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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.
Sci Rep ; 14(1): 3639, 2024 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-38351065

RESUMO

The prevalence of HIV-1 infection continues to pose a significant global public health issue, highlighting the need for antiretroviral drugs that target viral proteins to reduce viral replication. One such target is HIV-1 protease (PR), responsible for cleaving viral polyproteins, leading to the maturation of viral proteins. While darunavir (DRV) is a potent HIV-1 PR inhibitor, drug resistance can arise due to mutations in HIV-1 PR. To address this issue, we developed a novel approach using the fragment molecular orbital (FMO) method and structure-based drug design to create DRV analogs. Using combinatorial programming, we generated novel analogs freely accessible via an on-the-cloud mode implemented in Google Colab, Combined Analog generator Tool (CAT). The designed analogs underwent cascade screening through molecular docking with HIV-1 PR wild-type and major mutations at the active site. Molecular dynamics (MD) simulations confirmed the assess ligand binding and susceptibility of screened designed analogs. Our findings indicate that the three designed analogs guided by FMO, 19-0-14-3, 19-8-10-0, and 19-8-14-3, are superior to DRV and have the potential to serve as efficient PR inhibitors. These findings demonstrate the effectiveness of our approach and its potential to be used in further studies for developing new antiretroviral drugs.


Assuntos
Infecções por HIV , Inibidores da Protease de HIV , HIV-1 , Humanos , Darunavir/farmacologia , Inibidores da Protease de HIV/farmacologia , Inibidores da Protease de HIV/química , HIV-1/genética , Simulação de Acoplamento Molecular , Sulfonamidas/farmacologia , Proteínas Virais/genética , Protease de HIV/metabolismo , Mutação , Farmacorresistência Viral/genética
4.
Viruses ; 16(2)2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38400015

RESUMO

BACKGROUND: There are an increasing number of articles focused on the prevalence and clinical impact of pretreatment HIV drug resistance (PDR) detected by Sanger sequencing (SGS). PDR may contribute to the increased likelihood of virologic failure and the emergence of new resistance mutations. As SGS is gradually replaced by next-generation sequencing (NGS), it is necessary to assess the levels of PDR using NGS in ART-naïve patients systematically. NGS can detect the viral variants (low-abundance drug-resistant HIV-1 variants (LA-DRVs)) of virus quasi-species at levels below 20% that SGS may fail to detect. NGS has the potential to optimize current HIV drug resistance surveillance methods and inform future research directions. As the NGS technique has high sensitivity, it is highly likely that the level of pretreatment resistance would be underestimated using conventional techniques. METHODS: For the systematic review and meta-analysis, we searched for original studies published in PubMed, Web of Science, Scopus, and Embase before 30 March 2023 that focused exclusively on the application of NGS in the detection of HIV drug resistance. Pooled prevalence estimates were calculated using a random effects model using the 'meta' package in R (version 4.2.3). We described drug resistance detected at five thresholds (>1%, 2%, 5%, 10%, and 20% of virus quasi-species). Chi-squared tests were used to analyze differences between the overall prevalence of PDR reported by SGS and NGS. RESULTS: A total of 39 eligible studies were selected. The studies included a total of 15,242 ART-naïve individuals living with HIV. The prevalence of PDR was inversely correlated with the mutation detection threshold. The overall prevalence of PDR was 29.74% at the 1% threshold, 22.43% at the 2% threshold, 15.47% at the 5% threshold, 12.95% at the 10% threshold, and 11.08% at the 20% threshold. The prevalence of PDR to INSTIs was 1.22% (95%CI: 0.58-2.57), which is the lowest among the values for all antiretroviral drugs. The prevalence of LA-DRVs was 9.45%. At the 2% and 20% detection threshold, the prevalence of PDR was 22.43% and 11.08%, respectively. Resistance to PIs and INSTIs increased 5.52-fold and 7.08-fold, respectively, in those with a PDR threshold of 2% compared with those with PDR at 20%. However, resistance to NRTIs and NNRTIs increased 2.50-fold and 2.37-fold, respectively. There was a significant difference between the 2% and 5% threshold for detecting HIV drug resistance. There was no statistically significant difference between the results reported by SGS and NGS when using the 20% threshold for reporting resistance mutations. CONCLUSION: In this study, we found that next-generation sequencing facilitates a more sensitive detection of HIV-1 drug resistance than SGS. The high prevalence of PDR emphasizes the importance of baseline resistance and assessing the threshold for optimal clinical detection using NGS.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Soropositividade para HIV , HIV-1 , Humanos , HIV-1/genética , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Genótipo , Farmacorresistência Viral/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Prevalência , Mutação
5.
J Med Virol ; 96(3): e29484, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38402600

