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1.
Molecules ; 24(19)2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31561445

RESUMO

In spite of significant advancements and success in antiretroviral therapies directed against HIV infection, there is no cure for HIV, which scan persist in a human body in its latent form and become reactivated under favorable conditions. Therefore, novel antiretroviral drugs with different modes of actions are still a major focus for researchers. In particular, novel lead structures are being sought from natural sources. So far, a number of compounds from marine organisms have been identified as promising therapeutics for HIV infection. Therefore, in this paper, we provide an overview of marine natural products that were first identified in the period between 2013 and 2018 that could be potentially used, or further optimized, as novel antiretroviral agents. This pipeline includes the systematization of antiretroviral activities for several categories of marine structures including chitosan and its derivatives, sulfated polysaccharides, lectins, bromotyrosine derivatives, peptides, alkaloids, diterpenes, phlorotannins, and xanthones as well as adjuvants to the HAART therapy such as fish oil. We critically discuss the structures and activities of the most promising new marine anti-HIV compounds.


Assuntos
Antirretrovirais/química , Antirretrovirais/farmacologia , Organismos Aquáticos/química , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Desenvolvimento de Medicamentos , Óleos de Peixe/química , Óleos de Peixe/farmacologia , HIV-1/classificação , HIV-1/efeitos dos fármacos , Humanos , Relação Estrutura-Atividade
2.
Int J Nanomedicine ; 14: 6231-6247, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496683

RESUMO

Purpose: A palmitoylated prodrug of emtricitabine (FTC) was synthesized to extend the drug's half-life, antiretroviral activities and biodistribution. Methods: A modified FTC prodrug (MFTC) was synthesized by palmitoyl chloride esterification. MFTC's chemical structure was evaluated by nuclear magnetic resonance. The created hydrophobic prodrug nanocrystals were encased into a poloxamer surfactant and the pharmacokinetics (PK), biodistribution and antiretroviral activities of the nanoformulation (NMFTC) were assessed. The conversion of MFTC to FTC triphosphates was evaluated. Results: MFTC coated with poloxamer formed stable nanocrystals (NMFTC). NMFTC demonstrated an average particle size, polydispersity index and zeta potential of 350 nm, 0.24 and -20 mV, respectively. Drug encapsulation efficiency was 90%. NMFTC was readily taken up by human monocyte-derived macrophages yielding readily detected intracellular FTC triphosphates and an extended PK profile. Conclusion: NMFTC shows improved antiretroviral activities over native FTC. This is coordinate with its extended apparent half-life. The work represents an incremental advance in the development of a long-acting FTC formulation.


Assuntos
Composição de Medicamentos , Emtricitabina/farmacologia , Nanopartículas/química , Pró-Fármacos/farmacologia , Animais , Antirretrovirais/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Emtricitabina/sangue , Emtricitabina/síntese química , Emtricitabina/química , Humanos , Cinética , Macrófagos/efeitos dos fármacos , Masculino , Nanopartículas/ultraestrutura , Pró-Fármacos/síntese química , Pró-Fármacos/química , Espectroscopia de Prótons por Ressonância Magnética , Ratos Sprague-Dawley
3.
Infect Dis Clin North Am ; 33(3): 787-805, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31395145

RESUMO

Antiretroviral therapy has advanced significantly since zidovudine was first approved. Although 31 antiretrovirals have been approved by the FDA, only about half of those are commonly used. Newer, more tolerable agents have made human immunodeficiency virus into a chronic condition, which can be managed with medication. The most common antiretroviral regimens consist of 2 nucleoside reverse transcriptase inhibitors plus a third agent, often an integrase inhibitor because of better tolerability and fewer drug interactions than other regimens. Understanding the dosage forms, adverse effects, and drug interactions of antiretrovirals allow clinicians to choose the most appropriate regimen for their patient. New developments, such as branded generic regimens and long-acting intramuscular injections, may play a larger role in the future.


