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2.
Viruses ; 12(2)2020 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-31991877

RESUMO

Molecular cluster detection can be used to interrupt HIV transmission but is dependent on identifying clusters where transmission is likely. We characterized molecular cluster detection in Washington State, evaluated the current cluster investigation criteria, and developed a criterion using machine learning. The population living with HIV (PLWH) in Washington State, those with an analyzable genotype sequences, and those in clusters were described across demographic characteristics from 2015 to2018. The relationship between 3- and 12-month cluster growth and demographic, clinical, and temporal predictors were described, and a random forest model was fit using data from 2016 to 2017. The ability of this model to identify clusters with future transmission was compared to Centers for Disease Control and Prevention (CDC) and the Washington state criteria in 2018. The population with a genotype was similar to all PLWH, but people in a cluster were disproportionately white, male, and men who have sex with men. The clusters selected for investigation by the random forest model grew on average 2.3 cases (95% CI 1.1-1.4) in 3 months, which was not significantly larger than the CDC criteria (2.0 cases, 95% CI 0.5-3.4). Disparities in the cases analyzed suggest that molecular cluster detection may not benefit all populations. Jurisdictions should use auxiliary data sources for prediction or continue using established investigation criteria.


Assuntos
Análise por Conglomerados , Infecções por HIV/epidemiologia , HIV/genética , Monitoramento Epidemiológico , Feminino , Genótipo , Infecções por HIV/virologia , Humanos , Masculino , Epidemiologia Molecular , Estudos Retrospectivos , Aprendizado de Máquina Supervisionado , Washington/epidemiologia
3.
Talanta ; 206: 120201, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31514868

RESUMO

Human immunodeficiency virus (HIV) is a lentivirus that leads to acquired immunodeficiency syndrome (AIDS). With increasing awareness of AIDS emerging as a global public health threat, different HIV testing kits have been developed to detect antibodies (Ab) directed toward different parts of HIV. A great limitation of these tests is that they can not detect HIV antibodies during early virus infection. Therefore, to overcome this challenge, a wide range of biosensors have been developed for early diagnosis of HIV infection. A significant amount of these studies have been focused on the application of nanomaterials for improving the sensitivity and accuracy of the sensing methods. Following an introduction into this field, a first section of this review covers the synthesis and applicability of such nanomaterials as metal nanoparticles (NPs), quantum dots (QDs), carbon-based nanomaterials and metal nanoclusters (NCs). A second larger section covers the latest developments concerning nanomaterial-based biosensors for HIV diagnosis, with paying a special attention to the determination of CD4+ cells as a hall mark of HIV infection, HIV gene, HIV p24 core protein, HIV p17 peptide, HIV-1 virus-like particles (VLPs) and HIV related enzymes, particularly those that are passed on from the virus to the CD4+ T lymphocytes and are necessary for viral reproduction within the host cell. These studies are described in detail along with their diverse principles/mechanisms (e.g. electrochemistry, fluorescence, electromagnetic-piezoelectric, surface plasmon resonance (SPR), surface enhanced Raman spectroscopy (SERS) and colorimetry). Despite the significant progress in HIV biosensing in the last years, there is a great need for the development of point-of-care (POC) technologies which are affordable, robust, easy to use, portable, and possessing sufficient quantitative accuracy to enable clinical decision making. In the final section, the focus is on the portable sensing devices as a new standard of POC and personalized diagnostics.


Assuntos
Técnicas Biossensoriais/métodos , Infecções por HIV/diagnóstico , HIV , Nanoestruturas/química , Anticorpos Antivirais/análise , Anticorpos Antivirais/imunologia , Biomarcadores/análise , DNA Viral/análise , Diagnóstico Precoce , HIV/química , HIV/genética , HIV/imunologia , Humanos , Testes Imediatos , RNA Viral/análise , Proteínas Virais/análise
4.
PLoS One ; 14(12): e0216515, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31887110