RESUMO

Antiviral therapy based on neuraminidase (oseltamivir) or polymerase (baloxavir marboxil) inhibitors plays an important role in the management of influenza infections. However, the emergence of drug resistance and the uncontrolled inflammatory response are major limitations in the treatment of severe influenza disease. Protectins D1 (PD1) and DX (PDX), part of a family of pro-resolving mediators, have previously demonstrated anti-influenza activity as well as anti-inflammatory properties in various clinical contexts. Herein, we synthetized a series of simplified PDX analogs and assessed their in vitro antiviral activity against influenza A(H1N1) viruses, including oseltamivir- and baloxavir-resistant variants. In ST6GalI-MDCK cells, the PDX analog AN-137B reduced viral replication in a dose-dependent manner with IC50 values of 23.8 for A/Puerto Rico/8/1934 (H1N1) and between 32.6 and 36.7 µM for susceptible and resistant A(H1N1)pdm09 viruses. In MTS-based cell viability experiments, AN-137B showed a 50% cellular cytotoxicity (CC50 ) of 638.7 µM with a resulting selectivity index of 26.8. Of greater importance, the combination of AN-137B with oseltamivir or baloxavir resulted in synergistic and additive in vitro effects, respectively. Treatment of lipopolysaccharide (LPS)-stimulated macrophages with AN-137B resulted in a decrease of iNOS activity as shown by the reduction of nitrite production, suggesting an anti-inflammatory effect. In conclusion, our results indicate that the protectin analog AN-137B constitutes an interesting therapeutic modality against influenza A virus, warranting further evaluation in animal models.


Assuntos
Dibenzotiepinas , Ácidos Docosa-Hexaenoicos , Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A , Influenza Humana , Morfolinas , Piridonas , Triazinas , Animais , Humanos , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Influenza Humana/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Farmacorresistência Viral , Neuraminidase
6.
Drug Resist Updat ; 73: 101053, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38301487

RESUMO

Viral infections have a major impact in human health. Ongoing viral transmission and escalating selective pressure have the potential to favor the emergence of vaccine- and antiviral drug-resistant viruses. Target-based approaches for the design of antiviral drugs can play a pivotal role in combating drug-resistant challenges. Drug design computational tools facilitate the discovery of novel drugs. This review provides a comprehensive overview of current drug design strategies employed in the field of antiviral drug resistance, illustrated through the description of a series of successful applications. These strategies include technologies that enhance compound-target affinity while minimizing interactions with mutated binding pockets. Furthermore, emerging approaches such as virtual screening, targeted protein/RNA degradation, and resistance analysis during drug design have been harnessed to curtail the emergence of drug resistance. Additionally, host targeting antiviral drugs offer a promising avenue for circumventing viral mutation. The widespread adoption of these refined drug design strategies will effectively address the prevailing challenge posed by antiviral drug resistance.


Assuntos
Antivirais , Desenho de Fármacos , Humanos , Antivirais/farmacologia , Antivirais/uso terapêutico , Antivirais/metabolismo , Farmacorresistência Viral/genética , Mutação
7.
BMC Infect Dis ; 24(1): 155, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38302941

