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1.
Medicine (Baltimore) ; 99(39): e22352, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991450

RESUMO

BACKGROUND: Antiretroviral therapy for HIV in sub-Saharan Africa has transformed the highly infectious virus to a stable chronic condition, with the advent of Highly active antiretroviral therapy (HAART). The longterm effects of HAART on the oral health of children are understudied. OBJECTIVE: To compare the effect of lopinavir-ritonavir and lamivudine on oral health indicators (dental caries, gingivitis, tooth eruption, and oral health related quality of life) in 5 to 7 year old HIV-1 exposed uninfected children from the ANRS 12174 trial. METHODS: This study used data collected in 2017 among children aged 5 to 7 years from the Ugandan site of the ANRS 12174 randomized trial (ClinicalTrials.gov no: NCT00640263) implemented between 2009 and 2012 in Mbale district, Eastern Uganda. The intervention was lopinavir-ritonavir or lamuvudine treatment to prevent vertical HIV-1 transmission. One hundred thirty-seven and 139 children were randomized to receive lopinavir-ritonavir or lamivudine treatment at day 7 postpartum to compare efficacy of prevention of vertical HIV-1 transmission. At follow up, the children underwent oral examination using the World Health Organization methods for field conditions. The oral health related quality of life was assessed using the early childhood oral health impact scale. Negative binomial and logistic regression were used for the analysis of data. MAIN OUTCOME MEASURES: Dental caries, gingivitis, tooth eruption, and oral health related quality of life) in 5 to 7 year old HIV-1 exposed uninfected children. RESULTS: The prevalence of dental caries was 48% in the study sample: 49% in the lopinavir-ritonavir arm and 48% in the lamivudine treatment group. The corresponding mean decayed missing filled teeth and standard deviation was 1.7 (2.4) and 2.3 (3.7) The mean number (standard deviation) of erupted permanent teeth was 3.8 (3.7) and 4.6 (3.9) teeth in the lopinavir- and lamivudine group, respectively. The prevalence of reported impacts on oral health was 7% in the lopinavir-ritonavir and 18% in the lamivudine group. Gingivitis had a prevalence of 7% in the lopinavir-ritonavir and 14% lamivudine treatment group. The regression analysis revealed 70% less reported impacts on oral health in lopinavir-ritonavir group than the lamivudine treatment group with an incidence rate ratio of 0.3 (95% confidence interval: 0.1-0.9). CONCLUSIONS: HIV exposed uninfected infants in the lopinavir-ritonavir group reported less impacts on oral health than the lamivudine treatment group. Dental caries, gingivitis, and tooth eruption were not significantly affected by the treatment lopinavir-ritonavir or lamivudine. TRIAL REGISTRATION CLINICALTRIALS. GOV IDENTIFIER: NCT00640263.


Assuntos
Antirretrovirais/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , Saúde Bucal/estatística & dados numéricos , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Estudos de Casos e Controles , Criança , Pré-Escolar , Cárie Dentária/tratamento farmacológico , Cárie Dentária/epidemiologia , Quimioterapia Combinada , Feminino , Gengivite/tratamento farmacológico , Infecções por HIV/prevenção & controle , Infecções por HIV/transmissão , HIV-1/efeitos dos fármacos , Humanos , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Lamivudina/farmacologia , Lamivudina/uso terapêutico , Lopinavir/farmacologia , Lopinavir/uso terapêutico , Masculino , Avaliação de Resultados em Cuidados de Saúde , Prevalência , Qualidade de Vida , Ritonavir/farmacologia , Ritonavir/uso terapêutico , Erupção Dentária/efeitos dos fármacos , Uganda/epidemiologia
2.
Biomolecules ; 10(8)2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32764519

RESUMO

Lupane-type pentacyclic triterpenes such as betulin and betulinic acid play an important role in the search for new therapies that would be effective in controlling viral infections. The aim of this study was the synthesis and evaluation of in vitro anti-HIV-1 activity for phosphate derivatives of 3-carboxyacylbetulin 3-5 as well as an in silico study of new compounds as potential ligands of the C-terminal domain of the HIV-1 capsid-spacer peptide 1 (CA-CTD-SP1) as a molecular target of HIV-1 maturation inhibitors. In vitro studies showed that 28-diethoxyphosphoryl-3-O-(3',3'-dimethylsuccinyl)betulin (compound 3), the phosphate analog of bevirimat (betulinic acid derivative, HIV-1 maturation inhibitor), has IC50 (half maximal inhibitory concentration) equal to 0.02 µM. Compound 3 inhibits viral replication at a level comparable to bevirimat and is also more selective (selectivity indices = 1250 and 967, respectively). Molecular docking was used to examine the probable interaction between the phosphate derivatives of 3-carboxyacylbetulin and C-terminal domain (CTD) of the HIV-1 capsid (CA)-spacer peptide 1 (SP1) fragment of Gag protein, designated as CTD-SP1. Compared with interactions between bevirimat (BVM) and the protein, an increased number of strong interactions between ligand 3 and the protein, generated by the phosphate group, were observed. These compounds might have the potential to also inhibit SARS-CoV2 proteins, in as far as the intrinsically imprecise docking scores suggest.


