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1.
BMC Infect Dis ; 24(1): 316, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38486188

RESUMO

INTRODUCTION: In 2022, the WHO reported that 29.8 million people around the world were living with HIV (PLHIV) and receiving antiretroviral treatment (ART), including 25| 375 people in Gabon (54% of all those living with HIV in the country). The literature reports a frequency of therapeutic failure with first-line antiretrovirals (ARVs) of between 20% and 82%. Unfortunately, data relating to the failure of second-line ARVs are scarce in Gabon. This study aims to determine the profiles of HIV drug resistance mutations related to protease inhibitors in Gabon. METHODOLOGY: Plasma from 84 PLHIV receiving ARVs was collected from 2019 to 2021, followed by RNA extraction, amplification, and sequencing of the protease gene. ARV resistance profiles were generated using the Stanford interpretation algorithm version 8.9-1 ( https://hivdb.stanford.edu ) and statistical analyses were performed using EpiInfo software version 7.2.1.0 (CDC, USA). RESULTS: Of 84 HIV plasma samples collected from 45 men and 39 women, 342 mutations were detected. Of these, 43.3% (148/342) were associated with nucleoside reverse transcriptase inhibitors (NRTIs), 30.4% (104/342) with non-nucleoside reverse transcriptase inhibitors (NNRTIs), and 26.3% (90/342) with protease inhibitors (PIs). Most NRTI mutations were associated with thymidine analogues (TAMs) (50.7%; 75/148), including T215F/V (14.9%; 22/148), D67DN/E/G/N/T (10.1%; 15/148), M41L (9.5%; 14/148), and K70E/KN/S/R (9.5%; 14/148). Resistance mutations related to non-TAM NRTIs (33.1%; 49/148) were M184V (29.1%; 43/148), and L74I/V (8.1%; 12/148). NNRTI mutations were predominantly K103N/S (32.7%; 34/104), V108I (10.6%; 11/104), A98G (10.6%; 11/104), and P225H (9.6%; 10/104). Minor mutations associated with PIs (60.0%; 54/90) were predominantly K20I (15.6%; 14/90) and L10F/I/V (14.5%; 13/90). The major mutations associated with PIs (40.0%; 36/90) were M41L (12.2%; 11/90), I84V (6.7%; 06/90), and V82A (6.7%; 06/90). The four most prescribed therapeutic regimens were TDF + 3TC + LPV/r (20.3%; 17/84), ABC + DDI + LPV/r (17.9%; 15/84), TDF + FTC + LPV/r (11.9%; 10/84), and ABC + 3TC + LPV/r (11.9%; 10/84). CONCLUSION: This study revealed that HIV drug resistance mutations are common in Gabon. The major mutations associated with PIs were M41L, I84V, and V82A. There is a need for access to new NRTIs, NNRTIs, and PIs for a better therapeutic management of PLHIV in Gabon.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Masculino , Humanos , Feminino , Inibidores da Transcriptase Reversa/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/farmacologia , Infecções por HIV/tratamento farmacológico , Protease de HIV/genética , Gabão , HIV-1/genética , Antirretrovirais/uso terapêutico , Inibidores de Proteases/uso terapêutico , Mutação , Farmacorresistência Viral/genética
3.
Chem Biol Drug Des ; 103(3): e14510, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38519265

RESUMO

In this study, a novel series of diarylpyrimidine derivatives with Fsp3-enriched spirocycles were designed and synthesized to further explore the chemical space of the hydrophobic channel of the NNRTI-binding pocket. The biological evaluation results showed that most of the compounds displayed effective inhibitory potency against the HIV-1 wild-type strain, with EC50 values ranging from micromolar to submicromolar levels. Among them, TT6 turned out to be the most effective inhibitor with an EC50 value of 0.17 µM, demonstrating up to 47 times more active than that of reference drug 3TC (EC50 = 8.01 µM). More encouragingly, TT6 was found to potently inhibit the HIV-1 mutant strain K103N with an EC50 value of 0.69 µM, being about 6-fold more potent than 3TC (EC50 = 3.68 µM) and NVP (EC50 = 4.62 µM). Furthermore, TT6 exhibited the most potent inhibitory activity toward HIV-1 reverse transcriptase with an IC50 value of 0.33 µM. Additionally, molecular simulation studies were conducted to investigate the binding modes between TT6 and NNRTI-binding pocket, which may provide valuable clues for the follow-up structural optimizations.