RESUMO

The HIV genome is rich in A but not G or U and deficient in C. This nucleotide bias controls HIV phenotype by determining the highly unusual composition of all major HIV proteins. The bias is also responsible for the high frequency of narrow DNA minor groove sites in the double-stranded HIV genome as compared to cellular protein coding sequences and the bulk of the human genome. Since drugs that bind in the DNA minor groove disrupt nucleosomes on sequences that contain closely spaced oligo-A tracts which are prevalent in HIV DNA because of its bias, it was of interest to determine if these drugs exert this selective inhibitory effect on HIV chromatin. To test this possibility, nucleosomes were reconstituted onto five double-stranded DNA fragments from the HIV-1 pol gene in the presence and in the absence of several minor groove binding drugs (MGBDs). The results demonstrated that the MGBDs inhibited the assembly of nucleosomes onto all of the HIV-1 segments in a manner that was proportional to the A-bias, but had no detectable effect on the formation of nucleosomes on control cloned fragments or genomic DNA from chicken and human. Nucleosomes preassembled onto HIV DNA were also preferentially destabilized by the drugs as evidenced by enhanced nuclease accessibility in physiological ionic strength and by the preferential loss of the histone octamer in hyper-physiological salt solutions. The drugs also selectively disrupted HIV-containing nucleosomes in yeast as revealed by enhanced nuclease accessibility of the in vivo assembled HIV chromatin and reductions in superhelical densities of plasmid chromatin containing HIV sequences. A comparison of these results to the density of A-tracts in the HIV genome indicates that a large fraction of the nucleosomes that make up HIV chromatin should be preferred in vitro targets for the MGBDs. These results show that the MGBDs preferentially disrupt HIV-1 chromatin in vitro and in vivo and raise the possibility that non-toxic derivatives of certain MGBDs might serve as a novel class of anti-HIV agents.


Assuntos
Cromatina/efeitos dos fármacos , Cromatina/genética , HIV/genética , Sequência de Bases , Sítios de Ligação/genética , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina , Biologia Computacional/métodos , DNA/efeitos dos fármacos , DNA/genética , Genes pol/genética , HIV/metabolismo , Infecções por HIV/genética , Humanos
5.
PLoS Genet ; 15(11): e1008485, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31765391

RESUMO

Chimpanzees, humans' closest relatives, are in danger of extinction. Aside from direct human impacts such as hunting and habitat destruction, a key threat is transmissible disease. As humans continue to encroach upon their habitats, which shrink in size and grow in density, the risk of inter-population and cross-species viral transmission increases, a point dramatically made in the reverse with the global HIV/AIDS pandemic. Inhabiting central Africa, the four subspecies of chimpanzees differ in demographic history and geographical range, and are likely differentially adapted to their particular local environments. To quantitatively explore genetic adaptation, we investigated the genic enrichment for SNPs highly differentiated between chimpanzee subspecies. Previous analyses of such patterns in human populations exhibited limited evidence of adaptation. In contrast, chimpanzees show evidence of recent positive selection, with differences among subspecies. Specifically, we observe strong evidence of recent selection in eastern chimpanzees, with highly differentiated SNPs being uniquely enriched in genic sites in a way that is expected under recent adaptation but not under neutral evolution or background selection. These sites are enriched for genes involved in immune responses to pathogens, and for genes inferred to differentiate the immune response to infection by simian immunodeficiency virus (SIV) in natural vs. non-natural host species. Conversely, central chimpanzees exhibit an enrichment of signatures of positive selection only at cytokine receptors, due to selective sweeps in CCR3, CCR9 and CXCR6 -paralogs of CCR5 and CXCR4, the two major receptors utilized by HIV to enter human cells. Thus, our results suggest that positive selection has contributed to the genetic and phenotypic differentiation of chimpanzee subspecies, and that viruses likely play a predominate role in this differentiation, with SIV being a likely selective agent. Interestingly, our results suggest that SIV has elicited distinctive adaptive responses in these two chimpanzee subspecies.


Assuntos
Adaptação Fisiológica/genética , Imunidade Inata/genética , Pan troglodytes/genética , Seleção Genética/genética , Adaptação Fisiológica/imunologia , Animais , Demografia , Deriva Genética , Especiação Genética , HIV/genética , HIV/imunologia , HIV/patogenicidade , Humanos , Pan troglodytes/imunologia , Pan troglodytes/virologia , Polimorfismo de Nucleotídeo Único/genética , Receptores CCR/genética , Receptores CCR3/genética , Receptores CCR5/genética , Receptores CXCR4/genética , Receptores CXCR6/imunologia , Vírus da Imunodeficiência Símia/genética , Vírus da Imunodeficiência Símia/imunologia , Vírus da Imunodeficiência Símia/patogenicidade
6.
Org Biomol Chem ; 17(42): 9313-9320, 2019 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-31612165

RESUMO

Noncoding RNAs are increasingly promising drug targets yet ligand design is hindered by a paucity of methods that reveal driving factors in selective small molecule : RNA interactions, particularly given the difficulties of high-resolution structural characterization. HIV RNAs are excellent model systems for method development given their targeting history, known structure-function relationships, and the unmet need for more effective treatments. Herein we report a strategy combining synthetic diversification, profiling against multiple RNA targets, and predictive cheminformatic analysis to identify driving factors for selectivity and affinity of small molecules for distinct HIV RNA targets. Using this strategy, we discovered improved ligands for multiple targets and the first ligands for ESSV, an exonic splicing silencer critical to replication. Computational analysis revealed guiding principles for future designs and a predictive cheminformatics model of small molecule : RNA binding. These methods are expected to facilitate progress toward selective targeting of disease-causing RNAs.