Assuntos
Antirretrovirais/administração & dosagem , Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , Antirretrovirais/efeitos adversos , Antirretrovirais/farmacocinética , Antirretrovirais/farmacologia , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Interações de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos
4.
Infect Dis Clin North Am ; 33(3): 707-742, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31255384

RESUMO

Approximately 20% of people with HIV in the United States prescribed antiretroviral therapy are not virally suppressed. Thus, optimal management of virologic failure has a critical role in the ability to improve viral suppression rates to improve long-term health outcomes for those infected and to achieve epidemic control. This article discusses the causes of virologic failure, the use of resistance testing to guide management after failure, interpretation and relevance of HIV drug resistance patterns, considerations for selection of second-line and salvage therapies, and management of virologic failure in special populations.


Assuntos
Antirretrovirais/farmacologia , Antirretrovirais/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Gerenciamento Clínico , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , HIV/efeitos dos fármacos , Infecções por HIV/virologia , Humanos , Resposta Viral Sustentada , Falha de Tratamento , Estados Unidos
5.
J Pharm Biomed Anal ; 174: 588-594, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31261040

RESUMO

Dolutegravir was approved by USFDA, Canada and European regulatory authorities as antiretroviral medication. In this article, DLG forced degradation studies as per the International Council for Harmonization (ICH) prescribed stress conditions was conducted and the resulting degradants were fully characterized. DLG was stable in basic, thermal and photolytic stress conditions, whereas DLG was found to unstable in acidic and oxidative conditions. One degradant each from acid and peroxide treated solutions was resolved on LC-MS and labelled as DP-1 and DP-2 with RT 1.80 min and 1.41 min, respectively. DP-1 and DP-2 were isolated by preparative HPLC with C18 column using gradient elution method. Subsequently DP-1 and DP-2 peaks were subjected to HRMS for accurate mass. Molecular mass of DP-1 and DP-2 were m/z 420.1379 (positive mode) and m/z 214.0319 (negative mode), respectively. Further, DP-1 & DP-2 were subjected to NMR spectroscopic analysis (including 2D) for structural confirmation. DP-1 was identified as N-(2,4-difluorobenzyl)-9-hydroxy-2-(4-hydroxybutan-2-yl)-1,8-dioxo-2,8-dihydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide and it is earlier reported by Gudisela et al. [19] as DLG process impurity. DP-2 was identified as 2-(2,4difluorobenzylamino)-2-oxoacetic acid which is novel DLG degradant and not reported earlier to the best of our knowledge. DLG along its forced degradation products were found to be non-cytotoxic in in vitro assay conditions using HepG2 cells.


Assuntos
Antirretrovirais/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Células Hep G2 , Humanos , Hidrólise , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Oxirredução , Fotólise , Espectrometria de Massas por Ionização por Electrospray , Espectroscopia de Infravermelho com Transformada de Fourier
6.
Curr HIV Res ; 17(2): 134-145, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31309891

RESUMO

BACKGROUND: Viral kinetics impact humoral immune response to HIV; antibody avidity testing helps distinguish recent (<6 months) and long-term HIV infection. This study aims to determine the frequency of recent HIV-1 infection among clients attending ICTC (Integrated Counselling and Testing Centre) using a commercial EIA, to correlate it with a modified in-house avidity assay and to study the impact of ART on anti-HIV-1 antibody maturation. METHODS: Commercial LAg Avidity EIA was used to detect antibody avidity among 117 treatment naïve HIV-1 infected individuals. A second-generation HIV ELISA was modified for in-house antibody avidity testing and cutoff was set based on Receiver Operating Characteristic (ROC) analysis. Archived paired samples from 25 HIV-1 infected individuals before ART and after successful ART; samples from 7 individuals responding to ART and during virological failure were also tested by LAg Avidity EIA. RESULTS: Six individuals (5.1%) were identified as recently infected by a combination of LAg avidity assay and HIV-1 viral load testing. The modified in-house avidity assay demonstrated sensitivity and specificity of 100% and 98.2%, respectively, at AI=0.69 by ROC analysis. Median ODn values of individuals when responding to ART were significantly lower than pre-ART [4.136 (IQR 3.437- 4.827) vs 4.455 (IQR 3.748-5.120), p=0.006] whereas ODn values were higher during virological failure [4.260 (IQR 3.665 - 4.515) vs 2.868 (IQR 2.247 - 3.921), p=0.16]. CONCLUSION: This modified in-house antibody avidity assay is an inexpensive method to detect recent HIV-1 infection. ART demonstrated significant effect on HIV-1 antibody avidity owing to changes in viral kinetics.


