RESUMO
Rebound of SARS-CoV-2 shedding or COVID-19 signs and symptoms has been described after treatment with nirmatrelvir/ritonavir (Paxlovid). The direct association of nirmatrelvir/ritonavir to COVID-19 rebound remains unclear because most reports are based on individual cases or nonrandomized studies. Viral RNA shedding data from two phase 2/3, randomized, double-blind, placebo-controlled clinical trials of nirmatrelvir/ritonavir (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients [EPIC-HR] and Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients [EPIC-SR]) were analyzed to investigate the role of nirmatrelvir/ritonavir treatment in COVID-19 rebound. Rates of rebound of SARS-CoV-2 RNA shedding, identified based on an increase in nasopharyngeal viral RNA levels from day 5 (end-of-treatment) to day 10 or day 14, were similar between nirmatrelvir/ritonavir and placebo recipients. Among subjects with a virologic response through day 5, viral RNA rebound occurred in 6.4%-8.4% of nirmatrelvir/ritonavir recipients and 5.9%-6.5% of placebo recipients across EPIC-HR and the 2021/pre-Omicron and 2022/Omicron enrollment periods of EPIC-SR. Viral RNA rebound after nirmatrelvir/ritonavir treatment was not associated with COVID-19-related hospitalization or death. Data from randomized trials demonstrated that SARS-CoV-2 rebound can occur with or without antiviral treatment, supporting the Food and Drug Administration's determination of safety and efficacy of nirmatrelvir/ritonavir in eligible patients at high risk for severe COVID-19.
Assuntos
COVID-19 , RNA Viral , Humanos , Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Peptídeo Hidrolases , Ritonavir/uso terapêutico , SARS-CoV-2 , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
We analyzed post-treatment hepatitis C virus (HCV) RNA levels from 330 subjects who experienced virologic failure in clinical trials of direct-acting antivirals. We demonstrated that 97% had post-treatment Week 12 HCV RNA >10 000 IU/mL, above reported sensitivity limits of novel diagnostic assays being considered for simplified HCV treatment monitoring.
Assuntos
Antivirais , Hepatite C Crônica , Antivirais/uso terapêutico , Hepacivirus/genética , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/tratamento farmacológico , Humanos , RNA Viral , Resposta Viral SustentadaRESUMO
Several highly effective, interferon-free, direct-acting antiviral (DAA)-based regimens are available for the treatment of chronic hepatitis C virus (HCV) infection. Despite impressive efficacy overall, a small proportion of patients in registrational trials experienced treatment failure, which in some cases was associated with the detection of HCV resistance-associated substitutions (RASs) at baseline. In this article, we describe methods and key findings from independent regulatory analyses investigating the impact of baseline nonstructural (NS) 3 Q80K and NS5A RASs on the efficacy of current United States Food and Drug Administration (FDA)-approved regimens for patients with HCV genotype (GT) 1 or GT3 infection. These analyses focused on clinical trials that included patients who were previously naïve to the DAA class(es) in their investigational regimen and characterized the impact of baseline RASs that were enriched in the viral population as natural or transmitted polymorphisms (i.e., not drug-selected RASs). We used a consistent approach to optimize comparability of results across different DAA regimens and patient populations, including the use of a 15% sensitivity cutoff for next-generation sequencing results and standardized lists of NS5A RASs. These analyses confirmed that detection of NS3 Q80K or NS5A baseline RASs was associated with reduced treatment efficacy for multiple DAA regimens, but their impact was often minimized with the use of an intensified treatment regimen, such as a longer treatment duration and/or addition of ribavirin. We discuss the drug resistance-related considerations that contributed to pretreatment resistance testing and treatment recommendations in drug labeling for FDA-approved DAA regimens. CONCLUSION: Independent regulatory analyses confirmed that baseline HCV RASs can reduce the efficacy of certain DAA-based regimens in selected patient groups. However, highly effective treatment options are available for patients with or without baseline RASs. (Hepatology 2018;67:2430-2448).