Assuntos
Fármacos Anti-HIV , HIV-1 , Fármacos Anti-HIV/química , Relação Estrutura-Atividade , Desenho de Fármacos , Inibidores da Transcriptase Reversa/química , Simulação de Acoplamento Molecular , Transcriptase Reversa do HIV/metabolismo
4.
Rev Med Virol ; 34(2): e2529, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38520650

RESUMO

The discovery of anti-retroviral (ARV) drugs over the past 36 years has introduced various classes, including nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitor, fusion, and integrase strand transfer inhibitors inhibitors. The introduction of combined highly active anti-retroviral therapies in 1996 was later proven to combat further ARV drug resistance along with enhancing human immunodeficiency virus (HIV) suppression. As though the development of ARV therapies was continuously expanding, the variation of action caused by ARV drugs, along with its current updates, was not comprehensively discussed, particularly for HIV-1 infection. Thus, a range of HIV-1 ARV medications is covered in this review, including new developments in ARV therapy based on the drug's mechanism of action, the challenges related to HIV-1, and the need for combination therapy. Optimistically, this article will consolidate the overall updates of HIV-1 ARV treatments and conclude the significance of HIV-1-related pharmacotherapy research to combat the global threat of HIV infection.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Humanos , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade
5.
Rev Invest Clin ; 76(1): 29-36, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38442695

RESUMO

Background: Human immunodeficiency virus (HIV) drug resistance is a major cause of treatment failure in children and adolescents infected with the virus. Objectives: The objectives of the study are to investigate HIV drug resistance (HIVDR) in patients who attended a referral care center in Argentina over a 15-year period and to compare mutational patterns between HIV-1 polsequences characterized as B or BF recombinants. Methods: Individual resistance-associated mutations (RAMs) (to protease and reverse transcriptase inhibitors) were identified according to IAS-USA guidelines in 374 HIV-1-infected children and adolescents. HIV-1 subtype was characterized by phylogenetic and recombination analysis using MEGA5.1 and Simplot. Poisson linear regression was used to model the dynamics of the RAMs over time. Results: The prevalence of RAMs to protease inhibitors (R2 = 0.52, p = 0.0012) and nucleoside reverse transcriptase inhibitors (R2 = 0.30, p = 0.0225) decreased over time. HIVDR to non-nucleoside reverse transcriptase inhibitors remained moderate to high, ranging between 33% and 76%. BF recombinants showed a higher frequency of thymidine analog mutation 1 RAMs profile and I54V mutation. Conclusion: In Argentina, HIVDR observed in children and adolescents has decreased over the past 15 years, regardless of the viral subtype. (REV INVEST CLIN. 2024;76(1):29-36).


Assuntos
Infecções por HIV , HIV-1 , Adolescente , Criança , Humanos , Argentina/epidemiologia , HIV-1/genética , Filogenia , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia
6.
Lancet HIV ; 11(3): e167-e175, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38301668

RESUMO

BACKGROUND: Community-based oral pre-exposure prophylaxis (PrEP) provision has the potential to expand PrEP coverage. HIV self-testing can facilitate PrEP community-based delivery but might have lower sensitivity than facility-based HIV testing, potentially leading to inappropriate PrEP use among people with HIV and subsequent development of drug resistance. We aimed to evaluate the impact of HIV self-testing use for PrEP scale-up. METHODS: We parameterised an agent-based network model, EMOD-HIV, to simulate generic tenofovir disoproxil fumarate and emtricitabine PrEP scale-up in western Kenya using four testing scenarios: provider-administered nucleic acid testing, provider-administered rapid diagnostic tests detecting antibodies, blood-based HIV self-testing, or oral fluid HIV self-testing. Scenarios were compared with a no PrEP counterfactual. Individuals aged 18-49 years with one or more heterosexual partners who screened HIV-negative were eligible for PrEP. We assessed the cost and health impact of rapid PrEP scale-up with high coverage over 20 years, and the budget impact over 5 years, using various HIV testing modalities. FINDINGS: PrEP coverage of 29% was projected to avert approximately 54% of HIV infections and 17% of HIV-related deaths among adults aged 18-49 years over 20 years; health impacts were similar across HIV testing modalities used to deliver PrEP. The percentage of HIV infections with PrEP-associated nucleoside reverse transcriptase inhibitor (NRTI) drug resistance was 0·6% (95% uncertainty intervals 0·4-0·9) in the blood HIV self-testing scenario and 0·8% (0·6-1·0) in the oral HIV self-testing scenario, compared with 0·3% (0·2-0·3) in the antibody rapid diagnostic testing scenario and 0·2% (0·1-0·2) in the nucleic acid testing scenario. Accounting for background NRTI resistance, we found similarly low proportions of drug resistance across scenarios. The budget impact of implementing PrEP using HIV self-testing and provider-administered rapid diagnostic tests were similar, while nucleic acid testing was approximately 50% more costly. INTERPRETATION: Scaling up PrEP using HIV self-testing has similar health impacts, costs, and low risk of drug resistance as provider-administered rapid diagnostic tests. Policy makers should consider leveraging HIV self-testing to expand PrEP access among those at HIV risk. FUNDING: The Bill and Melinda Gates Foundation.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Ácidos Nucleicos , Profilaxia Pré-Exposição , Adulto , Humanos , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Fármacos Anti-HIV/uso terapêutico , Quênia/epidemiologia , Autoteste , Emtricitabina/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Teste de HIV , Ácidos Nucleicos/uso terapêutico
7.
Drug Dev Res ; 85(1): e22154, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38349259