RESUMO

BACKGROUND OBJECTIVE: This study aimed to understand the basic situation of adults with human immunodeficiency virus (HIV) receiving antiretroviral therapy (ART) in Meigu County, Liangshan Yi Autonomous Prefecture. The information of patients who had been on ART for more than 6 months, the effect of ART, the possible reasons for ART failure, knowledge of drug resistance among patients with ART failure and the possible reasons for the emergence of drug resistance were analyzed. METHODS: A total of 2753 people living with HIV (PLWH) were collected for HIV-1 RNA virus nucleic acid testing. Plasma specimens with HIV-1 RNA ≥ 1000 copies/mL were sent to the laboratory for nucleic acid extraction, PCR, electrophoresis and sequencing, and the sequencing results were submitted to the HIV drug resistance database of Stanford University for subtyping to determine the drug resistance mutation sites and drug sensitivity levels. RESULTS: A total of 2753 patients were enrolled in this study. Antiviral therapy failed in 288 patients and was successfully amplified in 245, of which 111 had resistance genes. The resistance rate to failure of viral suppression was 45.3% (111/245). The highest rates of resistance to NNRTIs were found for efavirenz (EFV) and nevirapine (NVP) (42.9%), and the highest rates of resistance to NRTIs were found for 3TC and emtricitabine (FTC) (15.9%). The most common NNRTI resistance mutation site was K103N (20.8%), followed by V179D (9.4%) and V106M (7.8%); the most common NRTI resistance mutation site was M184V/I/MV (14.3%), followed by K65R (6.9%); three PI-associated resistance mutation sites were identified. The subtype of the resistant strain was CRF07-BC in almost all patients (98.9%). CONCLUSIONS: Compared with the previous low ART efficacy in the county, this study showed that the overall virological failure (VF) resistance rate in the county is still low, dominated by resistance to EFV, NVP, 3TC, FTC, and didanosine (DDI). Due to economic constraints, the core regimen is still 3TC + TDF, but before initiating ART, testing for HIV-1 subtypes and resistance should be conducted to avoid resistance that can lead to VF, especially for patients with high risk factors for resistance as shown by epidemiologic investigations.


Assuntos
Síndrome de Imunodeficiência Adquirida , Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Ácidos Nucleicos , Adulto , Humanos , Síndrome de Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Emtricitabina/uso terapêutico , HIV-1/genética , Nevirapina/farmacologia , Nevirapina/uso terapêutico , Didanosina , Mutação , Resistência a Medicamentos , Farmacorresistência Viral/genética
8.
J Med Virol ; 96(2): e29427, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38288882

RESUMO

Influenza virus is known to cause mild to severe respiratory infections and is also prone to genetic mutations. Of all the mutations, neuraminidase (NA) gene mutations are a matter of concern, as most approved antivirals target this protein. During the 2020 influenza season, an emergence of mutation in the NA gene, affecting the binding of the World Health Organization (WHO)-recommended probes to the specific site of the NA gene, was reported by our group. As a result of this mutation, the WHO-recommended allelic discrimination real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay was unable to detect wild-type (H275) or mutant oseltamivir-resistant (Y275) strains of influenza A(H1N1)pmd09 viruses. In the current study, the WHO-recommended probes were redesigned according to the mutation in the probe binding site. Fifty undetermined samples (2020-2021) from the previous study were retested with the newly designed probes and found to be positive for H275 and/or Y275. The results obtained were similar to the Sanger sequencing results from the previous study, suggesting that the redesigned probes were efficient in discriminating between wild-type and mutant-type viruses. Furthermore, 133 samples from 2022, making a total of 183 samples (2020-2022), were tested using improved allelic discrimination real-time RT-PCR, and the overall prevalence rate of oseltamivir resistance in 2020-2022 was found to be 0.54%.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Influenza Humana , Humanos , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Vírus da Influenza A Subtipo H1N1/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Mutação de Sentido Incorreto , Proteínas Virais/genética , Farmacorresistência Viral/genética , Mutação , Neuraminidase/genética
9.
Arch Virol ; 169(2): 29, 2024 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-38216710