Assuntos
Amilorida/química , HIV/genética , RNA Viral/química , Amilorida/farmacologia , Antivirais/química , Antivirais/farmacologia , Descoberta de Drogas , Conformação de Ácido Nucleico , Processamento de RNA , RNA Viral/genética , RNA Viral/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo
7.
J Korean Med Sci ; 34(38): e239, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31583868

RESUMO

From December 2006 to December 2016, 1,429 patients enrolled in the Korea human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) Cohort Study were investigated. Based on the year of diagnosis, the time interval between HIV diagnosis and initiation of antiretroviral therapy (ART) was analyzed by dividing it into 2 years. The more recent the diagnosis, the more likely rapid treatment was initiated (P < 0.001) and the proportion of patients starting ART on the same day of HIV diagnosis was increased in 2016 (6.5%) compared to that in 2006 (1.7%). No significant difference in the median values of CD4+ cell counts according to the diagnosis year was observed. In the past 20 years, the time from the HIV diagnosis to the initiation of ART was significantly reduced. Rapid treatment was being implemented at the HIV diagnosis, regardless of CD4+ cell count. Considering the perspective "treatment is prevention," access to more rapid treatment is necessary at the time of HIV diagnosis.


Assuntos
Infecções por HIV/diagnóstico , Adulto , Antirretrovirais/uso terapêutico , Contagem de Linfócito CD4 , Estudos de Coortes , Feminino , HIV/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , República da Coreia , Tempo para o Tratamento
8.
Arch Virol ; 164(12): 3019-3026, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31598843

RESUMO

Polyethyleneimine (PEI) is a chemical compound that used is as a carrier in gene therapy/delivery. Some studies have investigated the microbicidal potential and antiviral activity (prophylactic or therapeutic) of PEI and its derivatives. The aim of this study was to investigate the effect of branched polyethyleneimine (bPEI) on human immunodeficiency virus (HIV) replication. Infected cells were treated with bPEI for 36 hours, and the concentration of the viral protein P24 (as a virus replication marker) was determined in cell culture supernatants. This study indicated that bPEI increased HIV replication and decreased the viability of infected cells through cytotoxicity. The toxicity of bPEI its association with and cell death (apoptosis, autophagy and necrosis) have been reported in several studies. To investigate bPEI-induced cytotoxicity, we examined apoptosis and autophagy in cells treated with bPEI, and a significant increase in HIV viral load, the P24 antigen level, autophagy, and necrosis observed. Thus, treatment with bPEI leads to cytotoxicity and higher HIV virus yield.


Assuntos
Infecções por HIV/virologia , HIV/efeitos dos fármacos , Polietilenoimina/farmacologia , Replicação Viral/efeitos dos fármacos , Autofagia/efeitos dos fármacos , HIV/genética , HIV/fisiologia , Proteína do Núcleo p24 do HIV/genética , Proteína do Núcleo p24 do HIV/metabolismo , Infecções por HIV/fisiopatologia , Humanos , Polietilenoimina/química , Carga Viral/efeitos dos fármacos
9.
PLoS Med ; 16(9): e1002895, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31539371