RESUMO

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have significantly impacted the HIV-1 wild-type due to their high specificity and superior potency. As well as different combinations of NNRTIs have been used on clinically approved combining highly active antiretroviral therapy (HAART) to resist the growth of HIV-1 and decrease the mortality rate of HIV/AIDS. Although the feeble strength against the drug-resistant mutant strains and the long-term damaging effects have been reducing the effectiveness of HAART, it could be a crucial challenge to develop novel Anti-HIV leads with a vital mode of action and the least side effects. The extensive chemical reactivity and the diverse chemotherapeutic applications of the 1,3,5-triazine have provided a wide scope of research in medicinal chemistry via a structural modification. In this review, we focused on the Anti-HIV profile of the tri-substituted s-triazine derivatives with structure-based features and also discussed the active mode of action to evaluate the significant findings. The tri-substituted 1,3,5-triazine derivatives have been found more promising to inhibit the growth of the drug-sensitive and drug-resistant variants of HIV-1, especially HIV-1 wild-type, HIV-1 K103N/Y181C, and HIV-1 Tyr181Cys. It has been observed that these derivatives have interacted with the enzyme protein residues via a significant π $\pi $ - π $\pi $ interaction and hydrogen bonding to resist the proliferation of the viral genomes. Further, the SAR and the active binding modes are critically described and highlight the role of structural variations with functional groups along with the binding affinity of targeted enzymes, which may be beneficial for rational drug discovery to develop highly dynamic Anti-HIV agents.


Assuntos
HIV-1 , Triazinas , Triazinas/farmacologia , Triazinas/uso terapêutico , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Química Farmacêutica , Descoberta de Drogas
8.
BMJ Open ; 14(2): e080606, 2024 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-38341206

RESUMO

PURPOSE: The PRESTIGIO Registry was established in 2017 to collect clinical, virological and immunological monitoring data from people living with HIV (PLWH) with documented four-class drug resistance (4DR). Key research purposes include the evaluation of residual susceptibility to specific antiretrovirals and the validation of treatment and monitoring strategies in this population. PARTICIPANTS: The PRESTIGIO Registry collects annual plasma and peripheral blood mononuclear cell samples and demographic, clinical, virological, treatment and laboratory data from PLWH followed at 39 Italian clinical centres and characterised by intermediate-to-high genotypic resistance to ≥1 nucleoside reverse transcriptase inhibitors, ≥1 non-nucleoside reverse transcriptase inhibitors, ≥1 protease inhibitors, plus either intermediate-to-high genotypic resistance to ≥1 integrase strand transfer inhibitors (INSTIs) or history of virological failure to an INSTI-containing regimen. To date, 229 people have been recorded in the cohort. Most of the data are collected from the date of the first evidence of 4DR (baseline), with some prebaseline information obtained retrospectively. Samples are collected from the date of enrollment in the registry. FINDINGS TO DATE: The open-ended cohort has been used to assess (1) prognosis in terms of survival or development of AIDS-related or non-AIDS-related clinical events; (2) long-term efficacy and safety of different antiretroviral regimens and (3) virological and immunological factors predictive of clinical outcome and treatment efficacy, especially through analysis of plasma and cell samples. FUTURE PLANS: The registry can provide new knowledge on how to implement an integrated approach to study PLWH with documented resistance to the four main antiretroviral classes, a population with a limited number of individuals characterised by a high degree of frailty and complexity in therapeutic management. Given the scheduled annual updates of PLWH data, the researchers who collaborate in the registry can send study proposals at any time to the steering committee of the registry, which evaluates every 3 months whether the research studies can be conducted on data and biosamples from the registry and whether they are aimed at a better understanding of a specific health condition, the emergence of comorbidities or the effect of potential treatments or experimental drugs that may have an impact on disease progression and quality of life. Finally, the research studies should aim to be inclusive, innovative and in touch with the communities and society as a whole. TRIAL REGISTRATION NUMBER: NCT04098315.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Humanos , Inibidores da Transcriptase Reversa/uso terapêutico , Inibidores da Transcriptase Reversa/farmacologia , HIV-1/genética , Inibidores de Integrase/farmacologia , Inibidores de Integrase/uso terapêutico , Peptídeo Hidrolases/farmacologia , Peptídeo Hidrolases/uso terapêutico , Leucócitos Mononucleares , Qualidade de Vida , Estudos Retrospectivos , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Sistema de Registros , Itália , DNA Polimerase Dirigida por RNA/farmacologia , DNA Polimerase Dirigida por RNA/uso terapêutico
9.
Viruses ; 16(2)2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38399945