Assuntos
Antirretrovirais/farmacologia , Afinidade de Anticorpos/imunologia , Formação de Anticorpos/efeitos dos fármacos , Anticorpos Anti-HIV/imunologia , Infecções por HIV/diagnóstico , HIV-1 , Antirretrovirais/uso terapêutico , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática/normas , Anticorpos Anti-HIV/sangue , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Humanos , Sensibilidade e Especificidade
7.
Infect Dis Clin North Am ; 33(3): 681-692, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31239093

RESUMO

With the second-generation integrase inhibitors (dolutegravir and bictegravir) extending the attributes of earlier integrase inhibitors, three-drug regimens containing integrase inhibitors plus two nucleos(t)ide reverse transcriptase inhibitors are now widely recommended for first-line (initial) treatment of human immunodeficiency virus-1 infection. Led by dolutegravir plus lamivudine, two-drug therapy is emerging as a way to reduce antiretroviral therapy cost and adverse effects without compromising treatment options should virologic failure occur. Initial two-drug therapy has limitations, including the relative incompatibility with the coemerging concept of same-day antiretroviral therapy initiation.


Assuntos
Antirretrovirais/administração & dosagem , Antirretrovirais/farmacologia , Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/farmacologia , Antirretrovirais/efeitos adversos , Antirretrovirais/economia , Inibidores de Integrase de HIV/efeitos adversos , Inibidores de Integrase de HIV/economia , HIV-1/efeitos dos fármacos , Humanos , Resultado do Tratamento
8.
PLoS Comput Biol ; 15(6): e1007083, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31233494

RESUMO

The scale-up of antiretroviral therapy (ART) in South Africa substantially reduced AIDS-related deaths and new HIV infections. However, its success is threatened by the emergence of resistance to non-nucleoside reverse-transcriptase inhibitors (NNRTI). The MARISA (Modelling Antiretroviral drug Resistance In South Africa) model presented here aims at investigating the time trends and factors driving NNRTI resistance in South Africa. MARISA is a compartmental model that includes the key aspects of the local HIV epidemic: continuum of care, disease progression, and gender. The dynamics of NNRTI resistance emergence and transmission are then added to this framework. Model parameters are informed using data from HIV cohorts participating in the International epidemiology Databases to Evaluate AIDS (IeDEA) and literature estimates, or fitted to UNAIDS estimates. Using this novel approach of triangulating clinical and resistance data from various sources, MARISA reproduces the time trends of HIV in South Africa in 2005-2016, with a decrease in new infections, undiagnosed individuals, and AIDS-related deaths. MARISA captures the dynamics of the spread of NNRTI resistance: high levels of acquired drug resistance (ADR, in 83% of first-line treatment failures in 2016), and increasing transmitted drug resistance (TDR, in 8.1% of ART initiators in 2016). Simulation of counter-factual scenarios reflecting alternative public health policies shows that increasing treatment coverage would have resulted in fewer new infections and deaths, at the cost of higher TDR (11.6% in 2016 for doubling the treatment rate). Conversely, improving switching to second-line treatment would have led to lower TDR (6.5% in 2016 for doubling the switching rate) and fewer new infections and deaths. Implementing drug resistance testing would have had little impact. The rapid ART scale-up and inadequate switching to second-line treatment were the key drivers of the spread of NNRTI resistance in South Africa. However, even though some interventions could have substantially reduced the level of NNRTI resistance, no policy including NNRTI-based first line regimens could have prevented this spread. Thus, by combining epidemiological data on HIV in South Africa with biological data on resistance evolution, our modelling approach identified key factors driving NNRTI resistance, highlighting the need of alternative first-line regimens.


Assuntos
Antirretrovirais/farmacologia , Farmacorresistência Viral/efeitos dos fármacos , Infecções por HIV , HIV-1/efeitos dos fármacos , Modelos Biológicos , Adulto , Antirretrovirais/uso terapêutico , Biologia Computacional , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Humanos , Masculino , África do Sul
9.
Drug Des Devel Ther ; 13: 1667-1685, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31190745