Assuntos
Fármacos Anti-HIV/síntese química , Simulação de Acoplamento Molecular , Triterpenos/química , Produtos do Gene gag do Vírus da Imunodeficiência Humana/metabolismo , Fármacos Anti-HIV/farmacologia , Sítios de Ligação , Fosfatos/química , Ligação Proteica , Succinatos/química , Succinatos/farmacologia , Triterpenos/farmacologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/química
3.
PLoS One ; 15(8): e0236156, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32804970

RESUMO

BACKGROUND: HIV drug resistance (HIVDR) poses a threat to the HIV epidemic control in Zambia especially in sub-populations such as the 15-24 years where there is poor virological suppression. Understanding the prevalence and patterns of HIVDR in this population (15-24 years) will contribute to defining effective antiretroviral therapy (ART) regimens, improving clinical decision making, and supporting behavioral change interventions needed to achieve HIV epidemic control. METHODS: A cross-sectional analysis of study enrollment data from the Project YES! Youth Engaging for Success randomized controlled trial was conducted. Participants were 15 to 24 years old, who knew their HIV status, and had been on ART for at least 6 months. All participants completed a survey and underwent viral load (VL) testing. Participants with viral failure (VL ≥1,000 copies/mL) underwent HIVDR testing which included analysis of mutations in the protease and reverse transcriptase genes. RESULTS: A total of 99 out of 273 analyzed participants receiving ART had VL failure, of whom 77 had successful HIVDR amplification and analysis. Out of the 77, 75% (58) had at least one drug resistant mutation, among which 83% (48/58) required a drug change. Among the 58 with HIVDR mutations, the prevalence of at least one HIVDR mutation to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) were 81%, 65.5% and 1.7%. The mutation M184V which confers resistance to NRTI drugs of lamivudine (3TC) and emtricitabine (FTC) was the most common (81%) among NRTI associated mutations followed by K65R (34.5%) which is associated with both tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF) resistance. Thymidine analogue mutations (TAMs) which confer resistance primarily to zidovudine (AZT), stavudine (d4T) and other NRTIs were observed at 32.8%. Common TAMs were K70RTQNE (32.8%), K219QE (22.4%), D67N (17.2%) and T215IT (15.5%). The most common NNRTI associated mutation was the K103N (65.5%) which confers resistance to both efavirenz (EFV) and nevirapine (NVP). There was a relatively high occurrence of other NNRTI mutations V106A (36.2%), as well as Y188C (36.2%) and Y181C (36.2%) which confer resistance to etravirine. CONCLUSIONS: There is a high prevalence of HIVDR including TAMs despite majority of these patients (90.48%) being on AZT or d4T sparing first line ART among the youth. Emergence of these mutations including the NNRTI associated mutations (Y181C and Y188C) may compromise future second- and third-line regimens in the absence of routine HIVDR testing. HIVDR monitoring at start of ART or at first-line failure can better inform clinical decision making and ART programing.


Assuntos
Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , HIV-1/isolamento & purificação , Adolescente , Fármacos Anti-HIV/uso terapêutico , Tomada de Decisão Clínica , Estudos Transversais , Feminino , Infecções por HIV/epidemiologia , HIV-1/genética , Humanos , Masculino , Mutação , Prevalência , RNA Viral/genética , RNA Viral/isolamento & purificação , Ensaios Clínicos Controlados Aleatórios como Assunto , Timidina/genética , Carga Viral/efeitos dos fármacos , Adulto Jovem , Zâmbia
4.
PLoS One ; 15(6): e0230205, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32584821

RESUMO

BACKGROUND: As Zimbabwe approaches epidemic control of HIV, programs now prioritize viral load over CD4 monitoring, making it difficult to identify persons living with HIV (PLHIV) suffering from advanced disease (AD). We present an analysis of cross-sectional ZIMPHIA data, highlighting PLHIV with AD and concurrent viral load suppression (VLS). METHODS: ZIMPHIA collected blood specimens for HIV testing from 22,501 consenting adults (ages 15 years and older); 3,466 PLHIV had CD4 and VL results. Household HIV testing used the national serial algorithm, and those testing positive then received point-of-care CD4 enumeration with subsequent VL testing. We used logistic regression analysis to explore factors associated with concurrent AD and VLS (<1000 copies/mL). All analyses were weighted to account for complex survey design. RESULTS: Of the 3,466 PLHIV in the survey with CD4 and VL results, 17% were found to have AD (CD4<200cells/mm3). Of all AD patients, 30% had VLS. Concurrent AD and VLS was associated with male sex (aOR 2.45 95%CI 1.61-3.72), older age (35-49 years [aOR 2.46 95%CI 1.03-5.91] and 50+ years [aOR 4.82 95%CI 2.02-11.46] vs 15-24 years), and ART duration (<6 months [aOR 0.46 95%CI 0.29-0.76] and 6-24 months [aOR 2.07 95%CI 1.35-3.17] vs more than 2 years). The relationship between sex and AD is driven by age with significant associations among men aged 25-34, (aOR 3.37 95%CI 1.35-8.41), 35-49 (aOR 5.13 95%CI 2.16-12.18), and 50+ (aOR 12.56 95%CI 4.82-32.72) versus men aged 15-24. CONCLUSIONS: The percentage of PLHIV with AD and VLS illustrates the conundrum of decreased support for CD4 monitoring, as these patients may not receive appropriate clinical services for advanced HIV disease. In high-prevalence settings such as Zimbabwe, CD4 monitoring support warrants further consideration to differentiate care appropriately for the most vulnerable PLHIV. Males may need to be prioritized, given their over-representation in this sub-population.