RESUMO

This review article will describe the (wide) variety of approaches that I envisaged to develop a specific therapy for viral infections: (i) interferon and its inducers, (ii) HSV, VZV and CMV inhibitors, (iii) NRTIs (nucleoside reverse transcriptase inhibitors), NtRTIs (nucleotide reverse transcriptase inhibitors) and NNRTIs (non-nucleoside reverse transcriptase inhibitors) as HIV inhibitors, (iv) NtRTIs as HBV inhibitors, and finally, (v) the transition of an HIV inhibitor to a stem cell mobilizer, as exemplified by AMD-3100 (Mozobil®).


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Viroses , Humanos , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/uso terapêutico , Viroses/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Desenvolvimento de Medicamentos , Transcriptase Reversa do HIV
10.
Int J Mol Sci ; 25(4)2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38396919

RESUMO

High dose (S)-efavirenz (EFV) inhibits the HIV reverse transcriptase enzyme and is used to lower HIV load. Low-dose EFV allosterically activates CYP46A1, the key enzyme for cholesterol elimination from the brain, and is investigated as a potential treatment for Alzheimer's disease. Simultaneously, we evaluate EFV dihydroxymetabolites for in vivo brain effects to compare with those of (S)-EFV. We have already tested (rac)-8,14dihydroxy EFV on 5XFAD mice, a model of Alzheimer's disease. Herein, we treated 5XFAD mice with (rac)-7,8dihydroxy EFV. In both sexes, the treatment modestly activated CYP46A1 in the brain and increased brain content of acetyl-CoA and acetylcholine. Male mice also showed a decrease in the brain levels of insoluble amyloid ß40 peptides. However, the treatment had no effect on animal performance in different memory tasks. Thus, the overall brain effects of (rac)-7,8dihydroxy EFV were weaker than those of EFV and (rac)-8,14dihydroxy EFV and did not lead to cognitive improvements as were seen in treatments with EFV and (rac)-8,14dihydroxy EFV. An in vitro study assessing CYP46A1 activation in co-incubations with EFV and (rac)-7,8dihydroxy EFV or (rac)-8,14dihydroxy EFV was carried out and provided insight into the compound doses and ratios that could be used for in vivo co-treatments with EFV and its dihydroxymetabolite.


Assuntos
Doença de Alzheimer , Fármacos Anti-HIV , Infecções por HIV , Feminino , Masculino , Camundongos , Animais , Colesterol 24-Hidroxilase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Benzoxazinas/química , Alcinos/uso terapêutico , Ciclopropanos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/uso terapêutico
11.
Int J Immunopathol Pharmacol ; 38: 3946320241231465, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38296818