RESUMO

Background: The protease inhibitor (PI) darunavir (DRV) has proven to be highly effective and well tolerated for HIV treatment. The DAD (Data collection on Adverse Effects of Anti-HIV Drugs) cohort showed an increased 5-year cumulative cardiovascular (CV) risk in patients given various PIs, including DRV, whereas two other recent studies found no association between DRV and CV diseases. Methods: We performed a post-hoc analysis of CV adverse events (CVAEs) in an Italian cohort, the TMC114-HIV4042 observational study, where 875 patients treated with ritonavir-boosted DRV-based regimens were followed for a total of 1,566 patient-years. Results: We observed 23 CVAEs of any type, including 17 [12 (95%CI, 7-19) per 1,000 patient-years] primary; 14 [10 (95%CI, 5-17) per 1,000 patient-years] were primary Framingham-type general CVAEs, close to what expected according to the Framingham algorithm based on traditional risk factors. Age and systolic blood pressure (SBP) at the time of study enrolment were the only relevant (p<0.01) independent predictors of CVAEs in all models; patients with any CVAE were on average 10 years older and had an SBP 14 mmHg higher than patients without CVAEs. When controlling for age and SBP, the association with other traditional factors, including serum lipids, and with HIV-specific factors was not statistically significant (p>0.05). Models that also adjusted for previous ARV exposure showed no statistically significant association between any-type CVAEs and either DRV doses, 1,200 or 800 mg/daily (as also suggested by propensity score stratification), or previous DRV exposure duration. Conclusion : We found no evidence of a relationship between DRV use and increased CV risk.


Assuntos
Antirretrovirais/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Darunavir/efeitos adversos , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/efeitos adversos , Adulto , Antirretrovirais/farmacologia , Estudos de Coortes , Darunavir/farmacologia , Relação Dose-Resposta a Droga , Feminino , Inibidores da Protease de HIV/farmacologia , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Fatores de Risco
10.
Biomolecules ; 9(6)2019 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-31208153

RESUMO

Interleukin-7 receptor subunit alpha (IL7RA) rs6897932 polymorphism is related to CD4+ recovery after combination antiretroviral therapy (cART), but no studies so far have analyzed its potential impact in patients with very low CD4+ T-cells count. We aimed to analyze the association between IL7RA rs6897932 polymorphism and CD4+ T-cells count restoration in HIV-infected patients starting combination antiretroviral therapy (cART) with CD4+ T-cells count <200 cells/mm3. We performed a retrospective study in 411 patients followed for 24 months with a DNA sample available for genotyping. The change in CD4+ T-cells count during the follow-up was considered as the primary outcome. The rs6897932 polymorphism had a minimum allele frequency (MAF) >20% and was in Hardy-Weinberg equilibrium (p = 0.550). Of 411 patients, 256 carried the CC genotype, while 155 had the CT/TT genotype. The CT/TT genotype was associated with a higher slope of CD4+ T-cells recovery (arithmetic mean ratio; AMR = 1.16; p = 0.016), higher CD4+ T-cells increase (AMR = 1.19; p = 0.004), and higher CD4+ T-cells count at the end of follow-up (AMR = 1.13; p = 0.006). Besides, rs6897932 CT/TT was related to a higher odds of having a value of CD4+ T-cells at the end of follow-up ≥500 CD4+ cells/mm3 (OR = 2.44; p = 0.006). After multiple testing correction (Benjamini-Hochberg), only the increase of ≥ 400 CD4+ cells/mm3 lost statistical significance (p = 0.052). IL7RA rs6897932 CT/TT genotype was related to a better CD4+ T-cells recovery and it could be used to improve the management of HIV-infected patients starting cART with CD4+ T-cells count <200 cells/mm3.


Assuntos
Antirretrovirais/farmacologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina-7/genética , Adulto , Antirretrovirais/uso terapêutico , Contagem de Linfócito CD4 , Interações de Medicamentos , Feminino , Genótipo , Infecções por HIV/imunologia , Humanos , Masculino , Pessoa de Meia-Idade
11.
Retrovirology ; 16(1): 13, 2019 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-31036006