RESUMO

BACKGROUND: The global transition to use of dolutegravir (DTG) in WHO-preferred regimens for HIV treatment is limited by lack of knowledge on use in pregnancy. Here we assessed the relationship between drug concentrations (pharmacokinetics, PK), including in breastmilk, and impact on viral suppression when initiated in the third trimester (T3). METHODS AND FINDINGS: In DolPHIN-1, HIV-infected treatment-naïve pregnant women (28-36 weeks of gestation, age 26 (19-42), weight 67kg (45-119), all Black African) in Uganda and South Africa were randomised 1:1 to dolutegravir (DTG) or efavirenz (EFV)-containing ART until 2 weeks post-partum (2wPP), between 9th March 2017 and 16th January 2018, with follow-up until six months postpartum. The primary endpoint was pharmacokinetics of DTG in women and breastfed infants; secondary endpoints included maternal and infant safety and viral suppression. Intensive pharmacokinetic sampling of DTG was undertaken at day 14 and 2wPP following administration of a medium-fat breakfast, with additional paired sampling between maternal plasma and cord blood, breastmilk and infant plasma. No differences in median baseline maternal age, gestation (31 vs 30 weeks), weight, obstetric history, viral load (4.5 log10 copies/mL both arms) and CD4 count (343 vs 466 cells/mm3) were observed between DTG (n = 29) and EFV (n = 31) arms. Although DTG Ctrough was below the target 324ng/mL (clinical EC90) in 9/28 (32%) mothers in the third trimester, transfer across the placenta (121% of plasma concentrations) and into breastmilk (3% of plasma concentrations), coupled with slower elimination, led to significant infant plasma exposures (3-8% of maternal exposures). Both regimens were well-tolerated with no significant differences in frequency of adverse events (two on DTG-ART, one on EFV-ART, all considered unrelated to drug). No congenital abnormalities were observed. DTG resulted in significantly faster viral suppression (P = 0.02) at the 2wPP visit, with median time to <50 copies/mL of 32 vs 72 days. Limitations related to the requirement to initiate EFV-ART prior to randomisation, and to continue DTG for only two weeks postpartum. CONCLUSION: Despite low plasma DTG exposures in the third trimester, transfer across the placenta and through breastfeeding was observed in this study, with persistence in infants likely due to slower metabolic clearance. HIV RNA suppression <50 copies/mL was twice as fast with DTG compared to EFV, suggesting DTG has potential to reduce risk of vertical transmission in mothers who are initiated on treatment late in pregnancy. TRIAL REGISTRATION: clinicaltrials.gov NCT02245022.


Assuntos
Benzoxazinas/farmacocinética , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/farmacocinética , HIV/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Inibidores da Transcriptase Reversa/farmacocinética , Adulto , Benzoxazinas/administração & dosagem , Benzoxazinas/efeitos adversos , Feminino , HIV/genética , HIV/crescimento & desenvolvimento , Infecções por HIV/diagnóstico , Infecções por HIV/transmissão , Infecções por HIV/virologia , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Recém-Nascido , Troca Materno-Fetal , Leite Humano/metabolismo , Gravidez , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/efeitos adversos , Medição de Risco , África do Sul , Resultado do Tratamento , Uganda , Carga Viral , Adulto Jovem
10.
Anal Chim Acta ; 1079: 139-145, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31387704

RESUMO

A short G-rich sequence with three G-tracts can form a G-triplex (G3), a recently identified noncanonical DNA structure. Until now, very limited functional study and application of G3 is reported. Herein, we integrated G3 with isothermal exponential amplification reaction (EXPAR) for achieving simple and sensitive biosensing strategy. In this strategy, the cascade EXPAR cycles produces larger numbers of short G-rich sequences, which self-assemble into G3 structure and then bind hemin to form G3/hemin DNAzyme. This G3/hemin DNAzyme-based EXPAR strategy could detect as low as 4.7 fM target DNA with colorimetric detection, and the sensitivity of G3/hemin DNAzyme-based EXPAR strategy was much higher than that of the conventional G-quadruplex/hemin DNAzyme-based EXPAR strategy. We explored the reason for higher sensitivity of G3/hemin DNAzyme-based EXPAR strategy. The experimental results demonstrated that G3/hemin DNAzyme is an ideal signal generator for EXPAR-based biosensing platform. This work opens a new avenue to develop effective signal amplification strategy for ultrasensitive biosensing. This work is also helpful for a deeper understanding of G3 structure and the future application of G3.


Assuntos
Técnicas Biossensoriais/métodos , Colorimetria/métodos , DNA Catalítico/química , DNA Viral/análise , DNA/química , Hemina/química , Pareamento Incorreto de Bases , Benzotiazóis/química , DNA/genética , DNA Catalítico/genética , DNA Viral/genética , HIV/genética , Peróxido de Hidrogênio/química , Indicadores e Reagentes/química , Limite de Detecção , Técnicas de Amplificação de Ácido Nucleico/métodos , Conformação de Ácido Nucleico , Hibridização de Ácido Nucleico , Ácidos Sulfônicos/química
12.
Cell Mol Life Sci ; 76(24): 4869-4886, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31377844