RESUMO

OBJECTIVES: Antiretroviral therapy (ART) efficacy is jeopardized by the emergence of drug resistance mutations in HIV, compromising treatment effectiveness. This study aims to propose novel analogs of Effavirenz (EFV) as potential direct inhibitors of HIV reverse transcriptase, employing computer-aided drug design methodologies. METHODS: Three key approaches were applied: a mutational profile study, molecular dynamics simulations, and pharmacophore development. The impact of mutations on the stability, flexibility, function, and affinity of target proteins, especially those associated with NRTI, was assessed. Molecular dynamics analysis identified G190E as a mutation significantly altering protein properties, potentially leading to therapeutic failure. Comparative analysis revealed that among six first-line antiretroviral drugs, EFV exhibited notably low affinity with viral reverse transcriptase, further reduced by the G190E mutation. Subsequently, a search for EFV-similar inhibitors yielded 12 promising molecules based on their affinity, forming the basis for generating a pharmacophore model. RESULTS: Mutational analysis pinpointed G190E as a crucial mutation impacting protein properties, potentially undermining therapeutic efficacy. EFV demonstrated diminished affinity with viral reverse transcriptase, exacerbated by the G190E mutation. The search for EFV analogs identified 12 high-affinity molecules, culminating in a pharmacophore model elucidating key structural features crucial for potent inhibition. CONCLUSION: This study underscores the significance of EFV analogs as potential inhibitors of HIV reverse transcriptase. The findings highlight the impact of mutations on drug efficacy, particularly the detrimental effect of G190E. The generated pharmacophore model serves as a pivotal reference for future drug development efforts targeting HIV, providing essential structural insights for the design of potent inhibitors based on EFV analogs identified in vitro.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Humanos , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Inibidores da Transcriptase Reversa/química , Simulação de Dinâmica Molecular , Transcriptase Reversa do HIV/genética , Transcriptase Reversa do HIV/metabolismo , Transcriptase Reversa do HIV/uso terapêutico , Farmacóforo , Simulação de Acoplamento Molecular , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico
12.
J Clin Virol ; 171: 105639, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38219684

RESUMO

BACKGROUND: Tackling HIV drug resistance is one of major challenges for ending AIDS epidemic, but the elevated expense of cutting-edge genomics hampers the advancement of HIV genotype testing for clinical care. METHODS: We developed a HIV genotype testing pipeline that centers on a cost-efficient portable Nanopore sequencer. Accuracy verification was conducted through comparison with parallel data obtained via fixed-site Pacbio sequencing. Our complete pol-gene sequencing strategy coupled with portable high-throughput sequencing was applied to identify drug resistance mutations across 58 samples sourced from the ART-treated Los Angeles General Medical Center Rand Schrader Clinic (LARSC) cohort (7 samples from 7 individuals) and the ART-naïve Center for HIV/AIDS Vaccine Immunology (CHAVI) cohort (51 samples from 38 individuals). RESULTS: A total of 472 HIV consensus sequences, each tagged with a unique molecular identifier, were produced from over 1.4 million bases acquired through portable Nanopore sequencing, which matched those obtained independently via Pacbio sequencing. With this desirable accuracy, we first documented the linkage of multidrug cross-resistance mutations across Integrase Strand Transfer inhibitors (INSTIs) and Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) from an individual failing a second-generation INSTI regimen. By producing more than 500 full-length HIV pol gene sequences in a single portable sequencing run, we detected Protease Inhibitor (PI), Nucleoside Reverse Transcriptase Inhibitor (NRTI), NNRTI and INSTI resistance mutations. All drug resistance mutations identified through portable sequencing were cross-validated using fixed-site Pacbio sequencing. CONCLUSIONS: Our accurate and affordable HIV drug resistance testing solution is adaptable for both individual patient care and large-scale surveillance initiatives.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Inibidores de Integrase de HIV , Integrase de HIV , HIV-1 , Sequenciamento por Nanoporos , Humanos , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Inibidores da Transcriptase Reversa/uso terapêutico , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Genótipo , Inibidores de Integrase de HIV/uso terapêutico , Mutação , Resistência a Medicamentos , Farmacorresistência Viral/genética , Integrase de HIV/genética
13.
BMC Infect Dis ; 24(1): 29, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38166733

RESUMO

BACKGROUND: There is no systematic review on the prevalence of HIV drug resistance (HIVDR) in Iran. We aimed to estimate the prevalence of HIVDR among people living with HIV (PLHIV) in Iran. We assessed HIVDR prevalence in antiretroviral therapy (ART) naïve PLHIV (i.e., those without a history of ART) and PLHIV receiving ART. METHOD: We systematically searched Scopus, PubMed, Web of Science, Embase, Iranian databases (Iranian Medical Research Information System, Magiran, and Scientific Information Database), the references of studies, and Google Scholar until March 2023. A random-effects model was used to calculate a point estimate and 95% confidence interval (95% CI) for the prevalence of HIVDR in PLHIV. RESULTS: Among 461 potential publications, 22 studies were included in the meta-analysis. The pooled prevalence of acquired HIVDR in PLHIV receiving ART was 34% (95% CI: 19, 50) for nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), 27% (95% CI: 15, 41) for non-nucleoside reverse transcriptase inhibitors (NNRTIs), and 9% (95% CI: 3, 18) for protease inhibitors (PIs). The pooled prevalence of acquired HIVDR in treatment failure PLHIV was 50% (95% CI: 31, 69) for NRTIs, 49% (95% CI: 29, 69) for NNRTIs, 11% (95% CI: 2, 24) for PIs, and 1% (95% CI: 0, 4) for integrase inhibitors (INIs). The pooled prevalence of transmitted HIVDR in ART-naïve people was 3% (95% CI; 1, 6) for NRTIs, 5% (95% CI: 2, 9) for NNRTIs, and 0 for PIs and INIs. CONCLUSION: The prevalence of HIVDR was relatively high in both ART-naïve PLHIV and those receiving ART. Without universal pretreatment HIVDR testing and more frequent routine HIV viral load testing among PLHIV who are on ART, the HIVDR prevalence might increase in PLHIV in Iran.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Humanos , Irã (Geográfico)/epidemiologia , Inibidores da Transcriptase Reversa/uso terapêutico , Prevalência , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/farmacologia , Mutação
14.
Virol J ; 21(1): 14, 2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-38200531

