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Journal of Infection and Public Health Oct 2021COVID-19 disease caused by SARS-CoV-2 is lacking efficient medication although certain medications are used to relief its symptoms.
BACKGROUND
COVID-19 disease caused by SARS-CoV-2 is lacking efficient medication although certain medications are used to relief its symptoms.
OBJECTIVES
We tested an FDA-approved antiviral medication namely rilpivirine to find a drug against SARS-CoV-2.
METHODS
The inhibition of rilpivirine against multiple SARS-CoV-2 therapeutic targets was studied using in silico method. The binding attraction of the protein-ligand complexes were calculated using molecular docking analysis.
RESULTS
Docking rilpivirine with main protease (Mpro), papin like protease (PLpro), sprike protein (Spro), human angiotensin converting enzyme-2 (ACE2), and RNA dependent-RNA polymerase (RdRp) yielded binding energies of -8.07, -8.40, -7.55, -9.11, and -8.69 kcal/mol, respectively. The electrostatic interaction is the key force in stabilizing the RdRp-rilpivirine complex, while van der Waals interaction dominates in the ACE2 rilpivirine case. Our findings suggest that rilpivirine can inhibit SARS-CoV-2 replication by targeting not only ACE2, but also RdRp and other targets, and therefore, it can be used to invoke altered mechanisms at the pre-entry and post-entry phases.
CONCLUSION
As a result of our in silico molecular docking study, we suggest that rilpivirine is a compound that could act as a powerful inhibitor against SARS-CoV-2 targets. Although in vitro and in vivo experiments are needed to verify this prediction we believe that this antiviral drug may be used in preclinical trials to fight against SARS coronavirus.
Topics: Antiviral Agents; COVID-19; Humans; Molecular Docking Simulation; Pharmaceutical Preparations; Rilpivirine; SARS-CoV-2
PubMed: 34326009
DOI: 10.1016/j.jiph.2021.07.012 -
AIDS Research and Human Retroviruses Jun 2022HIV-1 gene sequences were analyzed from 77 HIV-1 positive children infected perinatally and exhibiting virological failure (VF). Viral subtyping, phylogenetic analysis,...
HIV-1 gene sequences were analyzed from 77 HIV-1 positive children infected perinatally and exhibiting virological failure (VF). Viral subtyping, phylogenetic analysis, and genotypic drug resistance analysis were carried out on samples collected before start of anti retroviral treatment (ART) (baseline, BL), and at 12 months post-ART initiation (M12). Subtype C was found to be most predominant, seen in 75 of the 77 (97.4%) children. The level of pretreatment drug resistance (PDR) was 14% among these children. At BL, K103N (5), E138A/G (4), and M184V (3) were the most common mutations. At M12 the prevalence of any resistance-associated mutation (RAM) (acquired drug resistance/ADR) was 81.8% (63/77). Dual class resistance mutations were seen in 64% (49/77) of children. M184V/I, K103N/S, and Y181C were the most commonly occurring mutations, seen in 76%, 51%, and 36% children. RAMs to the second-generation non-nucleoside reverse transcriptase inhibitors (NNRTI), etravirine (ETR) and rilpivirine (RPV), were seen in 40.2% (31/77) and 48.05% (37/77) of the children, respectively. Our findings reveal similar prevalence rates of PDR and ADR in children with VF as reported in other studies. Occurrence of ETR and RPV resistance associated mutations (RAMs) is of concern and highlights the need for timely switch of regimens guided by genotypic resistance testing in perinatally infected children from India.
Topics: Anti-HIV Agents; Child; Drug Resistance, Viral; Genes, pol; Genotype; HIV Infections; HIV Seropositivity; HIV-1; Humans; Infectious Disease Transmission, Vertical; Mutation; Phylogeny; Pyridazines; Reverse Transcriptase Inhibitors; Rilpivirine
PubMed: 35302390
DOI: 10.1089/AID.2021.0227 -
Medicine Jun 2022Switching dual therapy with dolutegravir (DTG) plus rilpivirine (RPV) was assessed in the SWORD-1 and SWORD-2 studies. Real-life data regarding the immunological impact...