RESUMO

Genetic reassortment of avian, swine, and human influenza A viruses (IAVs) poses potential pandemic risks. Surveillance is important for influenza pandemic preparedness, but the susceptibility of zoonotic IAVs to the cap-dependent endonuclease inhibitor baloxavir acid (BXA) has not been thoroughly researched. Although an amino acid substitution at position 38 in the polymerase acidic protein (PA/I38) in seasonal IAVs reduces BXA susceptibility, PA polymorphisms at position 38 are rarely seen in zoonotic IAVs. Here, we examined the impact of PA/I38 substitutions on the BXA susceptibility of recombinant A(H5N1) viruses. PA mutants that harbored I38T, F, and M were 48.2-, 24.0-, and 15.5-fold less susceptible, respectively, to BXA than wild-type A(H5N1) but were susceptible to the neuraminidase inhibitor oseltamivir acid and the RNA polymerase inhibitor favipiravir. PA mutants exhibited significantly impaired replicative fitness in Madin-Darby canine kidney cells at 24 h postinfection. In addition, in order to investigate new genetic markers for BXA susceptibility, we screened geographically and temporally distinct IAVs isolated worldwide from birds and pigs. The results showed that BXA exhibited antiviral activity against avian and swine viruses with similar levels to seasonal isolates. All viruses tested in the study lacked the PA/I38 substitution and were susceptible to BXA. Isolates harboring amino acid polymorphisms at positions 20, 24, and 37, which have been implicated in the binding of BXA to the PA endonuclease domain, were also susceptible to BXA. These results suggest that monitoring of the PA/I38 substitution in animal-derived influenza viruses is important for preparedness against zoonotic influenza virus outbreaks.


Assuntos
Dibenzotiepinas , Virus da Influenza A Subtipo H5N1 , Vírus da Influenza A , Influenza Humana , Morfolinas , Orthomyxoviridae , Piridonas , Tiepinas , Triazinas , Animais , Cães , Humanos , Suínos , Vírus da Influenza A/genética , Oxazinas/farmacologia , Piridinas/farmacologia , Piridinas/uso terapêutico , Virus da Influenza A Subtipo H5N1/genética , Tiepinas/farmacologia , Tiepinas/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Orthomyxoviridae/genética , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Substituição de Aminoácidos , Endonucleases/genética , Farmacorresistência Viral/genética
10.
Antiviral Res ; 222: 105792, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38163624

RESUMO

Therapeutic use of maribavir for human cytomegalovirus infection has renewed attention to the extent of cross-resistance with ganciclovir as the existing standard therapy. Each drug selects in vivo for a characteristic set of resistance mutations in the viral UL97 kinase gene. To improve the calibration of relative susceptibilities to each drug, genetic variants at relevant UL97 codons were extensively phenotyped using the same baseline viral clone, cell culture conditions and growth readout. Ganciclovir-selected mutations at codons 460, 520, 592, 594, 595 and 603 conferred 2.8-fold (C603Y) to 12-fold (M460I) increases in ganciclovir 50% inhibitory concentrations (EC50) over wild type baseline, while conferring maribavir EC50 fold changes ranging from 0.21-fold (M460I) to 1.9-fold (A594V). Maribavir-selected mutations at codons 409, 411 and 480 conferred maribavir EC50 fold changes ranging from 17 (H411Y) to 210 (C480F), while conferring ganciclovir EC50 fold changes ranging from 0.7 (H411Y) to 2.3 (C480F). The P-loop substitution F342Y, selected by either drug, is confirmed to confer 4.7-fold and 6-fold increases in maribavir and ganciclovir EC50s respectively, and suggests this part of the ATP-binding domain of UL97 to be involved in moderate resistance to both drugs. The maribavir hypersensitivity of M460I and M460V may be advantageous.


Assuntos
Citomegalovirus , Diclororribofuranosilbenzimidazol/análogos & derivados , Ganciclovir , Humanos , Ganciclovir/farmacologia , Antivirais/farmacologia , Mutação , Códon , Farmacorresistência Viral/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética
11.
Antiviral Res ; 222: 105818, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38280564