RESUMO

BACKGROUND: HIV-1 patients receiving combination antiretroviral therapy (cART) survive infection but require life-long adherence at high expense. In chronic cART-treated patients with undetectable viral titers, cell-associated viral RNA is still detectable, pointing to low-level viral transcriptional leakiness. To date, there are no FDA-approved drugs against HIV-1 transcription. We have previously shown that F07#13, a third generation Tat peptide mimetic with competitive activity against Cdk9/T1-Tat binding sites, inhibits HIV-1 transcription in vitro and in vivo. RESULTS: Here, we demonstrate that increasing concentrations of F07#13 (0.01, 0.1, 1 µM) cause a decrease in Tat levels in a dose-dependent manner by inhibiting the Cdk9/T1-Tat complex formation and subsequent ubiquitin-mediated Tat sequestration and degradation. Our data indicate that complexes I and IV contain distinct patterns of ubiquitinated Tat and that transcriptional inhibition induced by F07#13 causes an overall reduction in Tat levels. This reduction may be triggered by F07#13 but ultimately is mediated by TAR-gag viral RNAs that bind suppressive transcription factors (similar to 7SK, NRON, HOTAIR, and Xist lncRNAs) to enhance transcriptional gene silencing and latency. These RNAs complex with PRC2, Sin3A, and Cul4B, resulting in epigenetic modifications. Finally, we observed an F07#13-mediated decrease of viral burden by targeting the R region of the long terminal repeat (HIV-1 promoter region, LTR), promoting both paused polymerases and increased efficiency of CRISPR/Cas9 editing in infected cells. This implies that gene editing may be best performed under a repressed transcriptional state. CONCLUSIONS: Collectively, our results indicate that F07#13, which can terminate RNA Polymerase II at distinct sites, can generate scaffold RNAs, which may assemble into specific sets of "RNA Machines" that contribute to gene regulation. It remains to be seen whether these effects can also be seen in various clades that have varying promoter strength, mutant LTRs, and in patient samples.


Assuntos
Regulação Viral da Expressão Gênica/efeitos dos fármacos , HIV-1/genética , RNA não Traduzido/genética , Transcrição Genética , Antirretrovirais/farmacologia , Biomimética , Sistemas CRISPR-Cas , Linhagem Celular , Edição de Genes , Inativação Gênica , HIV-1/efeitos dos fármacos , Humanos , Regiões Promotoras Genéticas , RNA Viral/genética , Produtos do Gene tat do Vírus da Imunodeficiência Humana/química
12.
J Acquir Immune Defic Syndr ; 81(2): 163-165, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31095006

RESUMO

BACKGROUND: Progestin contraception has been linked to higher risk of female to male sexual HIV transmission. SETTING: A clinical trial among HIV-infected women in Lilongwe, Malawi, randomized to initiation of depomedroxyprogesterone acetate injectable or levonorgestrel implant, and followed for up to 33 months, with the outcome of HIV shedding in the genital tract. METHODS: We compared the frequency and magnitude of HIV genital shedding before and after initiation of contraception and between study arms among women receiving antiretroviral therapy (ART). Genital HIV RNA was measured in TearFlo Strips using the Abbott RealTime HIV-1 assay. RESULTS: Among 68 HIV-infected Malawian women on ART, randomization to depot medroxyprogesterone acetate compared with the levonorgestrel implant was not associated with genital shedding and neither progestin contraceptive was associated with increased HIV genital shedding, for up to 33 months after contraceptive initiation. Having detectable plasma HIV [adjusted risk ratio (RR) 10.5; 95% confidence interval (CI): 3.18 to 34.7] and detectable genital shedding before contraceptive initiation (adjusted RR 3.53; 95% CI: 1.31 to 9.47) were associated with a higher risk of detectable genital shedding after contraceptive initiation. Higher plasma efavirenz concentrations were associated with a lower risk of detectable genital shedding (adjusted RR 0.85; 95% CI: 0.73 to 0.99, per increase of 1000 ng/mL). CONCLUSION: Among HIV-infected women receiving ART, our results provide evidence that progestin contraception does not impact women's risk of transmission of HIV to partners. Our finding that detectable genital shedding before contraceptive initiation independently predicts shedding suggests that there may be other individual-level biological or behavioral factors that increase the risk for shedding.