Assuntos
Antivirais/farmacologia , Antivirais/uso terapêutico , Farmacorresistência Viral/genética , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Polimorfismo Genético , Combinação de Medicamentos , Humanos , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: Elbasvir (an NS5A inhibitor) and grazoprevir (an NS3/4A protease inhibitor) are direct-acting antiviral agents recently approved in the United States for treatment of chronic hepatitis C virus (HCV) genotype 1 and 4 infections, as a fixed-dose combination. Trials of elbasvir and grazoprevir, with or without ribavirin, demonstrated high rates of sustained virologic response 12 weeks after treatment ended (SVR12). However, 12 weeks of treatment with elbasvir and grazoprevir failed in a small proportion of patients with HCV genotype 1 infection. We summarize findings from independent US Food and Drug Administration analyses of drug resistance data from trials of elbasvir and grazoprevir, with and without ribavirin. METHODS: We independently analyzed HCV drug resistance and HCV RNA measurement results that were submitted to the US Food and Drug Administration to support the regulatory approval of elbasvir and grazoprevir. These data were reported from selected phase 2 and 3 clinical trials of elbasvir and grazoprevir, with and without ribavirin. Genotypic resistance analyses were conducted using Sanger population nucleotide sequencing data derived from blood samples from study patients. RESULTS: In 56 of 506 (11%) patients with HCV genotype 1a infection who received elbasvir and grazoprevir for 12 weeks, baseline HCV genetic variants encoding amino acid polymorphisms in NS5A (M28, Q30, L31, or Y93) reduced treatment efficacy; rates of SVR12 were 70% and 98% for patients with or without NS5A polymorphisms, respectively (P < .0001). Most patients with treatment failure acquired resistance-associated substitutions in NS3 and/or NS5A. Based on data from a small number of patients (n = 6), an intensified 16-week regimen of elbasvir and grazoprevir plus ribavirin could increase efficacy in patients with HCV genotype 1a infection with NS5A polymorphisms. Among patients with HCV genotype 4a or 4d infections with NS5A polymorphisms, all 26 who received the elbasvir and grazoprevir regimens recommended in prescribing information achieved an SVR12. CONCLUSIONS: The combination of elbasvir and grazoprevir, with or without ribavirin is safe and effective for patients with HCV genotype 1 or 4 infections. In patients with HCV genotype 1a infection, polymorphisms in NS5A at baseline (before treatment) can affect the efficacy of this direct-acting antiviral regimen, and pretreatment resistance analyses can optimize treatment selection.
Assuntos
Benzofuranos/uso terapêutico , Farmacorresistência Viral/genética , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Imidazóis/uso terapêutico , Quinoxalinas/uso terapêutico , RNA Viral/genética , Proteínas não Estruturais Virais/genética , Antivirais/uso terapêutico , Ensaios Clínicos como Assunto , Combinação de Medicamentos , Quimioterapia Combinada , Genótipo , Hepatite C Crônica/virologia , Humanos , Polimorfismo Genético , Ribavirina/uso terapêutico , Falha de Tratamento , Resultado do TratamentoRESUMO
UNLABELLED: Sofosbuvir (Sovaldi, SOF) is a nucleotide analog prodrug that targets the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) polymerase and inhibits viral replication. High sustained virological response rates are achieved when SOF is used in combination with ribavirin with or without pegylated interferon in subjects with chronic HCV infection. Potential mechanisms of HCV resistance to SOF and other nucleos(t)ide analog NS5B polymerase inhibitors are not well understood. SOF was the first U.S. Food and Drug Administration (FDA)-approved antiviral drug for which genotypic resistance analyses were based almost entirely on next-generation sequencing (NGS), an emerging technology that lacks a standard data analysis pipeline. The FDA Division of Antiviral Products developed an NGS analysis pipeline and performed independent analyses of NGS data from five SOF clinical trials. Additionally, structural bioinformatics approaches were used to characterize potential resistance-associated substitutions. Using protocols we developed, independent analyses of the NGS data reproduced results that were comparable to those reported by Gilead Sciences, Inc. Low-frequency, treatment-emergent substitutions occurring at conserved NS5B amino acid positions in subjects who experienced virological failure were also noted and further evaluated. The NS5B substitutions, L159F (sometimes in combination with L320F or C316N) and V321A, emerged in 2.2%-4.4% of subjects who failed SOF treatment across clinical trials. Moreover, baseline polymorphisms at position 316 were potentially associated with reduced response rates in HCV genotype 1b subjects. Analyses of these variants modeled in NS5B crystal structures indicated that all four substitutions could feasibly affect SOF anti-HCV activity. CONCLUSION: SOF has a high barrier to resistance; however, low-frequency NS5B substitutions associated with treatment failure were identified that may contribute to resistance of this important drug for chronic HCV infection.