Switching dual therapy with dolutegravir (DTG) plus rilpivirine (RPV) was assessed in the SWORD-1 and SWORD-2 studies. Real-life data regarding the immunological impact of this approach on CD4+ and CD8+ T lymphocyte counts and the CD4/CD8 ratio are scarce. We evaluated this strategy on the basis of clinical practice data.A multicentric retrospective cohort study.Treatment-experienced virologically suppressed HIV-1-infected patients who were switched to DTG plus RPV were included. Using different models for paired data, we evaluated the efficacy and immune status in terms of CD4+ and CD8+ T-cell counts and CD4/CD8 ratio at 24 and 48 weeks of treatment.The study population comprised of 524 patients from 34 centers in Spain. Men accounted for 76.9% of patients, with a median age of 53 years. Patients receiving DTG plus RPV reached weeks 24 and 48 in 99.4% and 83.8% of cases, respectively, with only three (0.57%) virological failures. We found a significant decrease in CD8+ T-cell count (log OR -40) at week 24 and an increase in CD4+ T-cell count at week 48 (log OR +22.8). In acquired immunodeficiency syndrome-diagnosed patients, we found a significant increase in the CD4+ T-cell count at week 48 (log OR = 41.7, P = .0038), but no significant changes in the CD8+ T-cell count (log OR = -23.4, P = .54). No differences were found in the CD4/CD8 ratio between the acquired immunodeficiency syndrome subgroup and sex or age.In patients with controlled treatment, dual therapy with DTG plus RPV slightly improved the immune status during the first 48 weeks after switching, not only in terms of CD4+ T-cell count but also in terms of CD8+ T-cell count, with persistently high rates of viral control.
Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; CD4 Lymphocyte Count; Child, Preschool; HIV Infections; Heterocyclic Compounds, 3-Ring; Humans; Infant; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Retrospective Studies; Rilpivirine; Viral Load
PubMed: 35713430
DOI: 10.1097/MD.0000000000029252 -
Journal of Veterinary Science Sep 2023Feline immunodeficiency virus (FIV) causes an acquired immunodeficiency-like syndrome in cats. FIV is latent. No effective treatment has been developed for treatment the...
BACKGROUND
Feline immunodeficiency virus (FIV) causes an acquired immunodeficiency-like syndrome in cats. FIV is latent. No effective treatment has been developed for treatment the infected cats. The first and second generations non-nucleoside reverse transcriptase inhibitors (NNRTIs) for HIV treatment, nevirapine (NVP) and efavirenz (EFV), and rilpivirine (RPV), were used to investigate the potential of NNRTIs for treatment of FIV infection.
OBJECTIVE
This study aims to use experimental and approaches to investigate the potential of NNRTIs, NVP, EFV, and RPV, for inhibition of FIV reverse transcriptase (FIV-RT).
METHODS
The FIV-RT and human immunodeficiency virus reverse transcriptase (HIV-RT) were expressed and purified using chromatography approaches. The purified proteins were used to determine the IC values with NVP, EFV, and RPV. Surface plasmon resonance (SPR) analysis was used to calculate the binding affinities of NNRTIs to HIV-RT and FIV-RT. The molecular docking and molecular dynamic simulations were used to demonstrate the mechanism of FIV-RT and HIV-RT with first and second generation NNRTI complexes.
RESULTS
The IC values of NNRTIs NVP, EFV, and RPV against FIV-RT were in comparable ranges to HIV-RT. The SPR analysis showed that NVP, EFV, and RPV could bind to both enzymes. Computational calculation also supports that these NNRTIs can bind with both FIV-RT and HIV-RT.
CONCLUSIONS
Our results suggest the first and second generation NNRTIs (NVP, EFV, and RPV) could inhibit both FIV-RT and HIV-RT.
Topics: Cats; Animals; Humans; Reverse Transcriptase Inhibitors; Anti-HIV Agents; Molecular Docking Simulation; HIV-1; Rilpivirine; Nevirapine; HIV Reverse Transcriptase; HIV Infections; Cat Diseases
PubMed: 38031646
DOI: 10.4142/jvs.22326 -
Life Sciences Apr 2022Antiretroviral therapy (ART), a life-saving treatment strategy in HIV/AIDS, has been implicated in increasing the risk of type 2 diabetes mellitus (T2DM). Direct...
Antiretroviral therapy (ART), a life-saving treatment strategy in HIV/AIDS, has been implicated in increasing the risk of type 2 diabetes mellitus (T2DM). Direct damaging effects on beta-cell function and survival by either non-nucleoside reverse transcriptase inhibitors (NNRTIs) or nucleoside/tide reverse transcriptase inhibitors (NRTIs) may predispose individuals to developing T2DM or if already type 2 diabetic, to insulin dependency. The aim of this study was to investigate the effects of the NNRTIs efavirenz, rilpivirine and doravirine, and the NRTIs tenofovir disoproxil fumarate and emtricitabine, on beta-cell function and survival while suggesting potential cellular and molecular mechanism(s). Our results show contrasting effects within the NNRTI class as doravirine did not cause damaging effects in the rat insulinoma INS-1E cells while efavirenz and rilpivirine reduced insulin release and cell viability, and induced apoptosis in INS-1E cells. Additionally, efavirenz and rilpivirine increased ROS generation, disrupted Δψm and upregulated the mRNA and protein expression of CHOP and GRP78, key markers of endoplasmic reticulum stress. In silico docking studies predict a possible inhibition of the mitochondrial ATP synthase by rilpivirine. On the contrary, both the NRTIs tenofovir disoproxil fumarate and emtricitabine did not affect GSIS, cell viability and apoptosis/necrosis levels in INS-1E cells. The deleterious effects observed in beta-cells exposed to efavirenz or rilpivirine may be, at least partially, mediated by oxidative stress and mitochondrial toxicity. These findings provide potential mechanism(s) by which efavirenz and rilpivirine may contribute to the pathogenesis of T2DM and the progression of T2DM to insulin dependency in HIV-infected type 2 diabetics.