RESUMO

The chemokine system mediates acute inflammation by driving leukocyte migration to damaged or infected tissues. However, elevated expression of chemokines and their receptors can contribute to chronic inflammation and malignancy. Thus, great effort has been taken to target these molecules. The first hint of the druggability of the chemokine system was derived from the role of chemokine receptors in HIV infection. CCR5 and CXCR4 function as essential co-receptors for HIV entry, with the former accounting for most new HIV infections worldwide. Not by chance, an anti-CCR5 compound, maraviroc, was the first FDA-approved chemokine receptor-targeting drug. CCR5, by directing leukocytes to sites of inflammation and regulating their activation, also represents an important player in the inflammatory response. This function is shared with CCR2 and its selective ligand CCL2, which constitute the primary chemokine axis driving the recruitment of monocytes/macrophages to inflammatory sites. Both receptors are indeed involved in the pathogenesis of several immune-mediated diseases, and dual CCR5/CCR2 targeting is emerging as a more efficacious strategy than targeting either receptor alone in the treatment of complex human disorders. In this review, we focus on the distinctive and complementary contributions of CCR5 and CCR2/CCL2 in HIV infection, multiple sclerosis, liver fibrosis and associated hepatocellular carcinoma. The emerging therapeutic approaches based on the inhibition of these chemokine axes are highlighted.


Assuntos
Quimiocina CCL2/genética , Inflamação/genética , Receptores CCR2/genética , Receptores CCR5/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Marcação de Genes , HIV/genética , HIV/patogenicidade , Infecções por HIV/genética , Infecções por HIV/terapia , Infecções por HIV/virologia , Humanos , Inflamação/terapia , Cirrose Hepática/genética , Cirrose Hepática/terapia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Esclerose Múltipla/genética , Esclerose Múltipla/terapia
13.
Nucleic Acids Res ; 47(18): e104, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31418021

RESUMO

Long-read next-generation amplicon sequencing shows promise for studying complete genes or genomes from complex and diverse populations. Current long-read sequencing technologies have challenging error profiles, hindering data processing and incorporation into downstream analyses. Here we consider the problem of how to reconstruct, free of sequencing error, the true sequence variants and their associated frequencies from PacBio reads. Called 'amplicon denoising', this problem has been extensively studied for short-read sequencing technologies, but current solutions do not always successfully generalize to long reads with high indel error rates. We introduce two methods: one that runs nearly instantly and is very accurate for medium length reads and high template coverage, and another, slower method that is more robust when reads are very long or coverage is lower. On two Mock Virus Community datasets with ground truth, each sequenced on a different PacBio instrument, and on a number of simulated datasets, we compare our two approaches to each other and to existing algorithms. We outperform all tested methods in accuracy, with competitive run times even for our slower method, successfully discriminating templates that differ by a just single nucleotide. Julia implementations of Fast Amplicon Denoising (FAD) and Robust Amplicon Denoising (RAD), and a webserver interface, are freely available.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Metagenômica , RNA Ribossômico 16S/genética , Vírus/genética , Algoritmos , Técnicas de Visualização da Superfície Celular/métodos , HIV/genética , Filogenia , Alinhamento de Sequência , Anticorpos de Cadeia Única/genética , Software
14.
Int J Infect Dis ; 87: 185-192, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31446175

RESUMO

BACKGROUND: Community Treatment Initiative (CTI) was developed in northern Nigeria as an intervention to link a cohort of people living with HIV (PLHIV) who refused antiretroviral treatment through a conventional linkage method to care and treatment. The CTI attempted to take treatment to PLHIV in the community. METHODS: This was a non-control interventional study that evaluated the proportion of linkage-resistant PLHIV linked to treatment through the CTI in nine geographical areas. Data were collected between October and December 2015. Linkage-resistant PLHIV were identified and linked to treatment using the CTI. Data were analyzed using Excel and IBM SPSS version 20.0. The simple proportion was used to estimate the linkage-resistant PLHIV who were eventually linked and retained in care and who ultimately achieved virological suppression (viral load <1000 copies/ml). The Chi-square test was used and the level of significance set at a p-value of <0.05. RESULTS: An estimated 541 (20%) PLHIV (239 (44.2%) male, 302 (55.8%) female) seen from October to December 2015 refused linkage to treatment. This was statistically significant at a p-value of <0.0001. Three hundred and seventy-seven (69.7%) of the PLHIV who refused linkage to treatment eventually accepted treatment using an alternative community treatment method; this was significant (p<0.0001). The 6-month retention rate for PLHIV who accepted the alternative treatment method was 88.1% (n=332); this was significant (p<0.0001). Seventy-eight percent of those retained in care attained virological suppression. CONCLUSIONS: The CTI improved linkage to care and treatment for a cohort of linkage-resistant PLHIV. Focus on this cohort of linkage-resistant positive clients is required to achieve HIV epidemic control.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/psicologia , Recusa do Paciente ao Tratamento/estatística & dados numéricos , Adulto , Feminino , HIV/genética , HIV/isolamento & purificação , HIV/fisiologia , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Nigéria/epidemiologia , Características de Residência/estatística & dados numéricos , Carga Viral
15.
S Afr Med J ; 109(7): 511-515, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31266578