Assuntos
Antirretrovirais/uso terapêutico , Anticoncepção , Infecções por HIV/tratamento farmacológico , Progestinas , Eliminação de Partículas Virais/efeitos dos fármacos , Adulto , Antirretrovirais/farmacologia , Benzoxazinas/sangue , Benzoxazinas/farmacologia , Colo do Útero/virologia , Anticoncepcionais Femininos/farmacologia , Implantes de Medicamento , Feminino , Seguimentos , Genitália Feminina , Infecções por HIV/transmissão , Infecções por HIV/virologia , Humanos , Levanogestrel/farmacologia , Levanogestrel/uso terapêutico , Malaui , Acetato de Medroxiprogesterona/farmacologia , Acetato de Medroxiprogesterona/uso terapêutico , Resultado do Tratamento
13.
Biomed Khim ; 65(2): 73-79, 2019 Feb.
Artigo em Russo | MEDLINE | ID: mdl-30950810

RESUMO

Despite significant advances in the application of highly active antiretroviral therapy, the development of new drugs for the treatment of HIV infection remains an important task because the existing drugs do not provide a complete cure, cause serious side effects and lead to the emergence of resistance. In 2015, a consortium of American and European scientists and specialists launched a project to create the SAVI (Synthetically Accessible Virtual Inventory) library. Its 2016 version of over 283 million structures of new easily synthesizable organic molecules, each annotated with a proposed synthetic route, were generated in silico for the purpose of searching for safer and more potent pharmacological substances. We have developed an algorithm for comparing large chemical databases (DB) based on the representation of structural formulas in SMILES codes, and evaluated the possibility of detecting new antiretroviral compounds in the SAVI database. After analyzing the intersection of SAVI with 97 million structures of the PubChem database, we found that only a small part of the SAVI (~0.015%) is represented in PubChem, which indicates a significant novelty of this virtual library. However, among those structures, 632 compounds tested for anti-HIV activity were detected, 41 of which had the desired activity. Thus, our studies for the first time demonstrated that SAVI is a promising source for the search for new anti-HIV compounds.


Assuntos
Antirretrovirais/farmacologia , Big Data , Bases de Dados de Compostos Químicos , Descoberta de Drogas , Algoritmos , Infecções por HIV , Humanos
14.
Drugs ; 79(6): 609-619, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30963509

RESUMO

Clinical studies have demonstrated that use of tenofovir disoproxil fumarate with or without emtricitabine as antiretroviral pre-exposure prophylaxis (PrEP) can decrease the risk of human immunodeficiency virus (HIV) acquisition when medication adherence is high. However, the potential for PrEP to promote antiretroviral resistance remains an important public health consideration. We performed a search of the medical literature to identify studies that address HIV drug resistance during PrEP use. In this review, we summarize findings about emergent drug resistance during clinical trials of PrEP, case reports of seroconversions in patients adherent to PrEP, and animal studies of PrEP effectiveness against drug-resistant viral strains. We also discuss the potential utility of novel PrEP formulations for protection against drug-resistant HIV, the impact of drug resistance on HIV treatment options, and mathematical models that estimate the potential contribution of PrEP to population-level drug resistance. Evidence suggests that selection for HIV drug resistance with PrEP use is infrequent and most likely to occur when PrEP is used during undiagnosed acute HIV infection. Breakthrough infections during PrEP use with high adherence are possible, but appear to be rare. The prevalence of drug-resistant HIV strains needs to be monitored as PrEP is scaled up. However, the benefit of a decreased HIV incidence with wider PrEP use is likely to outweigh the risk of harms from possible increases in the prevalence of HIV drug resistance.


Assuntos
Antirretrovirais/farmacologia , Farmacorresistência Viral/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Profilaxia Pré-Exposição/métodos , Tenofovir/farmacologia , Animais , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Antirretrovirais/uso terapêutico , Emtricitabina/uso terapêutico , Humanos , Tenofovir/uso terapêutico
15.
Can J Cardiol ; 35(3): 238-248, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30825947