Topics: Alkynes; Animals; Benzoxazines; Cyclopropanes; Endoplasmic Reticulum Stress; Insulin; Insulin-Secreting Cells; Insulinoma; Mitochondria; Oxidative Stress; Pancreatic Neoplasms; Rats; Reactive Oxygen Species; Reverse Transcriptase Inhibitors; Rilpivirine; Tumor Cells, Cultured
PubMed: 35090905
DOI: 10.1016/j.lfs.2022.120329 -
Clinical Infectious Diseases : An... Nov 2022Long-acting injectable antiretroviral therapy (LAI-ART) for the treatment and prevention of human immunodeficiency virus (HIV) holds great potential to shift treatment... (Review)
Review
Long-acting injectable antiretroviral therapy (LAI-ART) for the treatment and prevention of human immunodeficiency virus (HIV) holds great potential to shift treatment paradigms by offering an alternative to daily oral medication. However, significant challenges at the drug, patient, and system levels risk impeding the uptake and implementation of LAI-ART. This review aims to describe the known and anticipated barriers to uptake of LAI-ART in high-income countries, as well as the ongoing research addressing some of these barriers to improve the delivery and uptake of LAI-ART products.
Topics: Humans; Developed Countries; Anti-Retroviral Agents; Income; HIV Infections; HIV
PubMed: 36410385
DOI: 10.1093/cid/ciac716 -
Pharmaceutical Research Jul 2023Whilst significant progress has been made to defeat HIV infection, the efficacy of antiretroviral (ARV) therapy in the paediatric population is often hindered by poor...
Development and Evaluation of Dissolving Microarray Patches for Co-administered and Repeated Intradermal Delivery of Long-acting Rilpivirine and Cabotegravir Nanosuspensions for Paediatric HIV Antiretroviral Therapy.
PURPOSE
Whilst significant progress has been made to defeat HIV infection, the efficacy of antiretroviral (ARV) therapy in the paediatric population is often hindered by poor adherence. Currently, two long-acting (LA) intramuscular injectable nanosuspensions of rilpivirine (RPV) and cabotegravir (CAB) are in clinical development for paediatric populations. However, administration requires access to healthcare resources, is painful, and can result in needle-stick injuries to the end user. To overcome these barriers, this proof-of-concept study was developed to evaluate the intradermal delivery of RPV LA and CAB LA via self-disabling dissolving microarray patches (MAPs).
METHODS
Dissolving MAPs of two conformations, a conventional pyramidal and a bilayer design, were formulated, with various nanosuspensions of RPV and CAB incorporated within the respective MAP matrix. MAPs were mechanically robust and were capable of penetrating ex vivo skin with intradermal ARV deposition.
RESULTS
In a single-dose in vivo study in rats, all ARV MAPs demonstrated sustained release profiles, with therapeutically relevant plasma concentrations of RPV and CAB detected to at least 63 and 28 d, respectively. In a multi-dose in vivo study, repeated MAP applications at 14-d intervals maintained therapeutically relevant plasma concentrations throughout the duration of the study.
CONCLUSIONS
These results illustrate the potential of the platform to repeatedly maintain plasma concentrations for RPV and CAB. As such, these MAPs could represent a viable option to improve adherence in the paediatric population, one that is capable of being painlessly administered in the comfort of the patient's own home on a biweekly or less frequent basis.
Topics: Rats; Animals; Rilpivirine; HIV Infections; Anti-HIV Agents; Anti-Retroviral Agents; Pyridones
PubMed: 36224503
DOI: 10.1007/s11095-022-03408-6 -
Cell Death & Disease Apr 2022As the main extracellular matrix-producing cells, activated hepatic stellate cells (HSC) are fundamental mediators of liver fibrosis (LF), and understanding their...