RESUMO

BACKGROUND: Advances in HIV management have improved treatment outcomes in the HIV-infected population. However, these advances have not been without multifaceted challenges. In sub-Saharan Africa, their impact is reflected in the increased emergence of HIV drug resistance mutations. With the rise in exposure of children to protease inhibitors (PIs), the possibility of increasing PI resistance remains a concern. OBJECTIVES: To describe a group of antiretroviral-experienced children with PI drug resistance mutations after failure on first- or second-line regimens in a public sector setting in South Africa. METHODS: This was a retrospective cohort study of 22 children perinatally infected with HIV who had HIV genotyping conducted between January 2011 and December 2017. RESULTS: Of the 236 children who had HIV genotyping conducted, 22 (9.3%) had evidence of HIV PI resistance mutations. Twenty-one of the 22 children (95.5%) had major mutations in the protease region of the HIV genome. Of these children, 66.7% (14/21) had loss of response to both boosted lopinavir and atazanavir, with boosted darunavir remaining susceptible in only 12 (57.1%). The most frequent major PI mutations were V82A (76.2%), M46I/M46L (76.2%), I54V (62.0%) and L76V (33.3%). CONCLUSIONS: We observed a high rate of PI resistance mutations, with a resulting loss of PIs that could be used in construction of third-line regimens. To build on improvements from the introduction of antiretroviral therapy, increased efforts are needed by both health professionals and caregivers to improve adherence measures in children perinatally infected with HIV.


Assuntos
Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Inibidores da Protease de HIV/administração & dosagem , Mutação , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Genótipo , HIV/efeitos dos fármacos , HIV/genética , Inibidores da Protease de HIV/farmacologia , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos
16.
PLoS One ; 14(7): e0219526, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31295293

RESUMO

BACKGROUND AND AIMS: Although combined antiretroviral treatment (cART) has improved overall survival of HIV infected patients, liver fibrosis and liver related-mortality still constitute major challenges in HIV positive patients. Collagen accumulates in the liver during fibrogenesis. Recent studies showed that circulating levels of extracellular matrix (ECM) fragments might reflect degree of portal hypertension and fibrosis stage in liver disease. In this study, we analyzed the correlation between liver fibrosis assessed by Fibroscan and levels of the formation and degradation markers of type III and IV collagen in HIV positive patients receiving cART. METHODS: 116 HIV positive patients (82.7% male, median age 47 years) were enrolled into the study. Liver stiffness and liver fat content were determined using a Fibroscan with integrated CAP function. We quantified ECM formation and degradation fragments of collagen III and IV: PRO-C3, PRO-C4, C3M and C4M. These fragments were measured in peripheral serum by using specific ELISAs. RESULTS: Fifteen (12.9%) out of the 116 HIV positive patients had relevant fibrosis with a liver stiffness ≥ 7.1 kPa, and 79 patients had relevant steatosis with a CAP value > 248 dB/m. Circulating PRO-C3 levels significantly correlated with increasing degree of liver fibrosis assessed by Fibroscan (p = 0.0005), as well as with APRI score (p = 0.015). Interestingly, circulating PRO-C3 levels were significantly correlated with bilirubin (p = 0.022), reduced platelet count (p = 0.0008) and low albumin levels (p = 0.001), suggesting the association of type III collagen deposition with impaired liver function. None of the other measured ECM components significantly correlated with fibrosis or steatosis. CONCLUSION: The formation marker of type III collagen, PRO-C3 not only reflects liver fibrosis, but might also mirror liver dysfunction in HIV positive patients receiving cART. Therefore, the circulating levels of PRO-C3 might be suitable to monitor progression of liver fibrosis and deterioration of liver function in HIV positive patients receiving cART.


Assuntos
Complemento C3/metabolismo , Complemento C4/metabolismo , Fígado Gorduroso/sangue , Infecções por HIV/sangue , Cirrose Hepática/sangue , Adulto , Antirretrovirais/administração & dosagem , Terapia Antirretroviral de Alta Atividade , Biomarcadores/sangue , Colágeno Tipo III/sangue , Colágeno Tipo IV/sangue , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Matriz Extracelular/genética , Fígado Gorduroso/patologia , Fígado Gorduroso/virologia , Feminino , HIV/genética , HIV/patogenicidade , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , Infecções por HIV/virologia , Humanos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade
17.
PLoS Med ; 16(5): e1002811, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31150380