Assuntos
Farmacorresistência Viral/genética , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Uridina Monofosfato/análogos & derivados , Proteínas não Estruturais Virais/genética , Substituição de Aminoácidos , Ensaios Clínicos Fase III como Assunto , Biologia Computacional , Hepacivirus/enzimologia , Humanos , Análise de Sequência de RNA , Sofosbuvir , Estados Unidos , United States Food and Drug Administration , Uridina Monofosfato/uso terapêutico , Proteínas não Estruturais Virais/metabolismoRESUMO
In clinical trials of interferon-free, direct-acting antiviral treatment of chronic hepatitis C, subjects who received ribavirin had reduced lymphocyte levels (median decline of approximately 0.4-0.5 × 10(9) cells/L). A modest decline in CD4(+) T cells was observed in subjects with human immunodeficiency virus type 1 coinfection without documented opportunistic infections.
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Antivirais/administração & dosagem , Antivirais/efeitos adversos , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/imunologia , Linfopenia/induzido quimicamente , Ribavirina/administração & dosagem , Ribavirina/efeitos adversos , Humanos , Contagem de LinfócitosRESUMO
Progressive multifocal leukoencephalopathy is a rare but devastating demyelinating disease caused by the JC virus (JCV), for which no therapeutics are approved. To make progress towards addressing this unmet medical need, innovations in clinical trial design are needed. Quantitative JCV DNA in CSF has the potential to serve as a valuable biomarker of progressive multifocal leukoencephalopathy disease and treatment response in clinical trials to expedite therapeutic development, as do neuroimaging and other fluid biomarkers such as neurofilament light chain. Specifically, JCV DNA in CSF could be used in clinical trials as an entry criterion, stratification factor, or predictor of clinical outcomes. Insights from the investigation of candidate biomarkers for progressive multifocal leukoencephalopathy might inform approaches to biomarker development for other rare diseases.
Assuntos
Vírus JC , Leucoencefalopatia Multifocal Progressiva , Humanos , Biomarcadores , Variações do Número de Cópias de DNA , DNA Viral/genética , Ensaios Clínicos como AssuntoRESUMO
Retrospective analyses of the boceprevir and telaprevir phase 3 trial data demonstrate the clinical relevance of detected but not quantifiable hepatitis C virus (HCV) genotype 1 RNA during treatment. These analyses illustrate the importance of using precise and standard terminology in reporting low-level HCV RNA results for consistent data collection across clinical trials, and to ensure optimal virologic response-guided treatment decision making in clinical practice. In the context of currently available quantitative HCV RNA assays, we clarify that unquantifiable HCV RNA should be classified as target detected or target not detected, as both have been shown to reflect clinically different qualitative HCV RNA levels during treatment. Additionally, use of terms such as "undetectable" or "below limit of detection" should be avoided as such terms are imprecise, not consistently defined, and often misinterpreted.