Assuntos
Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Inquéritos e Questionários , Carga Viral/efeitos dos fármacos , Adolescente , Adulto , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Feminino , Infecções por HIV/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
5.
PLoS One ; 15(6): e0234937, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555643

RESUMO

We have previously reported on HIV-1 infected patients who fail anti-retroviral therapy but manage to re-suppress without a regimen change despite harbouring major drug resistance mutations. Here we explore phenotypic drug resistance in such patients in order to better understand this phenomenon. Patients (n = 71) failing a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen, but who subsequently re-suppressed on the same regimen, were assessed for HIV-1 genotypic drug resistance through Sanger sequencing. A subset (n = 23) of these samples, as well as genotypically matched samples from patients who did not re-suppress (n = 19), were further assessed for phenotypic drug resistance in an in vitro single cycle assay. Half of the patients (n = 36/71, 51%) harboured genotypic drug resistance, with M184V (n = 18/36, 50%) and K103N (n = 16/36, 44%) being the most prevalent mutations. No significant difference in the median time to re-suppression (31-39 weeks) were observed for either group (p = 0.41). However, re-suppressors with mutant virus rebounded significantly earlier than those with wild-type virus (16 vs. 33 weeks; p = 0.014). Similar phenotypic drug resistance profiles were observed between patients who re-suppressed and patients who failed to re-suppress. While most remained susceptible to stavudine (d4T) and zidovudine (AZT), both groups showed a reduced susceptibility to 3TC and NNRTIs. HIV- 1 infected patients on an NNRTI-based regimen can achieve viral re-suppression on the same regimen despite harbouring viruses with genotypic and phenotypic drug resistance. However, re-suppression was less durable in those with resistance, reinforcing the importance of appropriate regimen choices, ongoing viral load monitoring and adherence counselling.


Assuntos
Fármacos Anti-HIV , Farmacorresistência Viral , Infecções por HIV , HIV-1 , Inibidores da Transcriptase Reversa , Carga Viral/efeitos dos fármacos , Adulto , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Estudos de Coortes , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Masculino , Fenótipo , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico
6.
Proc Natl Acad Sci U S A ; 117(27): 15763-15771, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32571938

RESUMO

HIV-1 latency is a major barrier to cure. Identification of small molecules that destabilize latency and allow immune clearance of infected cells could lead to treatment-free remission. In vitro models of HIV-1 latency involving cell lines or primary cells have been developed for characterization of HIV-1 latency and high-throughput screening for latency-reversing agents (LRAs). We have shown that the majority of LRAs identified to date are relatively ineffective in cells from infected individuals despite activity in model systems. We show here that, for diverse LRAs, latency reversal observed in model systems involves a heat shock factor 1 (HSF1)-mediated stress pathway. Small-molecule inhibition of HSF1 attenuated HIV-1 latency reversal by histone deactylase inhibitors, protein kinase C agonists, and proteasome inhibitors without interfering with the known mechanism of action of these LRAs. However, latency reversal by second mitochondria-derived activator of caspase (SMAC) mimetics was not affected by inhibition of HSF1. In cells from infected individuals, inhibition of HSF1 attenuated latency reversal by phorbol ester+ionomycin but not by anti-CD3+anti-CD28. HSF1 promotes elongation of HIV-1 RNA by recruiting P-TEFb to the HIV-1 long terminal repeat (LTR), and we show that inhibition of HSF1 attenuates the formation of elongated HIV-1 transcripts. We demonstrate that in vitro models of latency have higher levels of the P-TEFb subunit cyclin T1 than primary cells, which may explain why many LRAs are functional in model systems but relatively ineffective in primary cells. Together, these studies provide insights into why particular LRA combinations are effective in reversing latency in cells from infected individuals.


Assuntos
Infecções por HIV/genética , HIV-1/genética , Fatores de Transcrição de Choque Térmico/genética , Latência Viral/genética , Fármacos Anti-HIV/farmacologia , Proteínas Reguladoras de Apoptose/genética , Ciclina T/genética , Infecções por HIV/virologia , HIV-1/patogenicidade , Fatores de Transcrição de Choque Térmico/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Humanos , Proteínas Mitocondriais/genética , Fator B de Elongação Transcricional Positiva/genética , Proteína Quinase C/genética , RNA Viral/efeitos dos fármacos , RNA Viral/genética , Bibliotecas de Moléculas Pequenas/farmacologia , Sequências Repetidas Terminais/genética , Ativação Viral/genética
7.
Molecules ; 25(10)2020 May 17.
Artigo em Inglês | MEDLINE | ID: covidwho-276849