RESUMO

Although the initial reports of increased cardiovascular (CV) disease in the setting of advanced AIDS were reported approximately 30 years ago, advances in antiretroviral therapy and immediate initiation of therapy on diagnosis have transformed what was once a deadly infectious disease into a chronic health condition. Accordingly, the types of CV diseases occurring in HIV have shifted from pericardial effusions and dilated cardiomyopathy to atherosclerosis and heart failure. The underlying pathophysiology of HIV-associated CV disease remains poorly understood, partly because of the rapidly evolving nature of HIV treatment and because clinical endpoints take many years to develop. The gut plays an important role in the early pathogenesis of HIV infection as HIV preferentially infects CD4+ T cells, 80% of which are located in gut mucosa. The loss of these T cells damages gut mucosa resulting in increased gut permeability and microbial translocation, which incites chronic inflammation and immune activation. Antiretroviral therapy does not cure HIV infection and immune abnormalities persist. These abnormalities correlate with mortality and CV events. The effects of antiretroviral therapy on CV risk are complex; treatment reduces inflammation and other markers of CV risk but induces lipid abnormalities, most commonly hypertriglyceridemia. On a molecular level, monocytes/macrophages, platelet reactivity, and immune cell activation, which play a role in the general population, may be heightened in the setting of HIV and contribute to HIV-associated atherosclerosis. Chronic inflammation represents an inviting therapeutic target in HIV, as it does in uninfected persons with atherosclerosis.


Assuntos
Antirretrovirais/farmacologia , Doenças Cardiovasculares , Infecções por HIV , Inflamação/imunologia , Doenças Cardiovasculares/classificação , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/prevenção & controle , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/fisiopatologia , Humanos , Hipertrigliceridemia/induzido quimicamente , Fatores de Risco
16.
Can J Cardiol ; 35(3): 270-279, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30825949

RESUMO

Understanding why persons with human immunodeficiency virus (HIV) have accelerated atherosclerosis and its sequelae, including coronary artery disease (CAD) and myocardial infarction, is necessary to provide appropriate care to a large and aging population with HIV. In this review, we delineate the diverse pathophysiologies underlying HIV-associated CAD and discuss how these are implicated in the clinical manifestations of CAD among persons with HIV. Several factors contribute to HIV-associated CAD, with chronic inflammation and immune activation likely representing the primary drivers. Increased monocyte activation, inflammation, and hyperlipidemia present in chronic HIV infection also mirror the pathophysiology of plaque rupture. Furthermore, mechanisms central to plaque erosion, such as activation of toll-like receptor 2 and formation of neutrophil extracellular traps, are also abundant in HIV. In addition to inflammation and immune activation in general, persons with HIV have a higher prevalence than uninfected persons of traditional cardiovascular risk factors, including dyslipidemia, hypertension, insulin resistance, and tobacco use. Antiretroviral therapies, although clearly necessary for HIV treatment and survival, have had varied effects on CAD, but newer generation regimens have reduced cardiovascular toxicities. From a clinical standpoint, this mix of risk factors is implicated in earlier CAD among persons with HIV than uninfected persons; whether the distribution and underlying plaque content of CAD for persons with HIV differs considerably from uninfected persons has not been definitively studied. Furthermore, the role of cardiovascular risk estimators in HIV remains unclear, as does the role of traditional and emerging therapies; no trials of CAD therapies powered to detect clinical events have been completed among persons with HIV.


Assuntos
Doença da Artéria Coronariana , Infecções por HIV/complicações , Antirretrovirais/farmacologia , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/imunologia , Doença da Artéria Coronariana/fisiopatologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Infecções por HIV/tratamento farmacológico , Humanos , Imunidade
17.
J Acquir Immune Defic Syndr ; 81(2): 207-215, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30865186

RESUMO

OBJECTIVE: Definitions of virological response vary from <50 up to 1000 copies of HIV-RNA/mL. Our previous models estimate the probability of HIV drug combinations reducing the viral load to <50 copies/mL, with no indication of whether higher thresholds of response may be achieved. Here, we describe the development of models that predict absolute viral load over time. METHODS: Two sets of random forest models were developed using 50,270 treatment change episodes from more than 20 countries. The models estimated viral load at different time points following the introduction of a new regimen from variables including baseline viral load, CD4 count, and treatment history. One set also used genotypes in their predictions. Independent data sets were used for evaluation. RESULTS: Both models achieved highly significant correlations between predicted and actual viral load changes (r = 0.67-0.68, mean absolute error of 0.73-0.74 log10 copies/mL). The models produced curves of virological response over time. Using failure definitions of <100, 400, or 1000 copies/mL, but not 50 copies/mL, both models were able to identify alternative regimens they predicted to be effective for the majority of cases where the new regimen prescribed in the clinic failed. CONCLUSIONS: These models could be useful for selecting the optimum combination therapy for patients requiring a change in therapy in settings using any definition of virological response. They also give an idea of the likely response curve over time. Given that genotypes are not required, these models could be a useful addition to the HIV-TRePS system for those in resource-limited settings.