Assuntos
Antivirais/uso terapêutico , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , RNA Viral/sangue , Ensaios Clínicos como Assunto , Hepacivirus/efeitos dos fármacos , Humanos , Limite de Detecção , Oligopeptídeos/uso terapêutico , Prolina/análogos & derivados , Prolina/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento , Carga ViralRESUMO
UNLABELLED: Boceprevir- and telaprevir-based treatments for chronic hepatitis C virus (HCV) infection use specific response-guided therapy (RGT) guidelines. Eligibility for shortened treatment duration is based on achieving undetectable HCV RNA early during treatment. It is unclear whether a detected HCV RNA level that is below the assay lower limit of quantitation (detectable/BLOQ) is comparable to an undetectable HCV RNA level for RGT decision making. We analyzed data from boceprevir and telaprevir clinical trials to obtain a comprehensive understanding of the frequency and clinical relevance of detectable/BLOQ HCV RNA measurements. In Phase 3 trials P05216 (boceprevir), C216 (telaprevir), and 108 (telaprevir), detectable/BLOQ levels were reported for approximately 10%-20% of all on-treatment HCV RNA measurements. In P05216 and C216, subjects with detectable/BLOQ HCV RNA, on average, had a reduced sustained virologic response (SVR) rate compared with subjects with undetectable HCV RNA at the same on-treatment timepoint. At key RGT timepoints (week 8 for boceprevir, week 4 for telaprevir), subjects with detectable/BLOQ HCV RNA had an approximately 20% lower SVR rate compared with subjects with undetectable HCV RNA, and this difference widened for later on-treatment timepoints. A similar trend was observed for Study 108, but the differences in SVR rates were modest, potentially explained by a higher frequency of reported detectable/BLOQ results. Analyses of Phase 2 boceprevir and telaprevir trials indicated subjects with detectable/BLOQ HCV RNA at RGT timepoints benefited from extended treatment duration. CONCLUSION: During boceprevir- and telaprevir-based treatment, subjects with detectable/BLOQ HCV RNA had a reduced virologic response compared with subjects with undetectable HCV RNA. Eligibility for shortened treatment duration should be based on achieving undetectable HCV RNA (i.e., HCV RNA not detected) at RGT decision timepoints.
Assuntos
Hepacivirus/genética , Hepatite C Crônica/sangue , Hepatite C Crônica/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Prolina/análogos & derivados , RNA Viral/sangue , Antivirais/uso terapêutico , Biomarcadores/sangue , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Tomada de Decisões , Seguimentos , Humanos , Valor Preditivo dos Testes , Prolina/uso terapêutico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
A distinctive feature of chronic human immunodeficiency virus type 1 (HIV-1) infection is the presence of multiple coexisting genetic variants, or subpopulations, that comprise the HIV-1 population detected in the peripheral blood. Analysis of HIV-1 RNA decay dynamics during the initiation of highly active antiretroviral therapy (HAART) has been a valuable tool for modeling the life span of infected cells that produce the bulk HIV-1 population. However, different HIV-1 target cells may have different turnover rates, and it is not clear whether the bulk HIV-1 RNA decay rate actually represents a composite of the decay rates of viral subpopulations compartmentalized in different cellular subsets with different life spans. Using heteroduplex tracking assays targeting the highly variable V3 or V4-V5 regions of the HIV-1 env gene in eight subjects, we found that all detectable coexisting HIV-1 variants in the peripheral blood generally decayed at similar rates during the initiation of HAART, suggesting that all of the variants were produced by cells with similar life spans. Furthermore, single genome amplification and coreceptor phenotyping revealed that in two subjects coexisting HIV-1 variants with distinct CXCR4 or CCR5 coreceptor phenotypes decayed with similar rates. Also, in nine additional subjects, recombination and a lack of genetic compartmentalization between X4 and R5 variants were observed, suggesting an overlap in host cell range. Our results suggest that the HIV-1 env subpopulations detectable in the peripheral blood are produced by cells with similar life spans and are not genetically isolated within particular cell types.