RESUMO

Remdesivir is a nucleotide prodrug that is currently undergoing extensive clinical trials for the treatment of COVID-19. The prodrug is metabolized to its active triphosphate form and interferes with the action of RNA-dependent RNA polymerase of SARS-COV-2. Herein, we report the antiviral activity of remdesivir against human coronavirus 229E (HCoV-229E) compared to known anti-HIV agents. These agents included tenofovir (TFV), 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), alovudine (FLT), lamivudine (3TC), and emtricitabine (FTC), known as nucleoside reverse-transcriptase inhibitors (NRTIs), and a number of 5'-O-fatty acylated anti-HIV nucleoside conjugates. The anti-HIV nucleosides interfere with HIV RNA-dependent DNA polymerase and/or act as chain terminators. Normal human fibroblast lung cells (MRC-5) were used to determine the cytotoxicity of the compounds. The study revealed that remdesivir exhibited an EC50 value of 0.07 µM against HCoV-229E with TC50 of > 2.00 µM against MRC-5 cells. Parent NRTIs were found to be inactive against (HCoV-229E) at tested concentrations. Among all the NRTIs and 5'-O-fatty acyl conjugates of NRTIs, 5'-O-tetradecanoyl ester conjugate of FTC showed modest activity with EC50 and TC50 values of 72.8 µM and 87.5 µM, respectively. These data can be used for the design of potential compounds against other coronaviruses.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Fármacos Anti-HIV/farmacologia , Coronavirus Humano 229E/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Monofosfato de Adenosina/farmacologia , Alanina/farmacologia , Fármacos Anti-HIV/química , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/enzimologia , Linhagem Celular , Coronavirus Humano 229E/enzimologia , Infecções por Coronavirus/tratamento farmacológico , Humanos , Pandemias , Pneumonia Viral/tratamento farmacológico , RNA Replicase/metabolismo , Inibidores da Transcriptase Reversa/química
8.
Proc Natl Acad Sci U S A ; 117(20): 10688-10698, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32371485

RESUMO

AIDS is a pandemic disease caused by HIV that affects 37 million people worldwide. Current antiretroviral therapy slows disease progression but does not eliminate latently infected cells, which resupply active virus, thus necessitating lifelong treatment with associated compliance, cost, and chemoexposure issues. Latency-reversing agents (LRAs) activate these cells, allowing for their potential clearance, thus presenting a strategy to eradicate the infection. Protein kinase C (PKC) modulators-including prostratin, ingenol esters, bryostatin, and their analogs-are potent LRAs in various stages of development for several clinical indications. While LRAs are promising, a major challenge associated with their clinical use is sustaining therapeutically meaningful levels of the active agent while minimizing side effects. Here we describe a strategy to address this problem based on LRA prodrugs, designed for controllable release of the active LRA after a single injection. As intended, these prodrugs exhibit comparable or superior in vitro activity relative to the parent compounds. Selected compounds induced higher in vivo expression of CD69, an activation biomarker, and, by releasing free agent over time, significantly improved tolerability when compared to the parent LRAs. More generally, selected prodrugs of PKC modulators avoid the bolus toxicities of the parent drug and exhibit greater efficacy and expanded tolerability, thereby addressing a longstanding objective for many clinical applications.


Assuntos
Fármacos Anti-HIV/farmacologia , Briostatinas/farmacologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Pró-Fármacos/farmacologia , Proteína Quinase C/metabolismo , Latência Viral/efeitos dos fármacos , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/uso terapêutico , Briostatinas/síntese química , Briostatinas/uso terapêutico , Linhagem Celular Tumoral , Células Cultivadas , Diterpenos/química , Infecções por HIV/tratamento farmacológico , HIV-1/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Ésteres de Forbol/química , Pró-Fármacos/síntese química , Pró-Fármacos/uso terapêutico , Proteína Quinase C/efeitos dos fármacos
9.
PLoS One ; 15(5): e0233355, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32421754

RESUMO

BACKGROUND: Incarcerated people are at increased risk of human immunodeficiency virus (HIV) infection relative to the general population. Despite a high burden of infection, HIV care use among prison populations is often suboptimal and varies among settings, and little evidence exists explaining the discrepancy. Therefore, this review assessed barriers to optimal use of HIV care cascade in incarcerated people. METHODS: Quantitative and qualitative studies investigating factors affecting linkage to care, ART (antiretroviral therapy) initiation, adherence and/or outcomes among inmates were systematically searched across seven databases. Studies published in English language and indexed up to 26 October 2018 were reviewed. We performed a narrative review for both quantitative and qualitative studies, and meta-analyses on selected quantitative studies. All retrieved quantitative studies were assessed for risk of bias. Meta-analyses were conducted using RevMan-5 software and pooled odds ratios were calculated using Mantel-Haenszel statistics with 95% confidence interval at a p<0.05. The review protocol has been published at the International Prospective Register of Systematic Reviews (PROSPERO; Number: CRD42019135502). RESULTS: Of forty-two studies included in the narrative review, eight were qualitative studies. Sixteen of the quantitative studies were eligible for meta-analyses. The narrative synthesis revealed structural factors such as: a lack of access to community standard of HIV care, particularly in resource limited countries; loss of privacy; and history of incarceration and re-incarceration as risk factors for poor HIV care use in prison populations. Among social and personal characteristics, lack of social support, stigma, discrimination, substance use, having limited knowledge about, and negative perception towards ART were the main determinants of suboptimal use of care in incarcerated people. In the meta-analyses, lower odds of ART initiation was noticed among inmates with higher baseline CD4 count (CD4 ≥500celss/mm3) (OR = 0.37, 95%CI: 0.14-0.97, I2 = 43%), new HIV diagnosis (OR = 0.07, 95%CI: 0.05-0.10, I2 = 68%), and in those who lacked belief in ART safety (OR = 0.32, 95%CI: 0.18-0.56, I2 = 0%) and efficacy (OR = 0.31, 95%CI: 0.17-0.57, I2 = 0%). Non-adherence was high among inmates who lacked social support (OR = 3.36, 95%CI: 2.03-5.56, I2 = 35%), had low self-efficiency score (OR = 2.50, 95%CI: 1.64,-3.80, I2 = 22%) and those with depressive symptoms (OR = 2.02, 95%CI: 1.34-3.02, I2 = 0%). Lower odds of viral suppression was associated with history of incarceration (OR = 0.40, 95%CI: 0.35-0.46, I2 = 0%), re-incarceration (OR = 0.09, 95%CI: 0.06-0.13, I2 = 64%) and male gender (OR = 0.55, 95%CI: 0.42-0.72, I2 = 0%). Higher odds of CD4 count <200cells/mm3 (OR = 2.01, 95%CI: 1.62, 2.50, I2 = 44%) and lower odds of viral suppression (OR = 0.20, 95%CI: 0.17-0.22, I2 = 0%) were observed during prison entry compared to those noticed during release. CONCLUSION: Given the high HIV risk in prison populations and rapid movements of these people between prison and community, correctional facilities have the potential to substantially contribute to the use of HIV treatment as a prevention strategy. Thus, there is an urgent need for reviewing context specific interventions and ensuring standard of HIV care in prisons, particularly in resource limited countries.