RESUMO

In this research, we employed a deep reinforcement learning (RL)-based molecule design platform to generate a diverse set of compounds targeting the neuraminidase (NA) of influenza A and B viruses. A total of 60,291 compounds were generated, of which 86.5 % displayed superior physicochemical properties compared to oseltamivir. After narrowing down the selection through computational filters, nine compounds with non-sialic acid-like structures were selected for in vitro experiments. We identified two compounds, DS-22-inf-009 and DS-22-inf-021 that effectively inhibited the NAs of both influenza A and B viruses (IAV and IBV), including H275Y mutant strains at low micromolar concentrations. Molecular dynamics simulations revealed a similar pattern of interaction with amino acid residues as oseltamivir. In cell-based assays, DS-22-inf-009 and DS-22-inf-021 inhibited IAV and IBV in a dose-dependent manner with EC50 values ranging from 0.29 µM to 2.31 µM. Furthermore, animal experiments showed that both DS-22-inf-009 and DS-22-inf-021 exerted antiviral activity in mice, conferring 65 % and 85 % protection from IAV (H1N1 pdm09), and 65 % and 100 % protection from IBV (Yamagata lineage), respectively. Thus, these findings demonstrate the potential of RL to generate compounds with promising antiviral properties.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A , Influenza Humana , Animais , Camundongos , Humanos , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Inteligência Artificial , Proteínas Virais , Farmacorresistência Viral , Vírus da Influenza B , Neuraminidase
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.
J Med Chem ; 67(2): 885-921, 2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38179950

RESUMO

Hepatitis C viral (HCV) infection is the leading cause of liver failure and still represents a global health burden. Over the past decade, great advancements made HCV curable, and sustained viral remission significantly improved to more than 98%. Historical treatment with pegylated interferon alpha and ribavirin has been displaced by combinations of direct-acting antivirals. These regimens include drugs targeting different stages of the HCV life cycle. However, the emergence of viral resistance remains a big concern. The design of peptidomimetic inhibitors (PIs) able to fit and fill the conserved substrate envelope region within the active site helped avoid contact with the vulnerable sites of the most common resistance-associated substitutions Arg155, Ala156, and Asp168. Herein, we give an overview of HCV NS3 PIs discovered during the past decade, and we deeply discuss the rationale behind the structural optimization efforts essential to achieve pangenotypic activity.


Assuntos
Hepatite C Crônica , Hepatite C , Peptidomiméticos , Humanos , Antivirais/farmacologia , Antivirais/uso terapêutico , Antivirais/química , Peptidomiméticos/farmacologia , Peptidomiméticos/uso terapêutico , Inibidores de Proteases/farmacologia , Hepatite C Crônica/tratamento farmacológico , Proteínas não Estruturais Virais , Hepatite C/tratamento farmacológico , Hepacivirus , Farmacorresistência Viral
16.
Pediatr Infect Dis J ; 43(1): 40-48, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-37922511

RESUMO

BACKGROUND: Virologic characterization of newly HIV-diagnosed adolescents could help to improve their specific needs. The objective was to describe the transmitted drug resistance mutations (TDR) and its transmission by clusters in this population in Spain. METHODS: TDR to retrotranscriptase and protease inhibitors included in the WHO TDR list 2009 implemented in the Calibrated Population Resistance tool v8.0 (Stanford) were studied in HIV pol sequences from all HIV-diagnosed adolescents (12-19-year-old) enrolled during 2004-2019 period in the Spanish pediatric and adult (CoRISpe-CoRIS) cohorts. The found TDR were compared with the provided by the Stanford algorithm v9.0 2021. HIV-1 variants and transmission clusters were also studied. RESULTS: Among 410 HIV-1 adolescents diagnosed, 141 (34.4%) had available ART-naive sequences. They were mostly male (81.6%), Spanish (55.3%) and with behavioral risk (92.2%), mainly male-to-male sexual contact (63.1%). TDR prevalence was significantly higher by Stanford versus WHO list (18.4% vs. 7.1%; P = 0.004). The most prevalent TDR by the WHO list was K103N (3.6%) and by Stanford E138A (6.6%), both at retrotranscriptase. E138A, related to rilpivirine/etravirine resistance, was absent in the WHO list. One in 4 adolescents carried HIV-1 non-B variants. We described 5 transmission clusters, and 2 carried TDR mutations. CONCLUSIONS: Our data suggest a high TDR prevalence in adolescents with a new HIV diagnosis in Spain, similar to adults, 2 active TDR transmission clusters, and the need for the WHO TDR list update. These findings could have implications for the options of the recently available rilpivirine-related long-acting treatment and in first-line regimen election.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Soropositividade para HIV , HIV-1 , Adulto , Humanos , Masculino , Adolescente , Criança , Adulto Jovem , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Espanha/epidemiologia , Farmacorresistência Viral/genética , Mutação , HIV-1/genética , Rilpivirina/uso terapêutico , Prevalência , Genótipo , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico
18.
J Infect Dis ; 229(2): 413-421, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-37506264