Assuntos
Produtos do Gene env/imunologia , HIV-1/imunologia , Produtos do Gene env/genética , Produtos do Gene env/metabolismo , Infecções por HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/genética , HIV-1/metabolismo , Humanos , Filogenia , Receptores CCR5/genética , Receptores CCR5/imunologia , Receptores CCR5/metabolismo , Receptores CXCR4/genética , Receptores CXCR4/imunologia , Receptores CXCR4/metabolismoRESUMO
The development and ultimate approval of tecovirimat for the antiviral treatment of smallpox, a disease that has been eradicated from the world for nearly 40 years, required a unique regulatory approach based on the US Food and Drug Administration's Animal Rule. We summarise the regulatory pathway and describe the challenges involved.
Assuntos
Antivirais/uso terapêutico , Benzamidas/uso terapêutico , Aprovação de Drogas , Isoindóis/uso terapêutico , Varíola/tratamento farmacológico , Erradicação de Doenças , Humanos , Resultado do Tratamento , Estados Unidos , United States Food and Drug AdministrationRESUMO
Neurodevelopmental abnormalities associated with HIV infection have been described since the first reports of pediatric AIDS in the 1980s. Before antiretroviral therapy (ART) became widely available, progressive HIV-1 encephalopathy (PHE) was reported in the US in 13-35% of children with HIV-1 infection and in 35-50% of children with AIDS. Introduction of ART can prevent PHE and reverse PHE present at ART initiation, but a high prevalence of residual problems has been described. Even though 90% of HIV-infected children live in the developing world, few children have access to ART and little is known regarding the neurological manifestations of perinatal HIV infection in those regions. Mechanisms of pediatric HIV-1 neuropathogenesis and factors associated with neurodevelopmental abnormalities in perinatally infected children are not yet fully understood. Studies have demonstrated that HIV-1 enters the CNS soon after infection and may persist in this compartment over the entire course of HIV-1 infection. The CNS is a distinct viral reservoir, differing from peripheral compartments in target cells and antiretroviral penetration. Neurotropic HIV-1 likely develops distinct genotypic characteristics in response to this unique environment. We reviewed the literature on pediatric neuroAIDS and identified gaps in the current knowledge.
Assuntos
Deficiências do Desenvolvimento/virologia , Infecções por HIV/complicações , Infecções por HIV/psicologia , Doenças do Sistema Nervoso/virologia , Criança , HumanosRESUMO
Elbasvir/grazoprevir demonstrated high sustained virologic response rates 12 weeks after the end of treatment (SVR12) across five clinical trials in subjects infected with chronic hepatitis C virus (HCV) genotype 1, including those with advanced chronic kidney disease (CKD), and GT4. Despite favorable results overall, the US Food and Drug Administration (FDA) encountered challenging regulatory issues due to the limitations of clinical trial data in certain subpopulations. In GT1a-infected subjects, baseline NS5A resistance-associated polymorphisms emerged as the strongest baseline characteristic associated with diminished SVR12 rates following 12 weeks of elbasvir/grazoprevir treatment. The decision for recommending 16 weeks of elbasvir/grazoprevir + ribavirin in this population and for extrapolating these recommendations to patients with advanced CKD was based on benefit-versus-risk analyses using the available data. Conversely, FDA had insufficient data to define a specific elbasvir/grazoprevir treatment regimen for GT1a-infected subjects with baseline NS5A resistance-associated polymorphisms who failed prior treatment with pegylated interferon + ribavirin (PR) and either boceprevir, simeprevir, or telaprevir. For GT4 PR-experienced patients, leveraging of data in related populations and additional pooled analyses were employed to support labeling for elbasvir/grazoprevir. This article describes FDA's rationale for labeling determinations in situations where limited data made these decisions challenging.