Assuntos
Infecções por HIV/tratamento farmacológico , Adesão à Medicação/psicologia , Prisioneiros/psicologia , Adulto , Fármacos Anti-HIV/farmacologia , Contagem de Linfócito CD4 , Infecções por HIV/virologia , Humanos , Masculino , Prisioneiros/estatística & dados numéricos , Fatores de Risco , Estigma Social
10.
PLoS One ; 15(5): e0220165, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32357149

RESUMO

OBJECTIVES: We extend the method of Significant Zero Crossings of Derivatives (SiZer) to address within-subject correlations of repeatedly collected longitudinal biomarker data and the computational aspects of the methodology when analyzing massive biomarker databases. SiZer is a powerful visualization tool for exploring structures in curves by mapping areas where the first derivative is increasing, decreasing or does not change (plateau) thus exploring changes and normalization of biomarkers in the presence of therapy. METHODS: We propose a penalized spline SiZer (PS-SiZer) which can be expressed as a linear mixed model of the longitudinal biomarker process to account for irregularly collected data and within-subject correlations. Through simulations we show how sensitive PS-SiZer is in detecting existing features in longitudinal data versus existing versions of SiZer. In a real-world data analysis PS-SiZer maps are used to map areas where the first derivative of weight change after antiretroviral therapy (ART) start is significantly increasing, decreasing or does not change, thus exploring the durability of weight increase after the start of therapy. We use weight data repeatedly collected from persons living with HIV initiating ART in five regions in the International Epidemiologic Databases to Evaluate AIDS (IeDEA) worldwide collaboration and compare the durability of weight gain between ART regimens containing and not containing the drug stavudine (d4T), which has been associated with shorter durability of weight gain. RESULTS: Through simulations we show that the PS-SiZer is more accurate in detecting relevant features in longitudinal data than existing SiZer variants such as the local linear smoother (LL) SiZer and the SiZer with smoothing splines (SS-SiZer). In the illustration we include data from 185,010 persons living with HIV who started ART with a d4T (53.1%) versus non-d4T (46.9%) containing regimen. The largest difference in durability of weight gain identified by the SiZer maps was observed in Southern Africa where weight gain in patients treated with d4T-containing regimens lasted 59.9 weeks compared to 133.8 weeks for those with non-d4T-containing regimens. In the other regions, persons receiving d4T-containing regimens experienced weight gains lasting 38-62 weeks versus 55-93 weeks in those receiving non-d4T-based regimens. DISCUSSION: PS-SiZer, a SiZer variant, can handle irregularly collected longitudinal data and within-subject correlations and is sensitive in detecting even subtle features in biomarker curves.


Assuntos
Fármacos Anti-HIV/farmacologia , Peso Corporal/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/fisiopatologia , Ganho de Peso , Adulto , África , África Austral , Fármacos Anti-HIV/uso terapêutico , Biomarcadores/sangue , Simulação por Computador , Interpretação Estatística de Dados , Feminino , Humanos , Estudos Longitudinais , Masculino
11.
Molecules ; 25(10)2020 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-32429580

RESUMO

Remdesivir is a nucleotide prodrug that is currently undergoing extensive clinical trials for the treatment of COVID-19. The prodrug is metabolized to its active triphosphate form and interferes with the action of RNA-dependent RNA polymerase of SARS-COV-2. Herein, we report the antiviral activity of remdesivir against human coronavirus 229E (HCoV-229E) compared to known anti-HIV agents. These agents included tenofovir (TFV), 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), alovudine (FLT), lamivudine (3TC), and emtricitabine (FTC), known as nucleoside reverse-transcriptase inhibitors (NRTIs), and a number of 5'-O-fatty acylated anti-HIV nucleoside conjugates. The anti-HIV nucleosides interfere with HIV RNA-dependent DNA polymerase and/or act as chain terminators. Normal human fibroblast lung cells (MRC-5) were used to determine the cytotoxicity of the compounds. The study revealed that remdesivir exhibited an EC50 value of 0.07 µM against HCoV-229E with TC50 of > 2.00 µM against MRC-5 cells. Parent NRTIs were found to be inactive against (HCoV-229E) at tested concentrations. Among all the NRTIs and 5'-O-fatty acyl conjugates of NRTIs, 5'-O-tetradecanoyl ester conjugate of FTC showed modest activity with EC50 and TC50 values of 72.8 µM and 87.5 µM, respectively. These data can be used for the design of potential compounds against other coronaviruses.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Fármacos Anti-HIV/farmacologia , Coronavirus Humano 229E/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Monofosfato de Adenosina/farmacologia , Alanina/farmacologia , Fármacos Anti-HIV/química , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/enzimologia , Linhagem Celular , Coronavirus Humano 229E/enzimologia , Infecções por Coronavirus/tratamento farmacológico , Humanos , Pandemias , Pneumonia Viral/tratamento farmacológico , RNA Replicase/metabolismo , Inibidores da Transcriptase Reversa/química
12.
Epidemiol Infect ; 148: e102, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32381145