Assuntos
Antirretrovirais/farmacologia , HIV/efeitos dos fármacos , Carga Viral/efeitos dos fármacos , Adulto , Antirretrovirais/uso terapêutico , Contagem de Linfócito CD4 , Quimioterapia Combinada , Feminino , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Masculino , Modelos Estatísticos , RNA Viral/sangue
19.
Int J Infect Dis ; 82: 124-128, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30904679

RESUMO

BACKGROUND: Protocols for HIV care are widely accepted by all international organizations and are proven to reduce mortality and complications from living with HIV. Unfortunately, executing best practice recommendations in Sierra Leone is difficult due to shortages in staff, training, and medications. METHODS: From June 2016 to August 2016, we implemented both an HIV guideline-based clinical evaluation protocol and a patient-centered workflow for TB screening and CD4 testing in the HIV clinic at Koidu Government Hospital (KGH) in rural Sierra Leone. The primary outcome of interest was how often this service center resulted in a clinically significant change in the patients' HIV regimen. Reasons for changing regimen included diagnosis of co-infection with tuberculosis (TB), diagnosis of clinical or presumed immunologic treatment failure of antiretroviral (ART) medications and, need for adherence to weight-based dosing in pediatric patients. FINDINGS: A total of 188 patients with HIV were seen in the clinic; 49 (26%) of these patients had a clinically significant change in their HIV regimen. The most common reason for regimen change was TB co-infection diagnosis in 38 (20%) patients. The other reasons for HIV regimen changes included: eight children whose ART was adjusted to meet appropriate levels for weight-based guidelines, five patients diagnosed with presumed immunologic treatment failure (some also co-infected with tuberculosis), and two patients with a serious side effect to ART. INTERPRETATION: A comprehensive, patient-centric HIV clinic can result in high rates of case detection for tuberculosis and recognition of immunological ART failure.


Assuntos
Antirretrovirais/farmacologia , Infecções por HIV/tratamento farmacológico , Tuberculose/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Coinfecção , Feminino , Infecções por HIV/complicações , Infecções por HIV/diagnóstico , Infecções por HIV/virologia , Humanos , Lactente , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Serra Leoa/epidemiologia , Falha de Tratamento , Tuberculose/complicações , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Adulto Jovem
20.
PLoS One ; 14(3): e0213086, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30856196

RESUMO

Invasive cervical cancer is the most prevalent cancer among women in Sub-Saharan Africa. In 2013, the World Health Organization (WHO) emitted recommendations to start Highly Active Antiretroviral Therapy (HAART) regardless of CD4 count. Although HAART has been shown to reduce the prevalence of high-risk human papillomavirus (HR-HPV) genotypes, it is unclear whether it confers a protective effect specifically for HPV 16. This review summarizes the existing evidence regarding the effect of HAART on HPV 16 infection, as this genotype may not be influenced by immunity level and explores its implications for Sub Saharan Africa. A comprehensive literature review was undertaken and quality assessment was carried out on the selected papers. Four cohort studies and three cross-sectional studies were identified for which the overall quality score assessment ranged from weak/moderate (Score of 1.8) to strong (Score of 3). The evidence yielded by our review was conflicting. Thus, the high heterogeneity between study populations and results did not allow us to draw any firm conclusions as to whether HAART has an impact on HPV 16 acquisition/prevalence. As only three studies were conducted in Africa, there are insufficient grounds for solid comparison between geographic regions. In light of inadequate data, HPV unvaccinated women on HAART should still receive more frequent follow-up.


Assuntos
Antirretrovirais/farmacologia , Terapia Antirretroviral de Alta Atividade/métodos , Papillomavirus Humano 16/efeitos dos fármacos , Infecções por Papillomavirus/epidemiologia , Neoplasias do Colo do Útero/tratamento farmacológico , Adulto , África ao Sul do Saara/epidemiologia , Antirretrovirais/uso terapêutico , Estudos Transversais , Feminino , Papillomavirus Humano 16/patogenicidade , Humanos , Pessoa de Meia-Idade , Infecções por Papillomavirus/prevenção & controle , Prevalência , Saúde Pública , Pesquisa Qualitativa , Neoplasias do Colo do Útero/virologia
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