RESUMO

The human T-lymphotropic virus type 1 (HTLV-1) infects millions of people globally and is endemic to various resource-limited regions. Infections persist for life and are associated with increased susceptibility to opportunistic infections and severe diseases including adult T cell leukemia/lymphoma and HTLV-1-associated myelopathy-tropical spastic paraparesis. No HTLV-1-specific anti-retrovirals have been developed and it is unclear whether existing anti-retrovirals developed for treatment of human immunodeficiency virus (HIV) have efficacy against HTLV-1. To understand the structural basis for therapeutic binding, homology modelling and machine learning were used to develop a structural model of the HTLV-1 reverse transcriptase. With this, molecular docking experiments using a panel of FDA-approved inhibitors of viral reverse transcriptases to assess their capacity for binding, and in turn, inhibition. Importantly, nucleoside/nucleotide reverse transcriptase inhibitor but not non-nucleoside reverse transcriptase inhibitors were predicted to bind the HTLV-1 reverse transcriptase, with similar affinity to HIV-1 reverse transcriptase. By strengthening the rationale for clinical testing of therapies such as tenofovir alafenamide, zidovudine, lamivudine, and azvudine for treatment of HTLV-1, this study has demonstrated the power of in silico structural biology approaches in drug design and therapeutic testing.


Assuntos
Vírus Linfotrópico T Tipo 1 Humano , Paraparesia Espástica Tropical , Adulto , Humanos , Nucleotídeos , Inibidores da Transcriptase Reversa/farmacologia , Simulação de Acoplamento Molecular
15.
Expert Opin Investig Drugs ; 33(2): 85-93, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38235744

RESUMO

INTRODUCTION: Islatravir (ISL) is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) that inhibits HIV RT through multiple mechanisms. Contrary to all approved NtRTIs, islatravir retains a 3'OH group. In vitro and clinical data show that ISL is an ultrapotent investigational drug with high tolerability. AREAS COVERED: The historical development of islatravir and its mechanisms of HIV and HBV inhibition and resistance are covered. Additionally, the outcomes of Phase I and Phase II clinical trials are discussed. EXPERT OPINION: Current first-line antiretroviral therapy, preexposure, and postexposure prophylactic interventions are highly effective in maintaining low or undetectable viral load. Despite these measures, an unusually high rate of new infections every year warrants developing novel antivirals that can suppress drug-resistant HIV and improve compliance. ISL, an NRTTI once deemed a long-acting drug, was placed on a clinical hold. The outcome of ongoing clinical trials with a reduced ISL dose will decide its future clinical application. Additionally, MK-8527, which inhibits HIV via same mechanism as that of ISL may supersede ISL. Data on ISL inhibition of HBV are scarce, and preclinical data show dramatically lower ISL efficacy against HBV than currently preferred nucleos(t)ide drugs, indicating that ISL may not be a potent anti-HBV drug.


Assuntos
Fármacos Anti-HIV , Desoxiadenosinas , Infecções por HIV , Humanos , Fármacos Anti-HIV/farmacologia , Vírus da Hepatite B , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/efeitos adversos
16.
Proc Natl Acad Sci U S A ; 121(4): e2319162121, 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38227662