RESUMO

HIV-1 drug resistance can compromise the effectiveness of antiretroviral therapy (ART). A survey of pretreatment HIV-1 drug resistance (PDR) was conducted in Lincang Prefecture of Yunnan Province. From 372 people living with HIV/AIDS initiating ART for the first time during 2017-2018, 322 pol sequences were obtained, of which 11 HIV-1 strain types were detected. CRF08_BC (70.2%, 226/322) was the predominant strain, followed by URF strains (10.6%, 34/322). Drug resistance mutations (DRMs) were detected among 34.2% (110/322) of the participants. E138A/G/K/R (14.3%, 46/322) and V179E/D/T (13.7%, 47/322) were the predominant DRMs. Specifically, E138 mutations commonly occurred in CRF08_BC (19.9%, 45/226). Among the DRMs detected, some independently conferred resistance, such as K65R (1.6%, 5/322), Y188C/F/L (0.9%, 3/322), K103N (0.6%, 2/322) and G190A (0.3%, 1/322), which conferred high-level resistance. The prevalence of PDR was 7.5% (95% CI: 4.6-10.3%) and the prevalence of non-nucleotide reverse transcriptase inhibitor (NNRTI) resistance was 5.0% (95% CI: 2.6-7.4%), which is below the threshold (⩾10%) of initiating a public health response. In conclusion, HIV-1 genetic diversity and an overall moderate level of PDR prevalence were found in western Yunnan. PDR surveillance should be continually performed to decide whether a public health response to NNRTI resistance should be initiated.


Assuntos
Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Adolescente , Adulto , Idoso , Fármacos Anti-HIV/uso terapêutico , China/epidemiologia , Feminino , Infecções por HIV/epidemiologia , HIV-1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Filogenia , Adulto Jovem
13.
PLoS One ; 15(5): e0232358, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32469876

RESUMO

BACKGROUND: Kenya's guidelines for prevention of mother-to-child transmission of HIV (PMTCT) recommend routine viral load (VL) monitoring for pregnant and breastfeeding women. METHOD: We assessed PMTCT VL monitoring and clinical action occurring between last menstrual period (LMP) and 6 months postpartum at 4 Kenyan government hospitals. Pregnant women enrolled in the HIV Infant Tracking System from May 2016-March 2018 were included. We computed proportions who received VL testing within recommended timeframes and who received clinical action after unsuppressed VL result. RESULTS: Of 424 participants, any VL testing was documented for 305 (72%) women and repeat VL testing was documented for 79 (19%). Only 115 women (27%) received a guideline-adherent baseline VL test and 27 (6%) received a guideline-adherent baseline and repeat VL test sequence. Return of baseline and repeat VL test results to the facility was high (average 96%), but patient notification of VL results was low (36% baseline and 49% repeat). Clinical action for unsuppressed VL results was even lower: 11 of 38 (29%) unsuppressed baseline results and 2 of 14 (14%) unsuppressed repeat results triggered clinical action. DISCUSSION: Guideline-adherent VL testing and clinical intervention during PMTCT must be prioritized to improve maternal care and reduce the risk of HIV transmission to infants.


Assuntos
HIV/fisiologia , Hospitais/estatística & dados numéricos , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Mães , Carga Viral , Adulto , Fármacos Anti-HIV/farmacologia , Feminino , HIV/efeitos dos fármacos , Humanos , Lactente , Gravidez
14.
Nat Commun ; 11(1): 1830, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286350

RESUMO

A synthetic biology method based on heterologous biosynthesis coupled with genome mining is a promising approach for increasing the opportunities to rationally access natural product with novel structures and biological activities through total biosynthesis and combinatorial biosynthesis. Here, we demonstrate the advantage of the synthetic biology method to explore biological activity-related chemical space through the comprehensive heterologous biosynthesis of fungal decalin-containing diterpenoid pyrones (DDPs). Genome mining reveals putative DDP biosynthetic gene clusters distributed in five fungal genera. In addition, we design extended DDP pathways by combinatorial biosynthesis. In total, ten DDP pathways, including five native pathways, four extended pathways and one shunt pathway, are heterologously reconstituted in a genetically tractable heterologous host, Aspergillus oryzae, resulting in the production of 22 DDPs, including 15 new analogues. We also demonstrate the advantage of expanding the diversity of DDPs to probe various bioactive molecules through a wide range of biological evaluations.