RESUMO

BACKGROUND: This drug resistance analysis of a randomized trial includes 234 patients receiving maribavir and 116 receiving investigator-assigned standard therapy (IAT), where 56% and 24%, respectively, cleared cytomegalovirus DNA at week 8 (treatment responders). METHODS: Baseline and posttreatment plasma samples were tested for mutations conferring drug resistance in viral genes UL97, UL54, and UL27. RESULTS: At baseline, genotypic testing revealed resistance to ganciclovir, foscarnet, or cidofovir in 56% of patients receiving maribavir and 68% receiving IAT, including 9 newly phenotyped mutations. Among them, 63% (maribavir) and 21% (IAT) were treatment responders. Detected baseline maribavir resistance mutations were UL27 L193F (n = 1) and UL97 F342Y (n = 3). Posttreatment, emergent maribavir resistance mutations were detected in 60 (26%) of those randomized to maribavir, including 49 (48%) of 103 nonresponders and 25 (86%) of the 29 nonresponders where viral DNA initially cleared then rebounded while on maribavir. The most common maribavir resistance mutations were UL97 T409M (n = 34), H411Y (n = 26), and C480F (n = 21), first detected 26 to 130 (median 56) days after starting maribavir. CONCLUSIONS: Baseline maribavir resistance was rare. Drug resistance to standard cytomegalovirus antivirals did not preclude treatment response to maribavir. Rebound in plasma cytomegalovirus DNA while on maribavir strongly suggests emerging drug resistance. CLINICAL TRIALS REGISTRATION: NCT02931539.


Assuntos
Infecções por Citomegalovirus , Diclororribofuranosilbenzimidazol , Ribonucleosídeos , Humanos , Antivirais/uso terapêutico , Antivirais/farmacologia , Benzimidazóis/uso terapêutico , Citomegalovirus/genética , Infecções por Citomegalovirus/tratamento farmacológico , Diclororribofuranosilbenzimidazol/análogos & derivados , DNA , Farmacorresistência Viral/genética , Ganciclovir/uso terapêutico , Mutação , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Ribonucleosídeos/uso terapêutico , Transplantados
19.
J Formos Med Assoc ; 123 Suppl 1: S47-S54, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37661527

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has reached a turning point. The non-pharmaceutical interventions for preventing COVID-19 are lifting. Vaccination uptake is increasing in general, but this strategy is continuously challenged by the rapid evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Of note, the Omicron subvariants spread globally for at least one year, and the most recently developed subvariants show strong immune evasion to preexisting immunity, either from previous infection, vaccination or both. Therefore, early and appropriate antiviral agents to treat patients at risk for severe COVID-19 or death is crucial to decrease morbidities and mortalities, to restore the healthcare capacities and to facilitate a return to the new normal. Current antiviral therapy for COVID-19 consist of neutralizing monoclonal antibodies (mAbs) and direct antiviral agents. Each agent has been proved for early ambulatory treatment of COIVD-19, but suffer from variable effectiveness and limitations due to patients' comorbidities, drug properties, or antiviral resistance. Besides, some specific mAbs are indicated for prophylaxis of COVID-19 before or after close contact with confirmed COVID-19 patients. This review article summarizes the evidence and unmet needs of the currently available antiviral agents for management of COVID-19 in the context of the Omicron subvariants.


Assuntos
COVID-19 , Humanos , SARS-CoV-2 , Anticorpos Monoclonais , Farmacorresistência Viral , Antivirais/uso terapêutico
20.
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
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