As the main extracellular matrix-producing cells, activated hepatic stellate cells (HSC) are fundamental mediators of liver fibrosis (LF), and understanding their activation/inactivation mechanisms is paramount to the search for novel therapeutics. The antiretroviral drug Rilpivirine (RPV) has demonstrated a hepatoprotective effect in several animal models of chronic liver injury that is related to its antifibrogenic and apoptotic action in HSC. In the present study, we evaluated whether autophagy is implicated in the hepatoprotective action of RPV, as autophagy plays an important role in HSC transdifferentiation. We employed two standard mouse models of chronic liver injury - fatty liver disease and carbon tetrachloride (CCl)-induced hepatotoxicity -and cultured HSC activated with the profibrotic cytokine TGF-β. RPV enhanced autophagy in the whole liver of both mouse models and in activated HSC, evident in the protein expression of autophagy markers, increased autophagosome content and lysosomal mass. Moreover, increased autophagic flux was observed in RPV-exposed HSC as revealed by tandem fluorescence-tagged LC3 and p62 and analysis of LC3-II accumulation in cells exposed to the lysosomal inhibitor chloroquine. Importantly, autophagy was involved in the cytotoxic effect of RPV on HSC, though in a differential manner. Pharmacological inhibition of autophagy by 3-methyladenine (3-MA) did not affect the diminishing effect of RPV on viability, while treatment with wortmannin or depletion of specific autophagy proteins (ATG5, Beclin-1 and SQSTM1/p62) rescued the detrimental effect of high concentrations of RPV on the viability of activated HSC. Finally, we also provide evidence that RPV compromises the viability of TGF-β-induced HSC independently of its antifibrogenic effect, observed as reduced collagen 1A1 synthesis, and that this effect does not include RPV´s modulation of autophagy. In summary, as a contributor to the mechanisms involved in the hepatoprotective action of RPV, autophagy may be a good candidate to explore when developing novel therapeutics for LF.
Topics: Animals; Autophagy; Disease Models, Animal; Hepatic Stellate Cells; Liver Cirrhosis; Mice; Rilpivirine; Transforming Growth Factor beta
PubMed: 35443746
DOI: 10.1038/s41419-022-04789-7 -
Open Forum Infectious Diseases May 2023Intramuscular long-acting antiretroviral drugs can improve adherence to lifelong antiretroviral treatment. Nevertheless, adipose tissue thickness and distribution play a...
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/m.
PubMed: 37213429
DOI: 10.1093/ofid/ofad217 -
Antiviral Research Dec 2022Cabotegravir (CAB) is an integrase strand transfer inhibitor (INSTI) formulated as a long-acting injectable drug approved for pre-exposure prophylaxis and use with a...
Cabotegravir (CAB) is an integrase strand transfer inhibitor (INSTI) formulated as a long-acting injectable drug approved for pre-exposure prophylaxis and use with a long acting rilpivirine formulation for therapy in patients with virological suppression. However, there has been no comprehensive review of the genetic mechanisms of CAB resistance. Studies reporting the selection of drug resistance mutations (DRMs) by CAB and the results of in vitro CAB susceptibility testing were reviewed. The impact of integrase mutations on CAB susceptibility was assessed using regularized regression analysis. The most commonly selected mutations in the 24 persons developing virological failure while receiving CAB included Q148R (n = 15), N155H (n = 7), and E138K (n = 5). T97A, G118R, G140 A/R/S, and R263K each developed in 1-2 persons. With the exception of T97A, G118R, and G140 A/R, these DRMs were also selected in vitro while G140R was selected in the SIV macaque model. Although these DRMs are similar to those occurring in persons receiving the related INSTI dolutegravir, Q148R was more likely to occur with CAB while G118R and R263K were more likely to occur with dolutegravir. Regularized regression analysis identified 14 DRMs significantly associated with reduced CAB susceptibility including six primary DRMs which reduced susceptibility on their own including G118R, Q148 H/K/R, N155H, and R263K, and eight accessory DRMs including M50I, L74 F/M, T97A, E138K, and G140 A/C/S. Isolates with Q148 H/K/R in combination with L74M, E138 A/K, G140 A/S, and N155H often had >10-fold reduced CAB susceptibility. M50I, L74M, and T97A are polymorphic mutations that alone did not appear to increase the risk of virological failure in persons receiving a CAB-containing regimen. Careful patient screening is required to prevent CAB from being used during active virus replication. Close virological monitoring is required to minimize CAB exposure to active replication to prevent the emergence of DRMs associated with cross-resistance to other INSTIs.
Topics: Humans; HIV-1; HIV Integrase Inhibitors; Drug Resistance, Viral; HIV Integrase; Heterocyclic Compounds, 3-Ring; Pyridones; Virus Replication; Mutation; HIV Infections
PubMed: 36191692
DOI: 10.1016/j.antiviral.2022.105427