Assuntos
Diterpenos/farmacologia , Fungos/química , Naftalenos/farmacologia , Pironas/farmacologia , Biologia Sintética , Peptídeos beta-Amiloides/metabolismo , Animais , Fármacos Anti-HIV/farmacologia , Aspergillus/química , Vias Biossintéticas/efeitos dos fármacos , Vias Biossintéticas/genética , Proliferação de Células/efeitos dos fármacos , Diterpenos/química , Drosophila/efeitos dos fármacos , Fungos/genética , Genoma Fúngico , HIV-1/efeitos dos fármacos , Humanos , Células MCF-7 , Naftalenos/química , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Agregados Proteicos , Pironas/química , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Estereoisomerismo
15.
PLoS One ; 15(4): e0232104, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32324800

RESUMO

BACKGROUND: While the scale-up of HIV services has improved national health management information systems (HMIS), there remain challenges in using routine data to guide the introduction of optimized antiretroviral (ARV) drugs. METHODS: Building on the recent enhancements to the HMIS in Kenya and coinciding with the introduction of a new ARV regimen, tenofovir+lamivudine+dolutegravir (TLD), we developed and implemented an enhanced data system (EDS) to improve availability of safety and efficacy data among people living with HIV (PLHIV) in Kenya. Using data from one health facility, we showcase how the EDS can be used to monitor ARV transition and identify missed opportunities to transition eligible patients to optimized regimes. RESULTS: The EDS was designed to create a comprehensive PLHIV database by triangulating patient-level data from the EMR, the pharmacy ARV dispensing tool (ADT) and HIV viral load (VL) databases. On a monthly basis, the database is de-identified and uploaded into a national data warehouse, with interactive dashboards. Using the EDS, we determined that of the 5,500 PLHIV ≥15 years on first-line ART at one facility, 4,233 (77%) had transitioned to optimized ARVs. Of the 1,267 still on legacy regimens, 459 (36%) were determined to be eligible and prioritized to switch. CONCLUSIONS: This project illustrates how enhancements to the national HMIS can facilitate the use of routine patient-level data to monitor the transition to new ARVs and inform the national HIV response.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Sistemas de Dados , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/farmacologia , Sistemas de Gerenciamento de Base de Dados , Monitoramento de Medicamentos , Infecções por HIV/virologia , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Quênia , Lamivudina/uso terapêutico , Tenofovir/uso terapêutico , Resultado do Tratamento , Carga Viral/métodos
16.
J Nat Med ; 74(3): 571-578, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32328863

RESUMO

Three new quassinoids, javanicinols A and B (1 and 2) and 4-keto-(16S)-methoxyjavanicin B (3), together with three known quassinoids (4-6) were isolated from the chloroform-soluble fraction of the methanol extract of the Picrasma javanica wood. The structures of 1-3 were determined by spectroscopic analyses, including 1D and 2D NMR, HRESIMS, and CD. The anti-HIV-1 viral protein R (Vpr) assay revealed that 1 and 2 exhibited potent anti-Vpr activities at 1.25 µM. Furthermore, the assay also revealed the potent anti-Vpr activities of (16R)-methoxyjavanicin B (7) and (16S)-methoxyjavanicin B (8), which were previously isolated from the Picrasma javanica wood.


Assuntos
Fármacos Anti-HIV/farmacologia , Produtos do Gene vpr/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Picrasma/química , Quassinas/farmacologia , Fármacos Anti-HIV/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Quassinas/química , Quassinas/isolamento & purificação , Madeira/química
17.
Proc Natl Acad Sci U S A ; 117(19): 10286-10293, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32341150

RESUMO

HIV-1 maturation involves conversion of the immature Gag polyprotein lattice, which lines the inner surface of the viral membrane, to the mature capsid protein (CA) lattice, which encloses the viral RNA. Maturation inhibitors such as bevirimat (BVM) bind within six-helix bundles, formed by a segment that spans the junction between the CA and spacer peptide 1 (SP1) subunits of Gag, and interfere with cleavage between CA and SP1 catalyzed by the HIV-1 protease (PR). We report solid-state NMR (ssNMR) measurements on spherical virus-like particles (VLPs), facilitated by segmental isotopic labeling, that provide information about effects of BVM on the structure and dynamics of CA-SP1 junction helices in the immature lattice. Although BVM strongly blocks PR-catalyzed CA-SP1 cleavage in VLPs and blocks conversion of VLPs to tubular CA assemblies, 15N and 13C ssNMR chemical shifts of segmentally labeled VLPs with and without BVM are very similar, indicating that interaction with BVM does not alter the six-helix bundle structure appreciably. Only the 15N chemical shift of A280 (the first residue of SP1) changes significantly, consistent with BVM binding to an internal ring of hydrophobic side chains of L279 residues. Measurements of transverse 15N spin relaxation rates reveal a reduction in the amplitudes and/or timescales of backbone N-H bond motions, corresponding to a rigidification of the six-helix bundles. Overall, our data show that inhibition of HIV-1 maturation by BVM involves changes in structure and dynamics that are surprisingly subtle, but still sufficient to produce a large effect on CA-SP1 cleavage.