RESUMO

BACKGROUND: Although the success of HIV treatment programs depends on retention and viral suppression, routine program monitoring of these outcomes may be incomplete. We used data from the national electronic medical record (EMR) system in Zambia to enumerate a large and regionally representative cohort of patients on treatment. We traced a random sample with unknown outcomes (lost to follow-up) to document true care status and HIV RNA levels. METHODS AND FINDINGS: On 31 July 2015, we selected facilities from 4 provinces in 12 joint strata defined by facility type and province with probability proportional to size. In each facility, we enumerated adults with at least 1 clinical encounter after treatment initiation in the previous 24 months. From this cohort, we identified lost-to-follow-up patients (defined as 90 or more days late for their last appointment), selected a random sample, and intensively reviewed their records and traced them via phone calls and in-person visits in the community. In 1 of 4 provinces, we also collected dried blood spots (DBSs) for plasma HIV RNA testing. We used inverse probability weights to incorporate sampling outcomes into Aalen-Johansen and Cox proportional hazards regression to estimate retention and viremia. We used a bias analysis approach to correct for the known inaccuracy of plasma HIV RNA levels obtained from DBSs. From a total of 64 facilities with 165,464 adults on ART, we selected 32 facilities with 104,966 patients, of whom 17,602 (17%) were lost to follow-up: Those lost to follow-up had median age 36 years, 60% were female (N = 11,241), they had median enrollment CD4 count of 220 cells/µl, and 38% had WHO stage 1 clinical disease (N = 10,690). We traced 2,892 (16%) and found updated outcomes for 2,163 (75%): 412 (19%) had died, 836 (39%) were alive and in care at their original clinic, 457 (21%) had transferred to a new clinic, 255 (12%) were alive and out of care, and 203 (9%) were alive but we were unable to determine care status. Estimates using data from the EMR only suggested that 42.7% (95% CI 38.0%-47.1%) of new ART starters and 72.3% (95% CI 71.8%-73.0%) of all ART users were retained at 2 years. After incorporating updated data through tracing, we found that 77.3% (95% CI 70.5%-84.0%) of new initiates and 91.2% (95% CI 90.5%-91.8%) of all ART users were retained (at original clinic or transferred), indicating that routine program data underestimated retention in care markedly. In Lusaka Province, HIV RNA levels greater than or equal to 1,000 copies/ml were present in 18.1% (95% CI 14.0%-22.3%) of patients in care, 71.3% (95% CI 58.2%-84.4%) of lost patients, and 24.7% (95% CI 21.0%-29.3%). The main study limitations were imperfect response rates and the use of self-reported care status. CONCLUSIONS: In this region of Zambia, routine program data underestimated retention, and the point prevalence of unsuppressed HIV RNA was high when lost patients were accounted for. Viremia was prevalent among patients who unofficially transferred: Sustained engagement remains a challenge among HIV patients in Zambia, and targeted sampling is an effective strategy to identify such gaps in the care cascade and monitor programmatic progress.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV/efeitos dos fármacos , Retenção nos Cuidados , Adulto , Registros Eletrônicos de Saúde , Feminino , HIV/genética , HIV/crescimento & desenvolvimento , Infecções por HIV/diagnóstico , Infecções por HIV/mortalidade , Humanos , Perda de Seguimento , Masculino , Adesão à Medicação , Prevalência , Avaliação de Programas e Projetos de Saúde , RNA Viral/sangue , Amostragem , Fatores de Tempo , Resultado do Tratamento , Carga Viral , Zâmbia/epidemiologia
18.
BMJ Case Rep ; 12(5)2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31118171

RESUMO

Anticollapsin-responsive mediator protein 5 (CRMP-5) IgG is an antibody generally associated with small-cell lung cancer, which is known to cause paraneoplastic neurological syndromes, including encephalitis, myelitis and neuropathy. HIV escape is a phenomenon in which a patient with low or undetectable levels of HIV RNA in plasma is found to have elevated levels in cerebrospinal fluid (CSF). We present a case of a 58-year-old HIV-positive woman with undetectable plasma viral load who developed a subacute flaccid paraparesis. Over the course of 4 months, she had a broad inflammatory and infectious workup that was unrevealing until repeat imaging showed an inflammatory myelitis. Workup was notable for elevated HIV RNA copies in CSF, as well as anti-CRMP-5 autoantibodies in serum. Despite changing her antiretroviral therapy and multiple modalities of immunomodulation, the patient failed to respond adequately to treatment. This case illustrates a complex clinical picture with a unique presentation of anti-CRMP-5 myelitis.