Assuntos
Antivirais/administração & dosagem , Benzofuranos/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Imidazóis/administração & dosagem , Quinoxalinas/administração & dosagem , Antivirais/uso terapêutico , Combinação de Medicamentos , Genótipo , Hepacivirus/genética , Humanos , Insuficiência Renal Crônica/tratamento farmacológico , Ribavirina/administração & dosagem , Ribavirina/uso terapêutico , Resultado do TratamentoRESUMO
Human cytomegalovirus (HCMV) is a pathogen that can be life-threatening in immunocompromised individuals. Valganciclovir and its parent drug ganciclovir are currently the principle drugs used for the treatment or prevention of HCMV disease. The development of HCMV resistance to ganciclovir/valganciclovir has been documented in treated patients and is associated with the emergence of amino acid substitutions in the viral proteins pUL97, pUL54 or both. Generally, single amino acid substitutions associated with clinical resistance that alone do not confer decreased ganciclovir susceptibility in cell culture have been disregarded as causative or clinically significant. This review focuses on the analysis and mechanisms of antiviral drug resistance to HCMV. We also conducted a review of publicly available clinical and nonclinical data to construct a comprehensive list of pUL97 and pUL54 amino acid substitutions that are associated with a poor clinical response to the first line therapies ganciclovir and valganciclovir, or associated with reduced HCMV ganciclovir susceptibility in cell culture. Over 40 putative ganciclovir/valganciclovir resistance-associated substitutions were identified in this analysis. These include the commonly reported substitutions M460I/V and C592G in pUL97. There were additional substitutions that are not widely considered as ganciclovir/valganciclovir resistance-associated substitutions, including V466M in pUL97 and E315D in pUL54. Some of these ganciclovir/valganciclovir resistance-associated substitutions may confer cross-resistance to other HCMV therapies, such as cidofovir and foscarnet. Based on this review, we propose that there are more potential HCMV ganciclovir/valganciclovir resistance pathways than generally appreciated. The resulting comprehensive list of putative ganciclovir/valganciclovir resistance-associated substitutions provides a foundation for future investigations to characterize the role of specific substitutions or combinations of substitutions, which will enhance our understanding of HCMV mechanisms of ganciclovir/valganciclovir resistance and also provide insight regarding the potential for cross-resistance to other HCMV therapies.
Assuntos
Antivirais/farmacologia , Farmacorresistência Viral , Ganciclovir/análogos & derivados , Ganciclovir/farmacologia , Substituição de Aminoácidos , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/genética , DNA Polimerase Dirigida por DNA/genética , DNA Polimerase Dirigida por DNA/metabolismo , Humanos , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutação de Sentido Incorreto , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Valganciclovir , Proteínas Virais/genética , Proteínas Virais/metabolismoRESUMO
OBJECTIVES: To characterize HIV-1 env compartmentalization between cerebrospinal fluid (CSF) and peripheral blood plasma over all stages of the HIV-1 disease course, and to determine the relationship between the extent of CSF HIV-1 env compartmentalization and clinical neurologic disease status. DESIGN: Paired blood plasma and CSF specimens were collected from 66 HIV-infected patients cross-sectionally representing all major clinical stages relating to HIV-associated neurologic disease, including primary infection, asymptomatic chronic infection, chronic infection with minor global impairment, and immune deficiency with HIV-associated dementia. METHODS: Heteroduplex tracking assays and bulk sequence analysis targeting the V1/V2, C2-V3, and V4/V5 regions of env were performed to characterize the genetic makeup of complex HIV-1 populations in the cross-sectional blood plasma and CSF specimens. The levels of blood plasma/CSF env compartmentalization were quantified and compared across the different clinical stages of HIV-1 neurologic disease. RESULTS: Blood plasma/CSF env compartmentalization levels varied considerably by disease stage and were generally consistent across all three regions of env characterized. Little or no compartmentalization was observed in non-impaired individuals with primary HIV-1 infection. Compartmentalization levels were elevated in chronically infected patients, but were not significantly different between mildly impaired and non-impaired patients. Patients with HIV-associated dementia showed significantly greater blood plasma/CSF env compartmentalization relative to other groups. CONCLUSION: : Increased CSF compartmentalization of the HIV-1 env gene, which may reflect independent HIV-1 replication and evolution within the central nervous system, is specifically associated with HIV-associated dementia and not the less severe forms of HIV-1 neurologic disease.