Assuntos
Proteínas do Capsídeo/química , HIV-1/efeitos dos fármacos , Fragmentos de Peptídeos/química , Succinatos/farmacologia , Triterpenos/farmacologia , Vírion/efeitos dos fármacos , Replicação Viral , Produtos do Gene gag do Vírus da Imunodeficiência Humana/metabolismo , Fármacos Anti-HIV/farmacologia , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/metabolismo , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/genética , HIV-1/metabolismo , Humanos , Modelos Moleculares , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Conformação Proteica , Vírion/genética , Vírion/metabolismo , Montagem de Vírus , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética
18.
PLoS One ; 15(4): e0231031, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32267869

RESUMO

Acquisition of resistance mutations by HIV-1 isolates causes treatment failure among infected patients receiving antiretroviral therapy (ART). This study determined patterns of drug-resistance mutations (DRMs) among HIV-1 isolates from patients receiving first-line ART in South-eastern Nigeria. Blood samples were collected from HIV-1 infected patients accessing antiretroviral treatment centers at General Hospital Awo-Omamma, Imo state, State Hospital Asaba, Delta state and St Joseph's Catholic Hospital Adazi, Anambra state and used for HIV-1 DNA sequencing and phylogenetic analysis. DRMs were scored using combination of Stanford algorithm and the 2015 International Antiviral Society-USA list while drug susceptibility was predicted using Stanford algorithm. Twenty eight of the HIV-1 isolates were sequenced and identified as subtypes G (35.7%), CRF02_AG (57.1%) and unclassifiable, UG (7.1%). Major PI resistance-associated mutations were identified at two sites including M46L (16.7% of subtype G/UG) and V82L (6.3% of CRF02_AG). Minor PI resistance-associated mutations identified among subtype G/UG are L10V/I (8.3%) and K20I (100%) while L10V/I (50%), K20I (100%), L33F (6.3%) and N88D (6.3%) were identified among CRF02_AG. Other polymorphisms found include; I13V/A, E35Q, M36I/L, N37D/S/E/H, R57K/G, L63T/P/S/Q, C67E/S, H69K/R, K70R, V82I and L89M in the range of 28.6% to 100% among the different subtypes. Interpretation based on Stanford algorithm showed that Darunavir/ritonavir is the only regimen whose potency was not compromised by the circulating mutations. Identification of major and minor PI resistance mutations in this study underscores the need for drug resistance testing prior to initiation of second line antiretroviral therapy in Nigeria.


Assuntos
Fármacos Anti-HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Adulto , Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral/genética , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Inibidores da Protease de HIV/uso terapêutico , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Nigéria , Filogenia , Reação em Cadeia da Polimerase , Polimorfismo Genético/genética , Alinhamento de Sequência , Análise de Sequência de DNA
19.
Artigo em Inglês | MEDLINE | ID: mdl-32164970

RESUMO

Emtricitabine (Emtriva, FTC) is an antiviral medicine which decreases the body's amount of HIV. Emtricitabine on of Anti-HIV drugs slow down or protect the immune system against damage and reduce the risk of diseases related to developing of AIDS. Emtricitabine use also for treatment of hepatitis B virus. Emtricitabine is a drug class known as nucleoside reversing transcriptase inhibitors (NRTIs). In view of Emtricitabine's clinical significance, a thorough review of the physical and pharmaceutical characteristics and details of the multiple analytical techniques used to test the drug in pharmaceutical and biological systems was conducted. The methods investigated include identification test, Spectroscopy, chromatography, electrochemicals, and Thermal. Beside the analytical profile, the degradation and stability of Emtricitabine, its pharmacology and pharmacokinetics, Pharmaceutical Applications, Mechanism of Action, dosage forms and dose, ADME profile, and interactions have been debated.


Assuntos
Fármacos Anti-HIV/farmacologia , Emtricitabina/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Infecções por HIV/tratamento farmacológico , Hepatite B/tratamento farmacológico , Humanos
20.
Nat Chem Biol ; 16(5): 529-537, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32152540

RESUMO

Combination antiretroviral therapy has transformed HIV-1 infection, once a fatal illness, into a manageable chronic condition. Drug resistance, severe side effects and treatment noncompliance bring challenges to combination antiretroviral therapy implementation in clinical settings and indicate the need for additional molecular targets. Here, we have identified several small-molecule fusion inhibitors, guided by a neutralizing antibody, against an extensively studied vaccine target-the membrane proximal external region (MPER) of the HIV-1 envelope spike. These compounds specifically inhibit the HIV-1 envelope-mediated membrane fusion by blocking CD4-induced conformational changes. An NMR structure of one compound complexed with a trimeric MPER construct reveals that the compound partially inserts into a hydrophobic pocket formed exclusively by the MPER residues, thereby stabilizing its prefusion conformation. These results suggest that the MPER is a potential therapeutic target for developing fusion inhibitors and that strategies employing an antibody-guided search for novel therapeutics may be applied to other human diseases.


Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Proteína gp41 do Envelope de HIV/química , Proteína gp41 do Envelope de HIV/metabolismo , Internalização do Vírus/efeitos dos fármacos , Sítios de Ligação , Antígenos CD4/metabolismo , Membrana Celular/metabolismo , Dequalínio/química , Dequalínio/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Polarização de Fluorescência , Células HEK293 , Proteína gp41 do Envelope de HIV/genética , HIV-1/patogenicidade , Humanos , Interações Hidrofóbicas e Hidrofílicas , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Mutação , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Ressonância de Plasmônio de Superfície
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