RESUMO

The presence of bacteria in the bloodstream is associated with severe clinical outcomes. In mice, intravenous inoculation of Escherichia coli can lead to the formation of macroscopic abscesses in the liver. Abscesses are regions of severe necrosis and consist of millions of bacteria surrounded by inflammatory immune cells. Liver abscess susceptibility varies widely across strains of mice, but the host factors governing this variation are unknown. Here, we profiled hepatic transcriptomes in mice with varying susceptibility to liver abscess formation. We found that transcripts from endogenous retroviruses (ERVs) are robustly induced in the liver by E. coli infection and ERV expression positively correlates with the frequency of abscess formation. Hypothesizing that ERV-encoded reverse transcriptase may generate cytoplasmic DNA and heighten inflammatory responses, we tested whether nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) influence abscess formation. Strikingly, a single NRTI dose administered immediately following E. coli inoculation prevented abscess formation, leading to a concomitant 100,000-fold reduction in bacterial burden. We provide evidence that NRTIs inhibit abscess formation by preventing the tissue necrosis that facilitates bacterial replication. Together, our findings suggest that endogenous reverse transcriptases drive inflammatory responses during bacterial bloodstream infection to drive abscess formation. The high efficacy of NRTIs in preventing abscess formation suggests that the consequences of reverse transcription on inflammation should be further examined, particularly in infectious diseases where inflammation drives negative clinical outcomes, such as sepsis.


Assuntos
Infecções Bacterianas , Retrovirus Endógenos , Infecções por Escherichia coli , Abscesso Hepático , Sepse , Animais , Camundongos , Inibidores da Transcriptase Reversa/farmacologia , Escherichia coli/genética , Infecções por Escherichia coli/genética , Abscesso Hepático/tratamento farmacológico , Abscesso Hepático/genética , Infecções Bacterianas/tratamento farmacológico , Nucleotídeos , Sepse/tratamento farmacológico , Necrose/genética
17.
AIDS ; 38(4): 547-556, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-37967231

RESUMO

OBJECTIVES: Heart failure risk is elevated in people with HIV (PWH). We investigated whether initial antiretroviral therapy (ART) regimens influenced heart failure risk. DESIGN: Cohort study. METHODS: PWH who initiated an ART regimen between 2000 and 2016 were identified from three integrated healthcare systems. We evaluated heart failure risk by protease inhibitor, nonnucleoside reverse transcriptase inhibitors (NNRTI), and integrase strand transfer inhibitor (INSTI)-based ART, and comparing two common nucleotide reverse transcriptase inhibitors: tenofovir disoproxil fumarate (tenofovir) and abacavir. Follow-up for each pairwise comparison varied (i.e. 7 years for protease inhibitor vs. NNRTI; 5 years for tenofovir vs. abacavir; 2 years for INSTIs vs. PIs or NNRTIs). Hazard ratios were from working logistic marginal structural models, fitted with inverse probability weighting to adjust for demographics, and traditional cardiovascular risk factors. RESULTS: Thirteen thousand six hundred and thirty-four PWH were included (88% men, median 40 years of age; 34% non-Hispanic white, 24% non-Hispanic black, and 24% Hispanic). The hazard ratio (95% CI) were: 2.5 (1.5-4.3) for protease inhibitor vs. NNRTI-based ART (reference); 0.5 (0.2-1.8) for protease inhibitor vs. INSTI-based ART (reference); 0.1 (0.1-0.8) for NNRTI vs. INSTI-based ART (reference); and 1.7 (0.5-5.7) for tenofovir vs. abacavir (reference). In more complex models of cumulative incidence that accounted for possible nonproportional hazards over time, the only remaining finding was evidence of a higher risk of heart failure for protease inhibitor compared with NNRTI-based regimens (1.8 vs. 0.8%; P  = 0.002). CONCLUSION: PWH initiating protease inhibitors may be at higher risk of heart failure compared with those initiating NNRTIs. Future studies with longer follow-up with INSTI-based and other specific ART are warranted.


Assuntos
Fármacos Anti-HIV , Ciclopropanos , Didesoxiadenosina/análogos & derivados , Infecções por HIV , Inibidores da Protease de HIV , Insuficiência Cardíaca , Masculino , Humanos , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/efeitos adversos , Fármacos Anti-HIV/efeitos adversos , Estudos de Coortes , Inibidores da Protease de HIV/efeitos adversos , Didesoxinucleosídeos/efeitos adversos , Tenofovir/efeitos adversos , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/tratamento farmacológico
18.
J Immigr Minor Health ; 26(1): 15-22, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37973713

RESUMO

In recent years, especially as a result of war in Ukraine, enormous movements of migration to Poland from eastern European countries have been reported, including people living with Human Immunodeficiency Virus (HIV). We have conducted multi-center, prospective study, which aimed to establish HIV-1 subtype and assess the presence of primary drug resistance mutations to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors in antiretroviral treatment naïve patients. The clinical trial recruited 117 individuals during 2 years period (2020-2022). The prevalence of HIV-1 subtype A was statistically significantly more frequent in Ukrainian, and HIV-1 subtype B in Polish patients (p < 0.05). Drug resistance mutations were detected in 44% of all cases and the comparison of presence of mutations in the analyzed groups, as well as in the subgroups of subtype A and B HIV-1 has not revealed any significant differences (p > 0.05), nevertheless Polish patients had multidrug resistance mutations more frequent (p < 0.05). The results from our trial show no increased risk of transmission of multidrug resistant HIV strains in our cohort of Ukrainian migrants.Clinical trials. Gov number NCT04636736; date of registration: November 19, 2020.


