Human TERT (O14746) and HLA-B (P01889) genes. The protein-protein interaction of human five molecular targets (PNP, TERT, CCR5, HLA-B, and NR1I2) of ARVDs are well-coordinated/networked with CD4, AHR, FKBP4, NR3C1, HSP90AA1, and STUB1 proteins in the anti-HIV infection mechanism. The results showed that the free energy score of abacavir and zidovudine binding to HAdV DNA polymerase are -5.8 and -5.4 kcal mol-1 respectively. Also, the control drug, cidofovir and ganciclovir have less binding affinity for DNA polymerase of HAdV when compare to that of abacavir and zidovudine. Similarity was observed in the binding of abacavir and zidovudine to HAdV DNA polymerase (ASP742, ALA743, LEU772, ARG773 and VAL776). In conclusion, combination of abacavir and zidovudine was predicted to be potential therapy for controlling HAdV infection targeting HAdV DNA polymerase.

Gynoid Fat Distribution and Adipocyte Trapping May Explain Virological Failure With Intramuscular Long-Acting Cabotegravir and Rilpivirine.

Intramuscular long-acting antiretroviral drugs can improve adherence to lifelong antiretroviral treatment. Nevertheless, adipose tissue thickness and distribution play a critical role with injectable drugs. We describe a virological failure with cabotegravir and rilpivirine in a Black African woman with human immunodeficiency virus type 1 with gynoid fat distribution (ie, adipose tissue prevailing in the pelvis and hip area) and body mass index <30 kg/m2.

Pharmacokinetic Drug-Drug Interactions Involving Antiretroviral Agents: An Update.

Antiretroviral therapy is the recognized treatment for human immunodeficiency virus (HIV) infection involving several antiviral agents. Even though highly active antiretroviral therapy has been proven to be very effective in suppressing HIV replication, the antiretroviral drugs, belonging to different pharmacological classes, present quite complex pharmacokinetic properties such as extensive drug metabolism and transport by membrane-associated drug carriers. Moreover, due to uncomplications or complications in HIV-infected populations, an antiretroviralbased multiple-drug coadministration therapy strategy is usually applied for treatment effect, thus raising the possibility of drug-drug interactions between antiretroviral drugs and common drugs such as opioids, stains, and hormonal contraceptives. Herein, thirteen classical antiretroviral drugs approved by US Food and Drug Administration were summarized. Besides, relative drug metabolism enzymes and transporters known to interact with those antiretroviral drugs were detailed and described. Furthermore, one after the summarized antiretroviral drugs, the drug-drug interactions between two antiretroviral drugs or antiretroviral drug - conventional medical drugs of the past decade were discussed and summarized. This review is intended to deepen the pharmacological understanding of antiretroviral drugs and promote more secure clinical applications for antiretroviral drugs to treat HIV.