Assuntos
Genes env , Infecções por HIV/líquido cefalorraquidiano , HIV-1/genética , Doenças do Sistema Nervoso/líquido cefalorraquidiano , Complexo AIDS Demência/complicações , Complexo AIDS Demência/metabolismo , California , Doença Crônica , Estudos Transversais , Progressão da Doença , Infecções por HIV/sangue , Infecções por HIV/complicações , Humanos , Doenças do Sistema Nervoso/sangue , Doenças do Sistema Nervoso/complicações , North Carolina , São FranciscoRESUMO
UNLABELLED: BACKGROUND. Human immunodeficiency virus (HIV) replication and compartmentalization in the central nervous system, including in cerebrospinal fluid (CSF), are associated with severe neurological disease and may contribute to viral persistence during antiretroviral therapy. To understand the relationships between viral populations in multiple compartments, we performed a systematic longitudinal characterization of viral populations in blood plasma and CSF obtained at short time intervals over the full course of infection in 3 macaques infected with simian immunodeficiency virus (SIVsm strain E660). METHODS: Complex viral genetic populations in blood plasma and CSF were characterized using a heteroduplex tracking assay targeted to the V1/V2 hypervariable region of env. To identify signs of neurological disease, monocyte chemoattractant protein (MCP)-1 levels in CSF and CD68(+) monocyte/macrophage infiltration in brain tissues were quantified. RESULTS: Two patterns of blood/CSF viral dynamics were apparent as infection progressed: concordant blood/CSF viral evolution and discordant blood/CSF viral evolution. Perivascular CD68(+) cells in autopsy brain tissue and elevated CSF MCP-1 levels accompanied blood/CSF viral population discordance but not concordance. CONCLUSIONS: Two distinct patterns of blood/CSF viral population dynamics can be observed in SIV-infected macaques, and the patterns may be associated with different neurological disease outcomes.
Assuntos
Líquido Cefalorraquidiano/virologia , RNA Viral/sangue , Síndrome de Imunodeficiência Adquirida dos Símios/fisiopatologia , Vírus da Imunodeficiência Símia , Complexo AIDS Demência/imunologia , Complexo AIDS Demência/fisiopatologia , Complexo AIDS Demência/virologia , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Encéfalo/imunologia , Encéfalo/virologia , Quimiocina CCL2/metabolismo , Modelos Animais de Doenças , Evolução Molecular , Genótipo , Análise Heteroduplex , Humanos , Macaca mulatta , Macrófagos/imunologia , Monócitos/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/classificação , Vírus da Imunodeficiência Símia/genética , Vírus da Imunodeficiência Símia/patogenicidade , Vírus da Imunodeficiência Símia/fisiologia , Carga Viral , Replicação ViralRESUMO
Using DNA heteroduplex tracking assays, we characterized human immunodeficiency virus type 1 env V4/V5 genetic populations in multiple blood plasma samples collected over an average of 7 months from 24 chronically infected human subjects. We observed complex and dynamic V4/V5 genetic populations in most subjects. Comparisons of V4/V5 and V1/V2 population changes over the course of the study showed that major shifts in genetic populations frequently occurred in one region but not the other, and these observations were independently confirmed in one subject by single-genome sequencing. These results suggest that the V1/V2 and V4/V5 regions of env often evolve independently during chronic infection.