Assuntos
Sistema Nervoso Central/virologia , Infecções por HIV/líquido cefalorraquidiano , Hidrolases/imunologia , Proteínas Associadas aos Microtúbulos/imunologia , Mielite/imunologia , Antirretrovirais/uso terapêutico , Autoanticorpos/sangue , Feminino , HIV/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Imunoglobulina G/sangue , Pessoa de Meia-Idade , Mielite/tratamento farmacológico , Mielite/virologia , RNA Viral/líquido cefalorraquidiano , Resultado do Tratamento
19.
Invest Ophthalmol Vis Sci ; 60(6): 1853-1862, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31042791

RESUMO

Purpose: To evaluate risk factors for severity of cytomegalovirus (CMV) retinitis lesion whitening (opacity), using a standardized scoring system. Methods: We performed a cross-sectional, observational investigation of all individuals with newly diagnosed AIDS-related CMV retinitis in three randomized clinical trials and one prospective observational study. Opacity was scored by masked readers, using a prospectively defined ordinal 6-point scale. Demographic factors, laboratory data (CD4+, CD8+ T-lymphocyte counts, human immunodeficiency virus [HIV] blood levels), and lesion characteristics (location, size) were compared to the highest opacity score assigned to either eye. Among eyes with active lesions (scores ≥3), factors associated with severe opacity (scores 5, 6) were identified. Results: There were 299 participants (401 eyes with CMV retinitis). In one or more comparisons, increased opacity was associated with lower CD4+ and lower CD8+ T-lymphocyte counts, higher HIV blood level, lack of antiretroviral therapy, male sex, race/ethnicity, and bilateral disease. In eyes with active disease, severe opacity was associated with lower CD4+ T-lymphocyte count, higher HIV blood level, older age, Karnofsky score, lesion size, and bilateral disease. No relationship was identified between opacity and lesion location. Conclusions: Lesion border opacity (resulting from CMV activity) reflects level of immune function; as immunodeficiency becomes worse, CMV activity (and opacity) increases. The positive relationship between opacity and HIV blood level may reflect both immunodeficiency and increased CMV activity caused by transactivation of CMV by HIV. Scoring of opacity may be a useful, standard measure for continued study of CMV retinitis across different settings and populations. (Clinicaltrials.gov number for the HPMPC CMV Retinitis Trial: NCT00000142; Clinicaltrials.gov number for the Monoclonal Antibody CMV Retinitis Trial: NCT00000135; Clinicaltrials.gov number for the Ganciclovir-Cidofovir CMV Retinitis Trial: NCT0000014; Clinicaltrials.gov number for the Longitudinal Study of the Ocular Complications of AIDS: NCT00000168.).


Assuntos
Síndrome de Imunodeficiência Adquirida/diagnóstico , Retinite por Citomegalovirus/diagnóstico , HIV/genética , Retina/patologia , Síndrome de Imunodeficiência Adquirida/sangue , Síndrome de Imunodeficiência Adquirida/virologia , Adulto , Estudos Transversais , Retinite por Citomegalovirus/sangue , Retinite por Citomegalovirus/virologia , Feminino , Seguimentos , Humanos , Masculino , Estudos Prospectivos , RNA Viral/sangue , Índice de Gravidade de Doença
20.
Mol Biol Evol ; 36(9): 2069-2085, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31127303

RESUMO

The reconstruction of ancestral scenarios is widely used to study the evolution of characters along phylogenetic trees. One commonly uses the marginal posterior probabilities of the character states, or the joint reconstruction of the most likely scenario. However, marginal reconstructions provide users with state probabilities, which are difficult to interpret and visualize, whereas joint reconstructions select a unique state for every tree node and thus do not reflect the uncertainty of inferences. We propose a simple and fast approach, which is in between these two extremes. We use decision-theory concepts (namely, the Brier score) to associate each node in the tree to a set of likely states. A unique state is predicted in tree regions with low uncertainty, whereas several states are predicted in uncertain regions, typically around the tree root. To visualize the results, we cluster the neighboring nodes associated with the same states and use graph visualization tools. The method is implemented in the PastML program and web server. The results on simulated data demonstrate the accuracy and robustness of the approach. PastML was applied to the phylogeography of Dengue serotype 2 (DENV2), and the evolution of drug resistances in a large HIV data set. These analyses took a few minutes and provided convincing results. PastML retrieved the main transmission routes of human DENV2 and showed the uncertainty of the human-sylvatic DENV2 geographic origin. With HIV, the results show that resistance mutations mostly emerge independently under treatment pressure, but resistance clusters are found, corresponding to transmissions among untreated patients.


Assuntos
Biologia Computacional/métodos , Filogenia , Software , Teoria da Decisão , Vírus da Dengue/genética , HIV/genética
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