Assuntos
Infecções por HIV , HIV-1 , Humanos , HIV-1/genética , Inibidores da Transcriptase Reversa/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Estudos Prospectivos , Farmacorresistência Viral/genética , Europa Oriental , Genótipo
19.
HIV Med ; 25(2): 212-222, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37775947

RESUMO

OBJECTIVES: The main objective of this analysis was to evaluate the impact of pre-existing drug resistance by next-generation sequencing (NGS) on the risk of treatment failure (TF) of first-line regimens in participants enrolled in the START study. METHODS: Stored plasma from participants with entry HIV RNA >1000 copies/mL were analysed using NGS (llumina MiSeq). Pre-existing drug resistance was defined using the mutations considered by the Stanford HIV Drug Resistance Database (HIVDB v8.6) to calculate the genotypic susceptibility score (GSS, estimating the number of active drugs) for the first-line regimen at the detection threshold windows of >20%, >5%, and >2% of the viral population. Survival analysis was conducted to evaluate the association between the GSS and risk of TF (viral load >200 copies/mL plus treatment change). RESULTS: Baseline NGS data were available for 1380 antiretroviral therapy (ART)-naïve participants enrolled over 2009-2013. First-line ART included a non-nucleoside reverse transcriptase inhibitor (NNRTI) in 976 (71%), a boosted protease inhibitor in 297 (22%), or an integrase strand transfer inhibitor in 107 (8%). The proportions of participants with GSS <3 were 7% for >20%, 10% for >5%, and 17% for the >2% thresholds, respectively. The adjusted hazard ratio of TF associated with a GSS of 0-2.75 versus 3 in the subset of participants with mutations detected at the >2% threshold was 1.66 (95% confidence interval 1.01-2.74; p = 0.05) and 2.32 (95% confidence interval 1.32-4.09; p = 0.003) after restricting the analysis to participants who started an NNRTI-based regimen. CONCLUSIONS: Up to 17% of participants initiated ART with a GSS <3 on the basis of NGS data. Minority variants were predictive of TF, especially for participants starting NNRTI-based regimens.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Soropositividade para HIV , HIV-1 , Humanos , Infecções por HIV/epidemiologia , HIV-1/genética , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Soropositividade para HIV/tratamento farmacológico , Sequenciamento de Nucleotídeos em Larga Escala , Carga Viral , Farmacorresistência Viral/genética
20.
Chem Biol Drug Des ; 103(1): e14372, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37817296

RESUMO

Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS), a lethal disease that is prevalent worldwide. According to the Joint United Nations Programme on HIV/AIDS (UNAIDS) data, 38.4 million people worldwide were living with HIV in 2021. Viral reverse transcriptase (RT) is an excellent target for drug intervention. Nucleoside reverse transcriptase inhibitors (NRTIs) were the first class of approved antiretroviral drugs. Later, a new type of non-nucleoside reverse transcriptase inhibitors (NNRTIs) were approved as anti-HIV drugs. Zidovudine, didanosine, and stavudine are FDA-approved NRTIs, while nevirapine, efavirenz, and delavirdine are FDA-approved NNRTIs. Several agents are in clinical trials, including apricitabine, racivir, elvucitabine, doravirine, dapivirine, and elsulfavirine. This review addresses HIV-1 structure, replication cycle, reverse transcription, and HIV drug targets. This study focuses on NRTIs and NNRTIs, their binding sites, mechanisms of action, FDA-approved drugs and drugs in clinical trials, their resistance and adverse effects, their molecular docking studies, and highly active antiretroviral therapy (HAART).


Assuntos
Síndrome de Imunodeficiência Adquirida , Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Humanos , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Simulação de Acoplamento Molecular , Infecções por HIV/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida/induzido quimicamente , Síndrome de Imunodeficiência Adquirida/tratamento farmacológico , Transcriptase Reversa do HIV/metabolismo
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